US20210077627A1 - Method of treating cancer - Google Patents
Method of treating cancer Download PDFInfo
- Publication number
- US20210077627A1 US20210077627A1 US17/108,099 US202017108099A US2021077627A1 US 20210077627 A1 US20210077627 A1 US 20210077627A1 US 202017108099 A US202017108099 A US 202017108099A US 2021077627 A1 US2021077627 A1 US 2021077627A1
- Authority
- US
- United States
- Prior art keywords
- agent
- acid
- tumor
- therapeutic agent
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 349
- 238000000034 method Methods 0.000 title claims abstract description 172
- 201000011510 cancer Diseases 0.000 title claims abstract description 98
- 239000003814 drug Substances 0.000 claims abstract description 205
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 159
- 230000003834 intracellular effect Effects 0.000 claims abstract description 141
- 239000003961 penetration enhancing agent Substances 0.000 claims abstract description 129
- 210000004027 cell Anatomy 0.000 claims abstract description 106
- 239000002955 immunomodulating agent Substances 0.000 claims abstract description 68
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 35
- 229940022399 cancer vaccine Drugs 0.000 claims abstract description 16
- 238000009566 cancer vaccine Methods 0.000 claims abstract description 16
- 239000000556 agonist Substances 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 106
- 239000000203 mixture Substances 0.000 claims description 91
- 150000007523 nucleic acids Chemical group 0.000 claims description 53
- 102000039446 nucleic acids Human genes 0.000 claims description 49
- 108020004707 nucleic acids Proteins 0.000 claims description 49
- 150000001875 compounds Chemical group 0.000 claims description 46
- 230000001225 therapeutic effect Effects 0.000 claims description 46
- 238000011282 treatment Methods 0.000 claims description 42
- 229960004316 cisplatin Drugs 0.000 claims description 41
- -1 Alemtuzumab Chemical compound 0.000 claims description 40
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 40
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 37
- 239000002246 antineoplastic agent Substances 0.000 claims description 34
- 238000009472 formulation Methods 0.000 claims description 30
- 230000012010 growth Effects 0.000 claims description 28
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 25
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 23
- 108020004414 DNA Proteins 0.000 claims description 22
- 238000002591 computed tomography Methods 0.000 claims description 20
- 238000003384 imaging method Methods 0.000 claims description 20
- 238000002560 therapeutic procedure Methods 0.000 claims description 19
- 241000282414 Homo sapiens Species 0.000 claims description 18
- 229960005486 vaccine Drugs 0.000 claims description 18
- AIEMSTCGCMIJTI-UHFFFAOYSA-N 6-oxo-6-phenylhexanoic acid Chemical compound OC(=O)CCCCC(=O)C1=CC=CC=C1 AIEMSTCGCMIJTI-UHFFFAOYSA-N 0.000 claims description 17
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 17
- 229940127089 cytotoxic agent Drugs 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 229930186217 Glycolipid Natural products 0.000 claims description 15
- 150000004665 fatty acids Chemical group 0.000 claims description 15
- 206010039491 Sarcoma Diseases 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- FMRHJJZUHUTGKE-UHFFFAOYSA-N Ethylhexyl salicylate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1O FMRHJJZUHUTGKE-UHFFFAOYSA-N 0.000 claims description 13
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 claims description 13
- 229960004562 carboplatin Drugs 0.000 claims description 13
- 210000000056 organ Anatomy 0.000 claims description 13
- 150000001413 amino acids Chemical class 0.000 claims description 12
- 238000001356 surgical procedure Methods 0.000 claims description 12
- 206010027476 Metastases Diseases 0.000 claims description 11
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 11
- 239000002502 liposome Substances 0.000 claims description 11
- 230000009401 metastasis Effects 0.000 claims description 11
- 229910052697 platinum Inorganic materials 0.000 claims description 11
- 239000004055 small Interfering RNA Substances 0.000 claims description 11
- 201000009030 Carcinoma Diseases 0.000 claims description 10
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 10
- 125000001931 aliphatic group Chemical group 0.000 claims description 10
- 210000000481 breast Anatomy 0.000 claims description 10
- 201000002528 pancreatic cancer Diseases 0.000 claims description 10
- 230000005855 radiation Effects 0.000 claims description 10
- AKVBCGQVQXPRLD-UHFFFAOYSA-N 2-aminooctanoic acid Chemical compound CCCCCCC(N)C(O)=O AKVBCGQVQXPRLD-UHFFFAOYSA-N 0.000 claims description 9
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 9
- 108091027967 Small hairpin RNA Proteins 0.000 claims description 9
- 239000002671 adjuvant Substances 0.000 claims description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 9
- 229940088597 hormone Drugs 0.000 claims description 9
- 239000005556 hormone Substances 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 230000002452 interceptive effect Effects 0.000 claims description 9
- 210000004185 liver Anatomy 0.000 claims description 9
- 210000004072 lung Anatomy 0.000 claims description 9
- 102000040430 polynucleotide Human genes 0.000 claims description 9
- 108091033319 polynucleotide Proteins 0.000 claims description 9
- 239000002157 polynucleotide Substances 0.000 claims description 9
- 230000004044 response Effects 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 229960000575 trastuzumab Drugs 0.000 claims description 9
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 claims description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 8
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 8
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 8
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 8
- 238000005516 engineering process Methods 0.000 claims description 8
- 229960002949 fluorouracil Drugs 0.000 claims description 8
- 230000002163 immunogen Effects 0.000 claims description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 8
- 210000001672 ovary Anatomy 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- VQFKFAKEUMHBLV-BYSUZVQFSA-N 1-O-(alpha-D-galactosyl)-N-hexacosanoylphytosphingosine Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@H]([C@H](O)[C@H](O)CCCCCCCCCCCCCC)CO[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQFKFAKEUMHBLV-BYSUZVQFSA-N 0.000 claims description 7
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 7
- RDRFZPRBCJRPCU-UHFFFAOYSA-N 8-cyclohexyl-8-oxooctanoic acid Chemical compound OC(=O)CCCCCCC(=O)C1CCCCC1 RDRFZPRBCJRPCU-UHFFFAOYSA-N 0.000 claims description 7
- 102000004127 Cytokines Human genes 0.000 claims description 7
- 108090000695 Cytokines Proteins 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 7
- 229960000548 alemtuzumab Drugs 0.000 claims description 7
- 229960000473 altretamine Drugs 0.000 claims description 7
- 210000001072 colon Anatomy 0.000 claims description 7
- 230000014509 gene expression Effects 0.000 claims description 7
- 230000009368 gene silencing by RNA Effects 0.000 claims description 7
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 claims description 7
- 230000001939 inductive effect Effects 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- 210000000496 pancreas Anatomy 0.000 claims description 7
- 210000002307 prostate Anatomy 0.000 claims description 7
- 229960004641 rituximab Drugs 0.000 claims description 7
- 238000012360 testing method Methods 0.000 claims description 7
- 229960003087 tioguanine Drugs 0.000 claims description 7
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000013598 vector Substances 0.000 claims description 7
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 6
- 102100032937 CD40 ligand Human genes 0.000 claims description 6
- 229960000397 bevacizumab Drugs 0.000 claims description 6
- 210000000988 bone and bone Anatomy 0.000 claims description 6
- 229960005395 cetuximab Drugs 0.000 claims description 6
- 230000001472 cytotoxic effect Effects 0.000 claims description 6
- 229960005386 ipilimumab Drugs 0.000 claims description 6
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 6
- 229960002450 ofatumumab Drugs 0.000 claims description 6
- 229960001972 panitumumab Drugs 0.000 claims description 6
- 229940023041 peptide vaccine Drugs 0.000 claims description 6
- 150000003058 platinum compounds Chemical class 0.000 claims description 6
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical group CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 claims description 6
- 210000002784 stomach Anatomy 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 210000001550 testis Anatomy 0.000 claims description 6
- 229960005267 tositumomab Drugs 0.000 claims description 6
- 238000002604 ultrasonography Methods 0.000 claims description 6
- 210000004291 uterus Anatomy 0.000 claims description 6
- 229960002360 vintafolide Drugs 0.000 claims description 6
- KUZYSQSABONDME-QRLOMCMNSA-N vintafolide Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)NNC(=O)OCCSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(O)=O)NC(=O)CC[C@H](NC(=O)C=4C=CC(NCC=5N=C6C(=O)NC(N)=NC6=NC=5)=CC=4)C(O)=O)C(O)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KUZYSQSABONDME-QRLOMCMNSA-N 0.000 claims description 6
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 5
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 claims description 5
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 5
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 5
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 5
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 5
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 5
- 108010069236 Goserelin Proteins 0.000 claims description 5
- 108010002350 Interleukin-2 Proteins 0.000 claims description 5
- 108010000817 Leuprolide Proteins 0.000 claims description 5
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 5
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 5
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 5
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 claims description 5
- 210000004556 brain Anatomy 0.000 claims description 5
- 231100000433 cytotoxic Toxicity 0.000 claims description 5
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 5
- 210000003238 esophagus Anatomy 0.000 claims description 5
- 238000002594 fluoroscopy Methods 0.000 claims description 5
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims description 5
- 210000000232 gallbladder Anatomy 0.000 claims description 5
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 5
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 5
- 210000003734 kidney Anatomy 0.000 claims description 5
- 210000002429 large intestine Anatomy 0.000 claims description 5
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims description 5
- 238000002595 magnetic resonance imaging Methods 0.000 claims description 5
- 229960001428 mercaptopurine Drugs 0.000 claims description 5
- 210000003205 muscle Anatomy 0.000 claims description 5
- 210000000581 natural killer T-cell Anatomy 0.000 claims description 5
- 229960003921 octisalate Drugs 0.000 claims description 5
- 230000002611 ovarian Effects 0.000 claims description 5
- 239000013612 plasmid Substances 0.000 claims description 5
- 238000002600 positron emission tomography Methods 0.000 claims description 5
- 210000000813 small intestine Anatomy 0.000 claims description 5
- 210000000952 spleen Anatomy 0.000 claims description 5
- 210000003932 urinary bladder Anatomy 0.000 claims description 5
- 229960004528 vincristine Drugs 0.000 claims description 5
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 5
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 5
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims description 4
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 claims description 4
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 4
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 4
- JINGUCXQUOKWKH-UHFFFAOYSA-N 2-aminodecanoic acid Chemical compound CCCCCCCCC(N)C(O)=O JINGUCXQUOKWKH-UHFFFAOYSA-N 0.000 claims description 4
- IIWOLBQTYSVLNZ-UHFFFAOYSA-N 3-(3-methylcyclohexyl)oxypropanoic acid Chemical compound CC1CCCC(OCCC(O)=O)C1 IIWOLBQTYSVLNZ-UHFFFAOYSA-N 0.000 claims description 4
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 4
- QGCYUEIWRLWOSH-UHFFFAOYSA-N 4-(3-methylcyclohexyl)oxybutanoic acid Chemical compound CC1CCCC(OCCCC(O)=O)C1 QGCYUEIWRLWOSH-UHFFFAOYSA-N 0.000 claims description 4
- YFJPWCSWYQDNGQ-UHFFFAOYSA-N 4-cyclobutyl-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)C1CCC1 YFJPWCSWYQDNGQ-UHFFFAOYSA-N 0.000 claims description 4
- LOVFEGLWBFHQLB-UHFFFAOYSA-N 4-cyclopentyl-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)C1CCCC1 LOVFEGLWBFHQLB-UHFFFAOYSA-N 0.000 claims description 4
- ISZLFKWEBSKHTO-UHFFFAOYSA-N 4-cyclopropyl-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)C1CC1 ISZLFKWEBSKHTO-UHFFFAOYSA-N 0.000 claims description 4
- YQKCZJRLIOVJPZ-UHFFFAOYSA-N 5-(3-methylcyclohexyl)oxypentanoic acid Chemical compound CC1CCCC(OCCCCC(O)=O)C1 YQKCZJRLIOVJPZ-UHFFFAOYSA-N 0.000 claims description 4
- BRBJICIEJBXXJQ-UHFFFAOYSA-N 5-cyclobutyl-5-oxopentanoic acid Chemical compound OC(=O)CCCC(=O)C1CCC1 BRBJICIEJBXXJQ-UHFFFAOYSA-N 0.000 claims description 4
- DRLJGCXABGDQMI-UHFFFAOYSA-N 5-cyclopentyl-5-oxopentanoic acid Chemical compound OC(=O)CCCC(=O)C1CCCC1 DRLJGCXABGDQMI-UHFFFAOYSA-N 0.000 claims description 4
- GHDNXBQUOFVFDF-UHFFFAOYSA-N 5-cyclopropyl-5-oxopentanoic acid Chemical compound OC(=O)CCCC(=O)C1CC1 GHDNXBQUOFVFDF-UHFFFAOYSA-N 0.000 claims description 4
- ZLISLBQFNDTLMV-UHFFFAOYSA-N 6-(3-methylcyclohexyl)oxyhexanoic acid Chemical compound CC1CCCC(OCCCCCC(O)=O)C1 ZLISLBQFNDTLMV-UHFFFAOYSA-N 0.000 claims description 4
- NIRYFHPBAWKZBA-UHFFFAOYSA-N 6-cyclobutyl-6-oxohexanoic acid Chemical compound OC(=O)CCCCC(=O)C1CCC1 NIRYFHPBAWKZBA-UHFFFAOYSA-N 0.000 claims description 4
- ITWAGYWPYYIURG-UHFFFAOYSA-N 6-cyclohexyl-6-oxohexanoic acid Chemical compound OC(=O)CCCCC(=O)C1CCCCC1 ITWAGYWPYYIURG-UHFFFAOYSA-N 0.000 claims description 4
- IMEXAZLWJSUWAX-UHFFFAOYSA-N 6-cyclopentyl-6-oxohexanoic acid Chemical compound OC(=O)CCCCC(=O)C1CCCC1 IMEXAZLWJSUWAX-UHFFFAOYSA-N 0.000 claims description 4
- CYYSWLBWCYNGQX-UHFFFAOYSA-N 6-cyclopropyl-6-oxohexanoic acid Chemical compound OC(=O)CCCCC(=O)C1CC1 CYYSWLBWCYNGQX-UHFFFAOYSA-N 0.000 claims description 4
- NHMDXTLKHVNDCX-UHFFFAOYSA-N 7-(3-methylcyclohexyl)oxyheptanoic acid Chemical compound CC1CCCC(OCCCCCCC(O)=O)C1 NHMDXTLKHVNDCX-UHFFFAOYSA-N 0.000 claims description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 4
- GPEPRRMJQZGFFB-UHFFFAOYSA-N 7-cyclobutyl-7-oxoheptanoic acid Chemical compound OC(=O)CCCCCC(=O)C1CCC1 GPEPRRMJQZGFFB-UHFFFAOYSA-N 0.000 claims description 4
- KPYUQMVVPZHXIK-UHFFFAOYSA-N 7-cyclohexyl-7-oxoheptanoic acid Chemical compound OC(=O)CCCCCC(=O)C1CCCCC1 KPYUQMVVPZHXIK-UHFFFAOYSA-N 0.000 claims description 4
- NCMFHVOZSIOSMD-UHFFFAOYSA-N 7-cyclopentyl-7-oxoheptanoic acid Chemical compound OC(=O)CCCCCC(=O)C1CCCC1 NCMFHVOZSIOSMD-UHFFFAOYSA-N 0.000 claims description 4
- TXAAUKKBIMJGHY-UHFFFAOYSA-N 7-cyclopropyl-7-oxoheptanoic acid Chemical compound OC(=O)CCCCCC(=O)C1CC1 TXAAUKKBIMJGHY-UHFFFAOYSA-N 0.000 claims description 4
- DEGYUOUBWNZATP-UHFFFAOYSA-N 8-(2,5-dichlorophenyl)-8-oxooctanoic acid Chemical compound OC(=O)CCCCCCC(=O)C1=CC(Cl)=CC=C1Cl DEGYUOUBWNZATP-UHFFFAOYSA-N 0.000 claims description 4
- XRTHAPZDZPADIL-UHFFFAOYSA-N 8-[(5-chloro-2-hydroxybenzoyl)amino]octanoic acid Chemical compound OC(=O)CCCCCCCNC(=O)C1=CC(Cl)=CC=C1O XRTHAPZDZPADIL-UHFFFAOYSA-N 0.000 claims description 4
- PFFDQUOOAOYQHO-UHFFFAOYSA-N 8-cyclobutyl-8-oxooctanoic acid Chemical compound OC(=O)CCCCCCC(=O)C1CCC1 PFFDQUOOAOYQHO-UHFFFAOYSA-N 0.000 claims description 4
- QVTINBMJKAORHL-UHFFFAOYSA-N 8-cyclopentyl-8-oxooctanoic acid Chemical compound OC(=O)CCCCCCC(=O)C1CCCC1 QVTINBMJKAORHL-UHFFFAOYSA-N 0.000 claims description 4
- KQOVMVZQORRTLN-UHFFFAOYSA-N 8-cyclopropyl-8-oxooctanoic acid Chemical compound OC(=O)CCCCCCC(=O)C1CC1 KQOVMVZQORRTLN-UHFFFAOYSA-N 0.000 claims description 4
- UMCSRRHQLAVYRS-UHFFFAOYSA-N 8-oxo-8-phenyloctanoic acid Chemical compound OC(=O)CCCCCCC(=O)C1=CC=CC=C1 UMCSRRHQLAVYRS-UHFFFAOYSA-N 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 108010006654 Bleomycin Proteins 0.000 claims description 4
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 4
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 4
- 241000283707 Capra Species 0.000 claims description 4
- 241000700199 Cavia porcellus Species 0.000 claims description 4
- 241000282693 Cercopithecidae Species 0.000 claims description 4
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims description 4
- 108010092160 Dactinomycin Proteins 0.000 claims description 4
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 4
- 241000283073 Equus caballus Species 0.000 claims description 4
- 241000282326 Felis catus Species 0.000 claims description 4
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 4
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 4
- 102000006992 Interferon-alpha Human genes 0.000 claims description 4
- 108010047761 Interferon-alpha Proteins 0.000 claims description 4
- 108010002586 Interleukin-7 Proteins 0.000 claims description 4
- 102100021592 Interleukin-7 Human genes 0.000 claims description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 4
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 4
- 241001494479 Pecora Species 0.000 claims description 4
- 101000718529 Saccharolobus solfataricus (strain ATCC 35092 / DSM 1617 / JCM 11322 / P2) Alpha-galactosidase Proteins 0.000 claims description 4
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 4
- 229940122149 Thymidylate synthase inhibitor Drugs 0.000 claims description 4
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 4
- 238000002679 ablation Methods 0.000 claims description 4
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims description 4
- 229930013930 alkaloid Natural products 0.000 claims description 4
- NNISLDGFPWIBDF-MPRBLYSKSA-N alpha-D-Gal-(1->3)-beta-D-Gal-(1->4)-D-GlcNAc Chemical compound O[C@@H]1[C@@H](NC(=O)C)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@@H](CO)O1 NNISLDGFPWIBDF-MPRBLYSKSA-N 0.000 claims description 4
- 229960002932 anastrozole Drugs 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 229960000997 bicalutamide Drugs 0.000 claims description 4
- 229960001561 bleomycin Drugs 0.000 claims description 4
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 4
- 229960002092 busulfan Drugs 0.000 claims description 4
- 229960004117 capecitabine Drugs 0.000 claims description 4
- 229960005243 carmustine Drugs 0.000 claims description 4
- 229960004630 chlorambucil Drugs 0.000 claims description 4
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 4
- 229960002436 cladribine Drugs 0.000 claims description 4
- 229960004397 cyclophosphamide Drugs 0.000 claims description 4
- 229960000684 cytarabine Drugs 0.000 claims description 4
- 229960003901 dacarbazine Drugs 0.000 claims description 4
- 229960000640 dactinomycin Drugs 0.000 claims description 4
- 229960000975 daunorubicin Drugs 0.000 claims description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 4
- 229960003957 dexamethasone Drugs 0.000 claims description 4
- 229960003668 docetaxel Drugs 0.000 claims description 4
- 229960004679 doxorubicin Drugs 0.000 claims description 4
- 229960001904 epirubicin Drugs 0.000 claims description 4
- 229930013356 epothilone Natural products 0.000 claims description 4
- 229960001842 estramustine Drugs 0.000 claims description 4
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 claims description 4
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 4
- 229960000255 exemestane Drugs 0.000 claims description 4
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 4
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 4
- 229960000961 floxuridine Drugs 0.000 claims description 4
- 229960000390 fludarabine Drugs 0.000 claims description 4
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 4
- 229960002074 flutamide Drugs 0.000 claims description 4
- 229960005277 gemcitabine Drugs 0.000 claims description 4
- 230000030279 gene silencing Effects 0.000 claims description 4
- 238000001415 gene therapy Methods 0.000 claims description 4
- 150000004676 glycans Chemical class 0.000 claims description 4
- 229960002913 goserelin Drugs 0.000 claims description 4
- 229960000908 idarubicin Drugs 0.000 claims description 4
- 229960001101 ifosfamide Drugs 0.000 claims description 4
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 4
- 230000036039 immunity Effects 0.000 claims description 4
- 229960004768 irinotecan Drugs 0.000 claims description 4
- 229960002014 ixabepilone Drugs 0.000 claims description 4
- 150000004715 keto acids Chemical class 0.000 claims description 4
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 4
- 229960004942 lenalidomide Drugs 0.000 claims description 4
- 229960003881 letrozole Drugs 0.000 claims description 4
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims description 4
- 229960004338 leuprorelin Drugs 0.000 claims description 4
- 229960002247 lomustine Drugs 0.000 claims description 4
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 4
- 229960004961 mechlorethamine Drugs 0.000 claims description 4
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 4
- 229960001924 melphalan Drugs 0.000 claims description 4
- 229960000485 methotrexate Drugs 0.000 claims description 4
- 229960004857 mitomycin Drugs 0.000 claims description 4
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 4
- 229960001156 mitoxantrone Drugs 0.000 claims description 4
- 210000000214 mouth Anatomy 0.000 claims description 4
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 claims description 4
- 229960001756 oxaliplatin Drugs 0.000 claims description 4
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 4
- 229960001592 paclitaxel Drugs 0.000 claims description 4
- 229960005079 pemetrexed Drugs 0.000 claims description 4
- 229960002340 pentostatin Drugs 0.000 claims description 4
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 4
- 229920001282 polysaccharide Polymers 0.000 claims description 4
- 239000005017 polysaccharide Substances 0.000 claims description 4
- 239000001397 quillaja saponaria molina bark Substances 0.000 claims description 4
- 229930182490 saponin Natural products 0.000 claims description 4
- 150000007949 saponins Chemical class 0.000 claims description 4
- 229960001052 streptozocin Drugs 0.000 claims description 4
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 claims description 4
- 229960001603 tamoxifen Drugs 0.000 claims description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 4
- 229960004964 temozolomide Drugs 0.000 claims description 4
- 229960001278 teniposide Drugs 0.000 claims description 4
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 4
- 150000003505 terpenes Chemical class 0.000 claims description 4
- 235000007586 terpenes Nutrition 0.000 claims description 4
- 229960003433 thalidomide Drugs 0.000 claims description 4
- 229960001196 thiotepa Drugs 0.000 claims description 4
- 239000003734 thymidylate synthase inhibitor Substances 0.000 claims description 4
- 229960000303 topotecan Drugs 0.000 claims description 4
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 4
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 claims description 4
- 229960005026 toremifene Drugs 0.000 claims description 4
- 229960003048 vinblastine Drugs 0.000 claims description 4
- 229960002066 vinorelbine Drugs 0.000 claims description 4
- VGKZTCPRZPOHJD-ZEXGZJMNSA-N (2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-5-oxopentanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]hexanoic acid Chemical compound CCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC)NC(=O)[C@@H](N)CO)CC1=CN=CN1 VGKZTCPRZPOHJD-ZEXGZJMNSA-N 0.000 claims description 3
- AHOKKYCUWBLDST-QYULHYBRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s,3s)-2-[[(2s)-2,6-diaminohexanoyl]amino]-3-methylpentanoyl]amino]-3-phenylpropanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-3-phenylpropanoyl]amino Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)[C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=CC=C1 AHOKKYCUWBLDST-QYULHYBRSA-N 0.000 claims description 3
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 claims description 3
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 claims description 3
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 claims description 3
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 claims description 3
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 claims description 3
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 3
- FEHBUZYBKUOFIA-UHFFFAOYSA-N 5-cyclohexyl-5-oxopentanoic acid Chemical compound OC(=O)CCCC(=O)C1CCCCC1 FEHBUZYBKUOFIA-UHFFFAOYSA-N 0.000 claims description 3
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 claims description 3
- PQJVMHWKQWUMHQ-UHFFFAOYSA-N 8-(3-methylcyclohexyl)oxyoctanoic acid Chemical compound CC1CCCC(OCCCCCCCC(O)=O)C1 PQJVMHWKQWUMHQ-UHFFFAOYSA-N 0.000 claims description 3
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 claims description 3
- 102000015790 Asparaginase Human genes 0.000 claims description 3
- 108010024976 Asparaginase Proteins 0.000 claims description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 3
- 108010029697 CD40 Ligand Proteins 0.000 claims description 3
- 108010086433 CDX 1307 Proteins 0.000 claims description 3
- 229940038671 CDX-1401 vaccine Drugs 0.000 claims description 3
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 claims description 3
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 claims description 3
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 3
- 108010029961 Filgrastim Proteins 0.000 claims description 3
- 229940032072 GVAX vaccine Drugs 0.000 claims description 3
- 102000007563 Galectins Human genes 0.000 claims description 3
- 108010046569 Galectins Proteins 0.000 claims description 3
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 claims description 3
- 101000868215 Homo sapiens CD40 ligand Proteins 0.000 claims description 3
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 claims description 3
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 claims description 3
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 3
- 229940124672 IMA901 Drugs 0.000 claims description 3
- 101800000324 Immunoglobulin A1 protease translocator Proteins 0.000 claims description 3
- 102000003996 Interferon-beta Human genes 0.000 claims description 3
- 108090000467 Interferon-beta Proteins 0.000 claims description 3
- 102000014150 Interferons Human genes 0.000 claims description 3
- 108010050904 Interferons Proteins 0.000 claims description 3
- 102000000589 Interleukin-1 Human genes 0.000 claims description 3
- 108010002352 Interleukin-1 Proteins 0.000 claims description 3
- 102100030694 Interleukin-11 Human genes 0.000 claims description 3
- 102000015696 Interleukins Human genes 0.000 claims description 3
- 108010063738 Interleukins Proteins 0.000 claims description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 3
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 3
- 239000002067 L01XE06 - Dasatinib Substances 0.000 claims description 3
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 3
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 3
- 239000002146 L01XE16 - Crizotinib Substances 0.000 claims description 3
- 229930192392 Mitomycin Natural products 0.000 claims description 3
- 102100034256 Mucin-1 Human genes 0.000 claims description 3
- XHAZJQSTGGLMLZ-MSDGEDAMSA-N N([C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(O)=O)C(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)CN Chemical compound N([C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(O)=O)C(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)CN XHAZJQSTGGLMLZ-MSDGEDAMSA-N 0.000 claims description 3
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 3
- 108010016076 Octreotide Proteins 0.000 claims description 3
- 229940032310 PROSTVAC vaccine Drugs 0.000 claims description 3
- 108091030071 RNAI Proteins 0.000 claims description 3
- 101001039269 Rattus norvegicus Glycine N-methyltransferase Proteins 0.000 claims description 3
- 108010002687 Survivin Proteins 0.000 claims description 3
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 3
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 claims description 3
- 108010017842 Telomerase Proteins 0.000 claims description 3
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims description 3
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 3
- XYVNHPYNSPGYLI-UUOKFMHZSA-N [(2r,3s,4r,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)-4-hydroxy-2-(phosphonooxymethyl)oxolan-3-yl] dihydrogen phosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H]1O XYVNHPYNSPGYLI-UUOKFMHZSA-N 0.000 claims description 3
- 229950005186 abagovomab Drugs 0.000 claims description 3
- 229960004103 abiraterone acetate Drugs 0.000 claims description 3
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 claims description 3
- 229960001686 afatinib Drugs 0.000 claims description 3
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 claims description 3
- 229950008459 alacizumab pegol Drugs 0.000 claims description 3
- 229960005310 aldesleukin Drugs 0.000 claims description 3
- 108700025316 aldesleukin Proteins 0.000 claims description 3
- 229960001445 alitretinoin Drugs 0.000 claims description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 3
- 230000000735 allogeneic effect Effects 0.000 claims description 3
- 229950009106 altumomab Drugs 0.000 claims description 3
- 229950001537 amatuximab Drugs 0.000 claims description 3
- 229960001097 amifostine Drugs 0.000 claims description 3
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 claims description 3
- 229960003437 aminoglutethimide Drugs 0.000 claims description 3
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 claims description 3
- 229960001694 anagrelide Drugs 0.000 claims description 3
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 claims description 3
- 229950006061 anatumomab mafenatox Drugs 0.000 claims description 3
- 230000000890 antigenic effect Effects 0.000 claims description 3
- 229950003145 apolizumab Drugs 0.000 claims description 3
- 229950005725 arcitumomab Drugs 0.000 claims description 3
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 claims description 3
- 229960002594 arsenic trioxide Drugs 0.000 claims description 3
- 229960003272 asparaginase Drugs 0.000 claims description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 claims description 3
- 229960002756 azacitidine Drugs 0.000 claims description 3
- 229960002170 azathioprine Drugs 0.000 claims description 3
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 claims description 3
- 229960003270 belimumab Drugs 0.000 claims description 3
- 229960002707 bendamustine Drugs 0.000 claims description 3
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 3
- 229960005522 bivatuzumab mertansine Drugs 0.000 claims description 3
- 229960003008 blinatumomab Drugs 0.000 claims description 3
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 3
- 229960001467 bortezomib Drugs 0.000 claims description 3
- 229960000455 brentuximab vedotin Drugs 0.000 claims description 3
- 229950007296 cantuzumab mertansine Drugs 0.000 claims description 3
- 229950011547 cantuzumab ravtansine Drugs 0.000 claims description 3
- 229940034605 capromab pendetide Drugs 0.000 claims description 3
- 229960000419 catumaxomab Drugs 0.000 claims description 3
- 210000004970 cd4 cell Anatomy 0.000 claims description 3
- 229950010905 citatuzumab bogatox Drugs 0.000 claims description 3
- 229950006647 cixutumumab Drugs 0.000 claims description 3
- 229950002595 clivatuzumab tetraxetan Drugs 0.000 claims description 3
- 229950007276 conatumumab Drugs 0.000 claims description 3
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 claims description 3
- 229960005061 crizotinib Drugs 0.000 claims description 3
- 229960002482 dalotuzumab Drugs 0.000 claims description 3
- 229960002448 dasatinib Drugs 0.000 claims description 3
- 229960003603 decitabine Drugs 0.000 claims description 3
- 229940029030 dendritic cell vaccine Drugs 0.000 claims description 3
- 108010017271 denileukin diftitox Proteins 0.000 claims description 3
- 229960002923 denileukin diftitox Drugs 0.000 claims description 3
- 229960001251 denosumab Drugs 0.000 claims description 3
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 claims description 3
- 229950005454 doxifluridine Drugs 0.000 claims description 3
- 229950009964 drozitumab Drugs 0.000 claims description 3
- 229960001776 edrecolomab Drugs 0.000 claims description 3
- 229950003048 enavatuzumab Drugs 0.000 claims description 3
- 150000003883 epothilone derivatives Chemical class 0.000 claims description 3
- 229940082789 erbitux Drugs 0.000 claims description 3
- 229960001433 erlotinib Drugs 0.000 claims description 3
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 3
- 229960005420 etoposide Drugs 0.000 claims description 3
- 229960005167 everolimus Drugs 0.000 claims description 3
- 229960004177 filgrastim Drugs 0.000 claims description 3
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 claims description 3
- 229960001751 fluoxymesterone Drugs 0.000 claims description 3
- 229940014144 folate Drugs 0.000 claims description 3
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 3
- 235000019152 folic acid Nutrition 0.000 claims description 3
- 239000011724 folic acid Substances 0.000 claims description 3
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 claims description 3
- 235000008191 folinic acid Nutrition 0.000 claims description 3
- 239000011672 folinic acid Substances 0.000 claims description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960002584 gefitinib Drugs 0.000 claims description 3
- 229960000578 gemtuzumab Drugs 0.000 claims description 3
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 claims description 3
- 238000012226 gene silencing method Methods 0.000 claims description 3
- 229960001001 ibritumomab tiuxetan Drugs 0.000 claims description 3
- 229960002411 imatinib Drugs 0.000 claims description 3
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 3
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 3
- 229960001388 interferon-beta Drugs 0.000 claims description 3
- 229960004891 lapatinib Drugs 0.000 claims description 3
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims description 3
- 229960001691 leucovorin Drugs 0.000 claims description 3
- 210000004698 lymphocyte Anatomy 0.000 claims description 3
- 229960001786 megestrol Drugs 0.000 claims description 3
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 claims description 3
- 229960000801 nelarabine Drugs 0.000 claims description 3
- 229960001346 nilotinib Drugs 0.000 claims description 3
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 3
- 229960002653 nilutamide Drugs 0.000 claims description 3
- 229960002700 octreotide Drugs 0.000 claims description 3
- 229960001840 oprelvekin Drugs 0.000 claims description 3
- 108010046821 oprelvekin Proteins 0.000 claims description 3
- 230000009057 passive transport Effects 0.000 claims description 3
- 229940067082 pentetate Drugs 0.000 claims description 3
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 3
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 claims description 3
- 229960000624 procarbazine Drugs 0.000 claims description 3
- 229960004622 raloxifene Drugs 0.000 claims description 3
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 claims description 3
- 150000004508 retinoic acid derivatives Chemical class 0.000 claims description 3
- 108010017584 romiplostim Proteins 0.000 claims description 3
- 229960004262 romiplostim Drugs 0.000 claims description 3
- 229960002530 sargramostim Drugs 0.000 claims description 3
- 108010038379 sargramostim Proteins 0.000 claims description 3
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 claims description 3
- 210000003491 skin Anatomy 0.000 claims description 3
- 210000001626 skin fibroblast Anatomy 0.000 claims description 3
- 229960003787 sorafenib Drugs 0.000 claims description 3
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 3
- 229960001796 sunitinib Drugs 0.000 claims description 3
- 238000011521 systemic chemotherapy Methods 0.000 claims description 3
- 229960000235 temsirolimus Drugs 0.000 claims description 3
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 claims description 3
- 229960004066 trametinib Drugs 0.000 claims description 3
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 claims description 3
- 229960001727 tretinoin Drugs 0.000 claims description 3
- 241000701161 unidentified adenovirus Species 0.000 claims description 3
- 229960000653 valrubicin Drugs 0.000 claims description 3
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 claims description 3
- 239000002525 vasculotropin inhibitor Substances 0.000 claims description 3
- 229960004355 vindesine Drugs 0.000 claims description 3
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 claims description 3
- 229940023148 viral-based vaccine Drugs 0.000 claims description 3
- 108010069784 vitespin Proteins 0.000 claims description 3
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 claims description 3
- 229960000237 vorinostat Drugs 0.000 claims description 3
- 108010041397 CD4 Antigens Proteins 0.000 claims description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 claims description 2
- 239000013604 expression vector Substances 0.000 claims description 2
- 150000002334 glycols Chemical class 0.000 claims description 2
- 229940079322 interferon Drugs 0.000 claims description 2
- 229950007221 nedaplatin Drugs 0.000 claims description 2
- 150000004040 pyrrolidinones Chemical class 0.000 claims description 2
- 229960005399 satraplatin Drugs 0.000 claims description 2
- 190014017285 satraplatin Chemical group 0.000 claims description 2
- 102000003390 tumor necrosis factor Human genes 0.000 claims description 2
- 210000003679 cervix uteri Anatomy 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 claims 1
- JBVNBBXAMBZTMQ-CEGNMAFCSA-N megestrol Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 JBVNBBXAMBZTMQ-CEGNMAFCSA-N 0.000 claims 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims 1
- 210000000664 rectum Anatomy 0.000 claims 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 description 51
- 239000000243 solution Substances 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 241001465754 Metazoa Species 0.000 description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 38
- 239000003623 enhancer Substances 0.000 description 32
- 210000001519 tissue Anatomy 0.000 description 29
- 201000010099 disease Diseases 0.000 description 27
- 230000000694 effects Effects 0.000 description 27
- 238000012384 transportation and delivery Methods 0.000 description 26
- 108090000623 proteins and genes Proteins 0.000 description 25
- 239000002105 nanoparticle Substances 0.000 description 23
- 210000000987 immune system Anatomy 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 102000053602 DNA Human genes 0.000 description 19
- 230000029918 bioluminescence Effects 0.000 description 18
- 238000005415 bioluminescence Methods 0.000 description 18
- 230000028993 immune response Effects 0.000 description 18
- 239000000126 substance Substances 0.000 description 18
- 230000035515 penetration Effects 0.000 description 17
- 229920002477 rna polymer Polymers 0.000 description 17
- 239000000427 antigen Substances 0.000 description 16
- 102000036639 antigens Human genes 0.000 description 16
- 108091007433 antigens Proteins 0.000 description 16
- 230000006378 damage Effects 0.000 description 16
- 238000002512 chemotherapy Methods 0.000 description 15
- 239000002773 nucleotide Substances 0.000 description 15
- 125000003729 nucleotide group Chemical group 0.000 description 15
- 230000000692 anti-sense effect Effects 0.000 description 14
- 238000009169 immunotherapy Methods 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 14
- 230000008685 targeting Effects 0.000 description 14
- 239000003981 vehicle Substances 0.000 description 14
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 13
- 208000032839 leukemia Diseases 0.000 description 13
- 229920001184 polypeptide Polymers 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- 229910052708 sodium Inorganic materials 0.000 description 13
- 206010025323 Lymphomas Diseases 0.000 description 12
- 230000027455 binding Effects 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 12
- 239000008280 blood Substances 0.000 description 12
- 230000004614 tumor growth Effects 0.000 description 12
- 239000013543 active substance Substances 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 239000012634 fragment Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000013459 approach Methods 0.000 description 8
- 239000008367 deionised water Substances 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 208000003174 Brain Neoplasms Diseases 0.000 description 7
- 108020004459 Small interfering RNA Proteins 0.000 description 7
- 210000001744 T-lymphocyte Anatomy 0.000 description 7
- 230000004888 barrier function Effects 0.000 description 7
- 230000000295 complement effect Effects 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 230000002708 enhancing effect Effects 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 239000000017 hydrogel Substances 0.000 description 7
- 239000012678 infectious agent Substances 0.000 description 7
- 230000002601 intratumoral effect Effects 0.000 description 7
- 125000005647 linker group Chemical group 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 7
- 230000003211 malignant effect Effects 0.000 description 7
- 238000007920 subcutaneous administration Methods 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 206010018338 Glioma Diseases 0.000 description 6
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 description 6
- 125000003169 alpha-Gal epitope group Chemical group [C@H]1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)O[C@@H]1[C@H]([C@@H](O[C@@H]([C@@H]1O)CO)O[C@H]1[C@@H]([C@H](C(O[C@@H]1CO)*)NC(C)=O)O)O 0.000 description 6
- 230000001413 cellular effect Effects 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 108020004999 messenger RNA Proteins 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 206010009944 Colon cancer Diseases 0.000 description 5
- 108091034117 Oligonucleotide Proteins 0.000 description 5
- 229940100198 alkylating agent Drugs 0.000 description 5
- 239000002168 alkylating agent Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 230000022131 cell cycle Effects 0.000 description 5
- 210000000170 cell membrane Anatomy 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 229940044683 chemotherapy drug Drugs 0.000 description 5
- 208000029742 colonic neoplasm Diseases 0.000 description 5
- 238000013270 controlled release Methods 0.000 description 5
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 210000001808 exosome Anatomy 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000002062 proliferating effect Effects 0.000 description 5
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- ODDPRQJTYDIWJU-UHFFFAOYSA-N 3'-beta-D-galactopyranosyl-lactose Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(OC2C(OC(O)C(O)C2O)CO)OC(CO)C1O ODDPRQJTYDIWJU-UHFFFAOYSA-N 0.000 description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
- 206010003571 Astrocytoma Diseases 0.000 description 4
- OFNFROPLKWQRQD-UHFFFAOYSA-N C1(CCCCC1)OC(CCCCCCC=O)=O.[Na] Chemical compound C1(CCCCC1)OC(CCCCCCC=O)=O.[Na] OFNFROPLKWQRQD-UHFFFAOYSA-N 0.000 description 4
- VQFKFAKEUMHBLV-MGSIYYPRSA-N CCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](COC1OC(CO)C(O)C(O)C1O)[C@H](O)[C@H](O)CCCCCCCCCCCCCC Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](COC1OC(CO)C(O)C(O)C1O)[C@H](O)[C@H](O)CCCCCCCCCCCCCC VQFKFAKEUMHBLV-MGSIYYPRSA-N 0.000 description 4
- 108700012941 GNRH1 Proteins 0.000 description 4
- 208000032612 Glial tumor Diseases 0.000 description 4
- 208000034578 Multiple myelomas Diseases 0.000 description 4
- 208000003788 Neoplasm Micrometastasis Diseases 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 239000002269 analeptic agent Substances 0.000 description 4
- 239000012491 analyte Substances 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 210000001185 bone marrow Anatomy 0.000 description 4
- 239000008366 buffered solution Substances 0.000 description 4
- 229940106189 ceramide Drugs 0.000 description 4
- 230000000973 chemotherapeutic effect Effects 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 230000008029 eradication Effects 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 4
- 229910052737 gold Inorganic materials 0.000 description 4
- 239000010931 gold Substances 0.000 description 4
- 238000001794 hormone therapy Methods 0.000 description 4
- 230000002267 hypothalamic effect Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- FABUFPQFXZVHFB-PVYNADRNSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-PVYNADRNSA-N 0.000 description 4
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 230000000474 nursing effect Effects 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-L 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 201000000849 skin cancer Diseases 0.000 description 4
- 201000008261 skin carcinoma Diseases 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- 238000011269 treatment regimen Methods 0.000 description 4
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 4
- 125000003816 2-hydroxybenzoyl group Chemical group OC1=C(C(=O)*)C=CC=C1 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 3
- 208000021309 Germ cell tumor Diseases 0.000 description 3
- 208000017604 Hodgkin disease Diseases 0.000 description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- 108700011259 MicroRNAs Proteins 0.000 description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 3
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 3
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 3
- 241000009328 Perro Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 206010038389 Renal cancer Diseases 0.000 description 3
- 108091081021 Sense strand Proteins 0.000 description 3
- 208000000453 Skin Neoplasms Diseases 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 210000000612 antigen-presenting cell Anatomy 0.000 description 3
- 239000002256 antimetabolite Substances 0.000 description 3
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 3
- 229960000074 biopharmaceutical Drugs 0.000 description 3
- 238000001815 biotherapy Methods 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 208000002458 carcinoid tumor Diseases 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000002254 cytotoxic agent Substances 0.000 description 3
- 230000002939 deleterious effect Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 201000010982 kidney cancer Diseases 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 210000001165 lymph node Anatomy 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 239000002679 microRNA Substances 0.000 description 3
- 230000000394 mitotic effect Effects 0.000 description 3
- 201000005962 mycosis fungoides Diseases 0.000 description 3
- 208000025113 myeloid leukemia Diseases 0.000 description 3
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 239000008177 pharmaceutical agent Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 201000004477 skin sarcoma Diseases 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 201000008205 supratentorial primitive neuroectodermal tumor Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000007910 systemic administration Methods 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 208000008732 thymoma Diseases 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 3
- 210000000239 visual pathway Anatomy 0.000 description 3
- 230000004400 visual pathway Effects 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- NJEKDCUDSORUJA-UHFFFAOYSA-N 8-[(2-hydroxybenzoyl)amino]octanoic acid Chemical compound OC(=O)CCCCCCCNC(=O)C1=CC=CC=C1O NJEKDCUDSORUJA-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 206010060971 Astrocytoma malignant Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 206010004593 Bile duct cancer Diseases 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 2
- 206010006143 Brain stem glioma Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010007275 Carcinoid tumour Diseases 0.000 description 2
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 230000004543 DNA replication Effects 0.000 description 2
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 206010014967 Ependymoma Diseases 0.000 description 2
- 208000012468 Ewing sarcoma/peripheral primitive neuroectodermal tumor Diseases 0.000 description 2
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 206010061252 Intraocular melanoma Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 208000000172 Medulloblastoma Diseases 0.000 description 2
- 101710151321 Melanostatin Proteins 0.000 description 2
- 206010027406 Mesothelioma Diseases 0.000 description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 2
- 208000003445 Mouth Neoplasms Diseases 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 102400000064 Neuropeptide Y Human genes 0.000 description 2
- 102000050267 Neurotensin Human genes 0.000 description 2
- 101800001814 Neurotensin Proteins 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 201000000582 Retinoblastoma Diseases 0.000 description 2
- 230000018199 S phase Effects 0.000 description 2
- MEFKEPWMEQBLKI-AIRLBKTGSA-O S-adenosyl-L-methionine Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H]([NH3+])C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-O 0.000 description 2
- 201000010208 Seminoma Diseases 0.000 description 2
- 208000009359 Sezary Syndrome Diseases 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 2
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 2
- 201000005969 Uveal melanoma Diseases 0.000 description 2
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 2
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 241000021375 Xenogenes Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000003012 bilayer membrane Substances 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 229920001222 biopolymer Polymers 0.000 description 2
- 201000000053 blastoma Diseases 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000012830 cancer therapeutic Substances 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000004203 carnauba wax Substances 0.000 description 2
- 235000013869 carnauba wax Nutrition 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 201000007335 cerebellar astrocytoma Diseases 0.000 description 2
- 208000030239 cerebral astrocytoma Diseases 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 201000008184 embryoma Diseases 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 230000002357 endometrial effect Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 208000024519 eye neoplasm Diseases 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 2
- 201000009277 hairy cell leukemia Diseases 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000029824 high grade glioma Diseases 0.000 description 2
- 230000003054 hormonal effect Effects 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 230000003308 immunostimulating effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 210000004153 islets of langerhan Anatomy 0.000 description 2
- 210000000244 kidney pelvis Anatomy 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 201000010260 leiomyoma Diseases 0.000 description 2
- 230000021633 leukocyte mediated immunity Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 2
- 206010024627 liposarcoma Diseases 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 208000030883 malignant astrocytoma Diseases 0.000 description 2
- 201000011614 malignant glioma Diseases 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000002923 metal particle Substances 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 208000018795 nasal cavity and paranasal sinus carcinoma Diseases 0.000 description 2
- PCJGZPGTCUMMOT-ISULXFBGSA-N neurotensin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 PCJGZPGTCUMMOT-ISULXFBGSA-N 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 201000008106 ocular cancer Diseases 0.000 description 2
- 201000002575 ocular melanoma Diseases 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- SOOXQKVMQBCEGW-UHFFFAOYSA-N phenyl hexanoate Chemical compound CCCCCC(=O)OC1=CC=CC=C1 SOOXQKVMQBCEGW-UHFFFAOYSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 102000054765 polymorphisms of proteins Human genes 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 239000004800 polyvinyl chloride Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 230000001124 posttranscriptional effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 239000013074 reference sample Substances 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- JVWNMDMGMZQAGL-UHFFFAOYSA-M sodium;6-oxo-6-phenylhexanoate Chemical compound [Na+].[O-]C(=O)CCCCC(=O)C1=CC=CC=C1 JVWNMDMGMZQAGL-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000012385 systemic delivery Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 206010044412 transitional cell carcinoma Diseases 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 210000000626 ureter Anatomy 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 1
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- ARLKVQYMFRECLV-JSGCOSHPSA-N (2s)-2-[[(2s)-2-amino-3-(1h-indol-3-yl)propanoyl]amino]-4-methylsulfanylbutanamide Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCSC)C(N)=O)=CNC2=C1 ARLKVQYMFRECLV-JSGCOSHPSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- WCOXQTXVACYMLM-UHFFFAOYSA-N 2,3-bis(12-hydroxyoctadecanoyloxy)propyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC(O)CCCCCC)COC(=O)CCCCCCCCCCC(O)CCCCCC WCOXQTXVACYMLM-UHFFFAOYSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- KODALSDOOPIEJT-UHFFFAOYSA-N 2-oxo-6-phenylhexanoic acid Chemical compound OC(=O)C(=O)CCCCC1=CC=CC=C1 KODALSDOOPIEJT-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- YGEHCIVVZVBCLE-FSYGUOKUSA-N 3alpha-galactobiose Chemical group OC[C@@H](O)[C@H](O)[C@@H]([C@@H](O)C=O)O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O YGEHCIVVZVBCLE-FSYGUOKUSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000002008 AIDS-Related Lymphoma Diseases 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 206010073360 Appendix cancer Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 102100026189 Beta-galactosidase Human genes 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 102000013585 Bombesin Human genes 0.000 description 1
- 108010051479 Bombesin Proteins 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- 108091005932 CCKBR Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007279 Carcinoid tumour of the gastrointestinal tract Diseases 0.000 description 1
- 206010007281 Carcinoid tumour of the stomach Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 101800001982 Cholecystokinin Proteins 0.000 description 1
- 102100025841 Cholecystokinin Human genes 0.000 description 1
- 102100036576 Coiled-coil domain-containing protein 174 Human genes 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 230000008265 DNA repair mechanism Effects 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 208000008743 Desmoplastic Small Round Cell Tumor Diseases 0.000 description 1
- 206010064581 Desmoplastic small round cell tumour Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 208000007033 Dysgerminoma Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 102000004678 Exoribonucleases Human genes 0.000 description 1
- 108010002700 Exoribonucleases Proteins 0.000 description 1
- 206010073306 Exposure to radiation Diseases 0.000 description 1
- 208000017259 Extragonadal germ cell tumor Diseases 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 102100036519 Gastrin-releasing peptide Human genes 0.000 description 1
- 208000008999 Giant Cell Carcinoma Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 229910004042 HAuCl4 Inorganic materials 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101710196315 High affinity copper uptake protein 1 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 206010021042 Hypopharyngeal cancer Diseases 0.000 description 1
- 206010056305 Hypopharyngeal neoplasm Diseases 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 244000237786 Lathyrus tuberosus Species 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 206010025312 Lymphoma AIDS related Diseases 0.000 description 1
- 102000043129 MHC class I family Human genes 0.000 description 1
- 108091054437 MHC class I family Proteins 0.000 description 1
- 208000030070 Malignant epithelial tumor of ovary Diseases 0.000 description 1
- 206010025557 Malignant fibrous histiocytoma of bone Diseases 0.000 description 1
- 206010073059 Malignant neoplasm of unknown primary site Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- 102000003792 Metallothionein Human genes 0.000 description 1
- 108090000157 Metallothionein Proteins 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
- 108091061960 Naked DNA Proteins 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 1
- 206010033268 Ovarian low malignant potential tumour Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108091093037 Peptide nucleic acid Proteins 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- 206010035052 Pineal germinoma Diseases 0.000 description 1
- 206010050487 Pinealoblastoma Diseases 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 201000005746 Pituitary adenoma Diseases 0.000 description 1
- 206010061538 Pituitary tumour benign Diseases 0.000 description 1
- 201000008199 Pleuropulmonary blastoma Diseases 0.000 description 1
- 229920000463 Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) Polymers 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000007660 Residual Neoplasm Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 102000003661 Ribonuclease III Human genes 0.000 description 1
- 108010057163 Ribonuclease III Proteins 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 208000003837 Second Primary Neoplasms Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 108700031126 Tetraspanins Proteins 0.000 description 1
- 102000043977 Tetraspanins Human genes 0.000 description 1
- 206010043515 Throat cancer Diseases 0.000 description 1
- 201000009365 Thymic carcinoma Diseases 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 206010044407 Transitional cell cancer of the renal pelvis and ureter Diseases 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 206010046431 Urethral cancer Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 102100038388 Vasoactive intestinal polypeptide receptor 1 Human genes 0.000 description 1
- 101710137655 Vasoactive intestinal polypeptide receptor 1 Proteins 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229940110282 alimta Drugs 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- GWCQSPUAEOPDKF-UHFFFAOYSA-N amino octanoate Chemical compound CCCCCCCC(=O)ON GWCQSPUAEOPDKF-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 208000021780 appendiceal neoplasm Diseases 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940078010 arimidex Drugs 0.000 description 1
- 229940087620 aromasin Drugs 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000016834 benign smooth muscle neoplasm Diseases 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- DNDCVAGJPBKION-DOPDSADYSA-N bombesin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC2=CC=CC=C2C=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CN=CN1 DNDCVAGJPBKION-DOPDSADYSA-N 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 201000008873 bone osteosarcoma Diseases 0.000 description 1
- 208000012172 borderline epithelial tumor of ovary Diseases 0.000 description 1
- 208000014581 breast ductal adenocarcinoma Diseases 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940082483 carnauba wax Drugs 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 229940097647 casodex Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000004656 cell transport Effects 0.000 description 1
- 230000006800 cellular catabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000001783 ceramides Chemical class 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 201000008522 childhood cerebral astrocytoma Diseases 0.000 description 1
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 229940107137 cholecystokinin Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000010415 colloidal nanoparticle Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 229940026692 decadron Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 229940000733 emcyt Drugs 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 201000008819 extrahepatic bile duct carcinoma Diseases 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 229940087861 faslodex Drugs 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229940087476 femara Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical class FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 201000007116 gestational trophoblastic neoplasm Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002339 glycosphingolipids Chemical class 0.000 description 1
- ZBKIUFWVEIBQRT-UHFFFAOYSA-N gold(1+) Chemical compound [Au+] ZBKIUFWVEIBQRT-UHFFFAOYSA-N 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 201000010235 heart cancer Diseases 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 210000003093 intracellular space Anatomy 0.000 description 1
- 230000010189 intracellular transport Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229940111707 ixempra Drugs 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 125000003473 lipid group Chemical group 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000000014 lung giant cell carcinoma Diseases 0.000 description 1
- 229940087857 lupron Drugs 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940090004 megace Drugs 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- 210000000716 merkel cell Anatomy 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000002082 metal nanoparticle Substances 0.000 description 1
- 238000004503 metal oxide affinity chromatography Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000037970 metastatic squamous neck cancer Diseases 0.000 description 1
- NXMXPVQZFYYPGD-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;methyl prop-2-enoate Chemical compound COC(=O)C=C.COC(=O)C(C)=C NXMXPVQZFYYPGD-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000002625 monoclonal antibody therapy Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 206010051747 multiple endocrine neoplasia Diseases 0.000 description 1
- 210000002487 multivesicular body Anatomy 0.000 description 1
- 208000017869 myelodysplastic/myeloproliferative disease Diseases 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229940099637 nilandron Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000242 nostrum Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 208000022982 optic pathway glioma Diseases 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 208000021284 ovarian germ cell tumor Diseases 0.000 description 1
- RUUFMHUAHUPZSS-UHFFFAOYSA-N oxido-oxo-sulfinophosphanium Chemical class P(=O)(=O)S(=O)O RUUFMHUAHUPZSS-UHFFFAOYSA-N 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 201000002526 pancreas sarcoma Diseases 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
- 201000002530 pancreatic endocrine carcinoma Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 201000007315 pineal gland astrocytoma Diseases 0.000 description 1
- 201000004838 pineal region germinoma Diseases 0.000 description 1
- 201000003113 pineoblastoma Diseases 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 208000010626 plasma cell neoplasm Diseases 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229940034080 provenge Drugs 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 208000030859 renal pelvis/ureter urothelial carcinoma Diseases 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 208000014212 sarcomatoid carcinoma Diseases 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 230000008684 selective degradation Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 229940087854 solu-medrol Drugs 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 208000037969 squamous neck cancer Diseases 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229940061353 temodar Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- 208000029387 trophoblastic neoplasm Diseases 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 208000018417 undifferentiated high grade pleomorphic sarcoma of bone Diseases 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 229940033942 zoladex Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/242—Gold; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/042—Gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
- A61K8/20—Halogens; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/34—Alcohols
- A61K8/342—Alcohols having more than seven atoms in an unbroken chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/34—Alcohols
- A61K8/345—Alcohols containing more than one hydroxy group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/37—Esters of carboxylic acids
- A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/41—Amines
- A61K8/416—Quaternary ammonium compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/42—Amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
- A61Q5/12—Preparations containing hair conditioners
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
- A61K2800/30—Characterized by the absence of a particular group of ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
- A61K2800/30—Characterized by the absence of a particular group of ingredients
- A61K2800/34—Free of silicones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/52—Stabilizers
- A61K2800/524—Preservatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the present invention relates to novel methods for treating cancer.
- the methods involve treating a carcinoma or sarcoma using a coadministration strategy that combines local codelivery of a therapeutic agent and an intracellular penetration enhancing agent, optionally in combination with at least one additional therapeutic agent (e.g., local or systemic administration of an immunotherapeutic agent).
- the methods of the invention reduce the growth, shrink, and/or eradicate a target tumor, as well as those cancerous cells that have metastasized to other parts of the body.
- cancer is used to describe a number of diseases in which there is uncontrolled division of abnormal cells. Cancer may initially arise in virtually any tissue or organ in the body and forms as a result of a complex interaction of both innate genetic factors and environmental factors, such as one's diet or exposure to radiation, toxins, and the like. Despite advances in medicine and the understanding of the molecular basis of cancer, the exact causes of any given type of cancer are largely unknown, especially in a particular individual. Given this lack of knowledge, it is not surprising that it remains highly difficult to find effective cancer treatments.
- metastasis enables cancer cells to spread to other vital parts of the body through the blood and lymph systems.
- Standard of care cancer therapies typically couple surgical removal of the affected tissue with chemotherapy or radiation treatments.
- Standard approaches for administering chemotherapeutics are through the blood, e.g., systemic delivery, which can be achieved by various routes such as intravenous and/or gastrointestinal delivery.
- toxicity is a major drawback associated with systemically delivered chemotherapeutic drugs.
- Standard of care surgical treatments also introduce problems, including dislodgement of cancer cells into the blood and/or lymph systems, which results in the opportunity for cancer cells to metastasize to other sites in the body and cause additional tumors to form.
- Regional chemotherapy represents a recent advance in the chemotherapeutic treatment of cancer. This approach involves delivering the chemotherapeutic agent directly to the tumor, e.g., proximal to, adjacent to, or intratumorally, as opposed to introducing the toxic agent into the bloodstream.
- One goal of regional chemotherapy is to minimize the toxic side effects typically associated with systemic chemotherapeutic administration.
- chemotherapeutic approaches generally have not been satisfactory.
- certain platinum compounds are mainly taken into cancer cells by an active transport process using the CTR1 pathway (see Holzer et al. Molecular Pharmacology 70:1390-1394 (2006)).
- chemotherapeutic agents generally are delivered by the blood, they should be soluble in the blood, making them generally water soluble. Water soluble materials such as chemotherapeutic agents do not effectively pass through lipid cell membranes passively, and thus, are not readily deliverable to the intracellular space of cancer cells especially at low concentrations.
- tumor cells have mechanisms and various processes designed to excrete the chemotherapeutic agents. For example, tumor cells are able to rid themselves of chemical agents using glutathione and/or metallothioneins complexing and have innate DNA repair mechanisms to overcome chemotherapies.
- cancer tumors resemble the body's tissue and thus diminish the immune system's otherwise innate ability to identify and kill them.
- Several cancer-fighting technologies e.g., cancer vaccines
- PROVENGE® by Dendreon Corporation, which is used against prostate cancer
- the success of cancer vaccines has been limited.
- tumor cells are derived from the individual with cancer, tumor cells are very similar to a person's own cells.
- the immune system's ability to mount an attack on the tumor cell is hindered because the tumor cell displays few, if any, antigens that are foreign to that individual.
- a tumor can have many different types of cells in it.
- tumors can secrete cytokines that directly inhibit immune activity.
- the tumor may be too advanced (e.g., bulky) for the vaccine to be effective.
- the invention provides methods for effectively treating a solid tumor by locally coadministering (e.g., proximally, locally, directly into, and the like) a combination of a therapeutic agent (e.g., a small molecule, pharmaceutical drug, antibody, and the like) together with an intracellular penetration enhancing agent.
- a therapeutic agent e.g., a small molecule, pharmaceutical drug, antibody, and the like
- the therapeutic agent and the intracellular penetration enhancing agent are administered in amounts and/or in a regimen that results in substantial tumor shrinkage and/or destruction.
- the exact administration regimen may vary, including that the agents may be delivered at the same time or concomitant with one another (e.g., same injection), or at different times and in any order.
- the administration regimen may involve multiple repetitions or rounds of administration, wherein the agents are delivered in the same or different fashions multiple times in a single day or on separate days.
- Administration of repetitive dosing for a defined period of time is often referred to as a drug cycle.
- the methods described may also involve multiple drug cycles.
- the methods may also vary depending on the tumor type.
- the method of the invention also involves enhancing the treatment effects of the therapeutic agent and intracellular penetration enhancing agent by coupling their local administration with the administration of an immune-stimulating agent, such as a cancer vaccine or T-cell agonist, which may be delivered prior to, at or at about the same time, or subsequent to the therapeutic and intracellular penetration enhancing agents.
- the therapeutic agent may be a combination of two or more agents selected from the group consisting of a chemotherapeutic agent, an antibody, and a nucleic acid molecule.
- the method of the invention can also be thought of as a two-phase therapeutic approach.
- a subject is locally coadministered both a therapeutic agent and an intracellular penetration enhancing agent in accordance with an effective dosing regimen.
- the agents may be delivered at the same time, or at approximately the same time, to a bodily location that is in the same region as the target tumor, or which is at the perimeter of the target tumor, or which is within (intratumoral) the tumor itself.
- the intracellular penetration enhancing agent surprisingly and unexpectedly results in a substantially high increase in drug permeability of the therapeutic agent into the tumor cells.
- an immune-stimulating agent such as a cancer vaccine, CD4 or NKT cell stimulating agent or combination of agents
- a cancer vaccine such as CD4 or NKT cell stimulating agent or combination of agents
- the invention also provides formulations for use in treating cancer in accordance with the methods of the invention.
- the formulations combine, separately or together, a therapeutic agent and an intracellular penetration enhancing agent.
- Such formulations may be administered locally or regionally, or intratumorally to a tumor in a subject.
- the invention provides formulations that further combine, separately or together, a therapeutic agent, an intracellular penetration enhancing agent, and an immunotherapeutic agent, e.g., a cancer vaccine.
- a therapeutic agent e.g., a human immunotherapeutic agent
- an immunotherapeutic agent e.g., a cancer vaccine.
- Such formulations may be administered locally or regionally, or intratumorally to a tumor in a subject.
- the invention provides methods for treating a subject in need thereof (e.g., a subject with one or more tumors) with an effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
- administration of the intracellular permeation agent increases the likelihood of effectiveness of the therapeutic agent.
- administration of the intracellular permeation agent increases the likelihood of effectiveness of the therapeutic agent by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more (or any number therebetween) as compared to treatment without the intracellular permeation agent.
- the invention provides methods for reducing the side effects of a therapeutic agent.
- the methods involve administering an effective amount of the therapeutic agent and an intracellular permeation enhancing agent to a subject (e.g., a subject with a tumor).
- the invention provides methods for destroying cancerous cells within a subject (e.g., a subject with one or more tumors).
- the methods involve administering an effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
- the invention provides methods for treating a tumor in a subject.
- the methods involve administering an effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
- the invention provides methods for inhibiting growth of a tumor in a subject.
- the methods involve administering an effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
- the therapeutic agent can be locally, regionally, or systemically administered to the subject.
- the intracellular permeation enhancing agent can be locally or regionally administered to the subject.
- the methods involve locally or regionally coadministering to the subject a therapeutic agent and an intracellular permeation enhancing agent.
- the tumor is a solid tumor. In some embodiments, the tumor has metastasized.
- the tumor is a carcinoma or sarcoma.
- the tumor is a carcinoma or sarcoma of the skin, bone, muscle, breast, oral cavity, colon, organ, kidney, liver, lung, gallbladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testes, ovaries, or uterus.
- the tumor is a carcinoma of the pancreas, colon, or liver.
- the therapeutic agent is administered intratumorally and/or the intracellular permeation enhancing agent is administered intratumorally. In some embodiments, the therapeutic agent is administered systemically and the intracellular permeation enhancing agent is administered intratumorally.
- the methods may reduce the growth of the one or more tumors, shrink the one or more tumors, or eradicate the one or more tumors.
- the tumor mass does not increase.
- the tumor shrinks by 10%, 25%, 50%, 75%, 85%, 90%, 95%, or 99% or more (or any number therebetween) as compared to its original mass.
- the methods may prevent tumor metastasis.
- the effective amount of the therapeutic agent can be selected based on the volume and type of the tumor.
- the effective amount of the intracellular permeation enhancing agent and/or drug agent can be selected based on the volume and type of the tumor.
- the methods involve administering the therapeutic agent on a first day and repeating the administration on one or more subsequent days.
- the first day and one or more subsequent days are separated by between 1 day and about 3 weeks.
- the methods involve administering the intracellular permeation enhancing agent on a first day and repeating the administration on one or more subsequent days.
- the first day and one or more subsequent days are separated by between 1 day and about 3 weeks.
- the intracellular permeation enhancing agent may be administered between 3 and 5 days consecutively or with one day of rest within the period.
- the methods involve coadministering the therapeutic agent and the intracellular permeation enhancing agent on the first day and repeating the administration on one or more subsequent days.
- the first day and one or more subsequent days are separated by between 1 day and about 3 weeks.
- the therapeutic agent and the intracellular permeation enhancing agent are coadministered in a ratio of about 1:2, 1:4, 1:10, 1:20, 1:25, 1:50, 1:100, or 1:200 (weight ratio of therapeutic agent: intracellular permeation enhancing agent).
- the intracellular permeation enhancing agent is administered at a concentration of between about 0.5 mgs per ml and about 50 mgs per ml. In still other embodiments, the intracellular permeation enhancing agent is administered at a concentration of between about 10 mgs per ml and about 30 megs per ml.
- the therapeutic agent and the intracellular permeation enhancing agent are delivered simultaneously in a single formulation or simultaneously in separate formulations. In other embodiments, the intracellular permeation enhancing agent is administered before the therapeutic agent.
- the therapeutic agent can be an anticancer agent.
- the anticancer agent is a chemotherapeutic agent (e.g., Abiraterone Acetate, Afatinib, Aldesleukin, Alemtuzumab, Alitretinoin, Altretamine, Amifostine, Aminoglutethimide Anagrelide, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, Azathioprine, Bendamustine, Bevacizumab, Bexarotine, Bicalutamide, Bleomycin, Bortezomib, Busulfan, Capecitabine, Carboplatin, Carmustine, Cetuximab, Chlorambucil, Cisplatin, Cladribine, Crizotinib, Cyclophosphamide, Cytarabine, dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, Denileukin diftitox, Decitabine, Docet
- the therapeutic agent is a therapeutic antibody or a combination of two or more therapeutic antibodies (e.g., Abagovomab, Alacizumab pegol, Alemtuzumab, Altumomab pentetate (Hybri-ceaker), Amatuximab, Anatumomab mafenatox, anti-PD-1 antibodies, Apolizumab, Arcitumomab (CEA-Scan), Belimumab, Bevacizumab, Bivatuzumab mertansine, Blinatumomab, Brentuximab vedotin, Cantuzumab mertansine, Cantuzumab ravtansine, Capromab pendetide (Prostascint), Catumaxomab (Removab), Cetuximab (Erbitux), Citatuzumab communicatingox, Cixutumumab, Clivatuzumab
- the therapeutic agent is a nucleic acid molecule.
- the nucleic acid molecule can be an interfering RNA (e.g., RNAi or shRNA), a gene therapy expression vector, or a gene silencing vector.
- the therapeutic agent is a radioisotope.
- the therapeutic agent is a thymidylate synthase inhibitor. In certain embodiments, the therapeutic agent is a platinum compound.
- the therapeutic agent is a vinca alkaloid agent.
- the intracellular permeation enhancing agent can be a chemical compound that enhances passive transport of the therapeutic compound into a cell.
- the intracellular permeation enhancing agent is a functionalized ketoacid, 6-Oxo-6-phenylhexanoic acid, 8-Oxo-8-phenyloctanoic acid, 8-(2,5-Dichlorophenyl)-8-oxooctanoic acid, a functionalized ketoester or aldehyde, a modified amino acid, modified amino acids, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, N-[8-(2-hydroxybenzoyl)aminodecanoic acid, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-[4-(4-chloro-2hydroxybenzoyl)amino]butanoic acid, 2-ethylhexyl 2-hydroxybenzoate, 5-Cyclohexyl-5-oxovaleric acid, 6-Cyclohexyl-6-oxohexanoic
- the intracellular permeation enhancing agent is 6-Oxo-6-phenylhexanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, a functionally effective salt of any of the foregoing, a derivative of any of the foregoing, or any combination thereof.
- the therapeutic agent is cisplatin or other platinum agent (e.g., satraplatin, pcioplatin, nedaplatin, triplatin, carboplatin or oxaplatin), and wherein the intracellular permeation enhancing agent is 6-oxo-6 phenylhexanoic acid, N-8-(2-hydroxybenzoyl)aminooctanoic acid, a salt or derivative of any of the foregoing, or any combination thereof.
- platinum agent e.g., satraplatin, pcioplatin, nedaplatin, triplatin, carboplatin or oxaplatin
- the intracellular permeation enhancing agent is 6-oxo-6 phenylhexanoic acid, N-8-(2-hydroxybenzoyl)aminooctanoic acid, a salt or derivative of any of the foregoing, or any combination thereof.
- the above methods further involve administering a therapeutically effective amount of an immunotherapeutic agent.
- the immunotherapeutic agent is a cancer vaccine, hormone, epitope, cytokine, tumor antigen, CD4 cell stimulator, NKT cell agonist, or adjuvant.
- the immunotherapeutic agent can be an interferon, interleukin, tumor necrosis factor, ovalabumin, Neuvenge®, Oncophage, CimaVax-EGF, Mobilan, a-Gal glycolipid, ⁇ -Galactosylceramide ( ⁇ -GalCer), ⁇ -mannosylceramide ( ⁇ -ManCer), adenovirus delivered vaccines, Celldex's CDX1307 and CDX1401; GRNVAC1, viral based vaccines, MVA-BN, PROSTVAC®, Advaxis'; ADXS11-001, ADXS31-001, ADXS31-164, BiovaxID, folate binding protein (E39), Granulocyte macrophage colony stimulating factor (GM-CSF) with and without E75 (NeuVax) or OncoVEX, trastuzumab, Ae-37, IMA901, SC1B1, Stimuvax, peptides that can elicit cytoplasmic
- the immunotherapeutic agent is an ⁇ -Gal glycolipid.
- the immunotherapeutic agent is a ⁇ -ManCer comprising a sphingosine moiety and a fatty acid moiety comprising a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 49 carbon atoms.
- the fatty acid moiety comprises a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 15 carbon atoms.
- the fatty acid moiety comprises a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 18 to about 30 carbon atoms.
- the ⁇ -ManCer comprises the following structure:
- the immunotherapeutic agent enhances the therapeutic effects of the therapeutic agent.
- the immunotherapeutic agent further reduces the growth of the tumor or further shrinks the tumor.
- the immunotherapeutic agent is administered after administration of the therapeutic agent and the intracellular permeation enhancing agent. In other embodiments, the immunotherapeutic agent is administered simultaneously with the first administration of the therapeutic agent and the intracellular permeation enhancing agent.
- the immunotherapeutic agent is administered locally, regionally, or systemically.
- the immunotherapeutic agent can be administered intraperitoneally.
- the immunotherapeutic agent can also be administered intratumorally.
- the therapeutic agent and the intracellular permeation enhancing agent can be coupled.
- the above methods can further involve administering a standard of care therapy to the subject.
- the standard of care therapy is surgery, radiation, radio frequency, cryogenic, ultranoic ablation, systemic chemotherapy, or a combination thereof.
- administration of the therapeutic agent, the intracellular permeation enhancing agent, or the immunotherapeutic agent can be conducted with the aid of an imaging system (e.g., X-ray computed tomography (CT), fluoroscopy, magnetic resonance imaging (MRI), ultrasound, or positron emission tomography (PET)/computed tomography (CT)).
- an imaging system e.g., X-ray computed tomography (CT), fluoroscopy, magnetic resonance imaging (MRI), ultrasound, or positron emission tomography (PET)/computed tomography (CT)
- the invention includes methods of imaging one or more tumors with an imaging system selected from the group consisting of X-ray computed tomography (CT), fluoroscopy, magnetic resonance imaging (MRI), ultrasound, and positron emission tomography (PET)/computed tomography (CT), determining the volume of the one or more tumors; and calculating, based on the determined tumor volume, a therapeutically effective tumor-specific dose amount of the therapeutic agent and the intracellular permeation enhancing agent.
- CT X-ray computed tomography
- MRI magnetic resonance imaging
- PET positron emission tomography
- CT computed tomography
- the subject can be a mammal (e.g., human, dog, cat, horse, cow, sheep, goat, pig, mouse, rat, guinea pig, or monkey).
- a mammal e.g., human, dog, cat, horse, cow, sheep, goat, pig, mouse, rat, guinea pig, or monkey.
- the invention also features methods of treating a subject in need thereof (e.g., a subject having a tumor) with an effective amount of an intracellular permeation enhancing agent.
- the invention provides methods for destroying cancerous cells within a subject (e.g., a subject having a tumor).
- the methods involve administering an effective amount of an intracellular permeation enhancing agent.
- the invention provides methods for treating a tumor in a subject.
- the methods involve administering an effective amount of an intracellular permeation enhancing agent.
- the invention provides methods for inhibiting growth of a tumor in a subject.
- the methods involve administering an effective amount of an intracellular permeation enhancing agent.
- the intracellular permeation enhancing agent can be locally or regionally administered to the subject.
- the tumor is a solid tumor. In some embodiments, the tumor has metastasized.
- the tumor is a carcinoma or sarcoma.
- the tumor is a carcinoma or sarcoma of the skin, bone, muscle, breast, oral cavity, organ, kidney, liver, lung, gallbladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testes, ovaries, or uterus.
- the tumor is a carcinoma or sarcoma of the pancreas.
- the intracellular permeation enhancing agent is administered intratumorally.
- the methods may reduce the growth of the tumor, shrinks the tumor, or eradicates the tumor.
- the tumor mass does not increase.
- the tumor shrinks by 10%, 25%, 50%, 75%, 85%, 90%, 95%, or 99% or more (or any number therebetween) as compared to its original mass.
- the methods may prevent tumor metastasis.
- the effective amount of the intracellular permeation enhancing agent can be selected based on the volume and type of the tumor.
- the methods involve administering the intracellular permeation enhancing agent on a first day and repeating the administration on one or more subsequent days.
- the first day and one or more subsequent days are separated by between 1 day and about 3 weeks.
- the intracellular permeation enhancing agent can be a chemical compound that enhances passive transport of the therapeutic compound into a cell.
- the intracellular permeation enhancing agent is a functionalized ketoacid, 6-Oxo-6-phenylhexanoic acid, 8-Oxo-8-phenyloctanoic acid, 8-(2,5-Dichlorophenyl)-8-oxooctanoic acid, a functionalized ketoester or aldehyde, a modified amino acid, modified amino acids, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, N-[8-(2-hydroxybenzoyl)aminodecanoic acid, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-[4-(4-chloro-2hydroxybenzoyl)amino]butanoic acid, 2-ethylhexyl 2-hydroxybenzoate, 5-Cyclohexyl-5-oxovaleric acid, 6-Cyclohexyl-6-oxohexanoic
- the intracellular permeation enhancing agent is 6-Oxo-6-phenylhexanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, or a functionally effective salt or derivative thereof.
- the subject can be a mammal (e.g., human, dog, cat, horse, cow, sheep, goat, pig, mouse, rat, guinea pig, or monkey).
- a mammal e.g., human, dog, cat, horse, cow, sheep, goat, pig, mouse, rat, guinea pig, or monkey.
- the invention further features pharmaceutical compositions for conducting the method described herein.
- the composition is optimized for intratumoral administration.
- the intracellular permeation enhancing agent and the therapeutic agent are coadministered intratumorally.
- agent or “therapeutic agent” is meant any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof.
- ameliorate is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease or a symptom thereof.
- an analog is meant a molecule that is not identical, but has analogous functional or structural features.
- a polypeptide analog retains the biological activity of a corresponding naturally-occurring polypeptide, while having certain biochemical modifications that enhance the analog's function relative to a naturally occurring polypeptide. Such biochemical modifications could increase the analog's protease resistance, membrane permeability, or half-life, without altering, for example, ligand binding.
- An analog may include an unnatural amino acid.
- an interfering RNA refers to any double stranded or single stranded RNA sequence, capable—either directly or indirectly (i.e., upon conversion)—of inhibiting or down regulating gene expression by mediating RNA interference.
- Interfering RNA includes but is not limited to small interfering RNA (“siRNA”) and small hairpin RNA (“shRNA”).
- siRNA small interfering RNA
- shRNA small hairpin RNA
- RNA interference refers to the selective degradation of a sequence-compatible messenger RNA transcript.
- an shRNA small hairpin RNA refers to an RNA molecule comprising an antisense region, a loop portion and a sense region, wherein the sense region has complementary nucleotides that base pair with the antisense region to form a duplex stem.
- the small hairpin RNA is converted into a small interfering RNA by a cleavage event mediated by the enzyme Dicer, which is a member of the RNase III family.
- RNAi refers to a post-transcriptional silencing mechanism initiated by small double-stranded RNA molecules that suppress expression of genes with sequence homology.
- anti-tumor therapy refers to any therapy to decrease tumor growth or metastasis, including surgery, radiation, and/or chemotherapy.
- control samples include, for example, cells in culture, one or more laboratory test animals, or one or more human subjects. Methods to select and test control samples are within the ability of those in the art.
- An analytic substance can be a naturally occurring substance that is characteristically expressed or produced by the cell or organism (e.g., antibodies, pathogenic peptides or particles, and the like) or a substance produced by a reporter construct (e.g, ⁇ -galactosidase or luciferase). Depending on the method used for detection the amount and measurement of the change can vary. Determination of statistical significance is within the ability of those skilled in the art.
- co-administering refers to the act of administering two or more agents (e.g., a therapeutic agent with a penetration enhancer), compounds, therapies, or the like, at or about the same time.
- agents e.g., a therapeutic agent with a penetration enhancer
- the order or sequence of administering the different agents of the invention e.g., chemotherapeutics, intracellular permeation enhancing agents, or immunotherapeutic agents, may vary and is not confined to any particular sequence.
- Co-administering may also refer to the situation where two or more agents are administered to different regions of the body or via different delivery schemes, e.g., where a first agent is administered systemically and a second agent is administered intratumorally, or where a first agent is administered intratumorally and a second agent is administering systemically into the blood or proximally to the tumor.
- Co-administering may also refer to two or more agents administered via the same delivery scheme, e.g., where a first agent is administered intratumorally and a second agent is administered intratumorally.
- the terms “comprises,” “comprising,” “containing” and “having” and the like are open-ended as defined by U.S. Patent law and can mean “includes,” “including,” and the like; “consisting essentially of” or “consists essentially” likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.
- Contacting a cell is understood herein as providing an agent to a cell e.g., a cell to be treated in culture, ex vivo, or in an animal, such that the agent can interact with the cell (e.g., cell to be treated), potentially be taken up by the cell, and have an effect on the cell.
- the agent e.g., an adjuvant
- the agent can be delivered to the cell directly (e.g., by addition of the agent to culture medium or by injection into the cell, tissue, or tumor of interest), or by delivery to the organism by a topical or parenteral route of administration for delivery to the cell by vascular, lymphatic, or other means.
- administration of a therapeutic agent to a subject involves contacting the therapeutic agent with a cell, tumor, or tissue of the subject.
- the term “coupled,” as in reference to two or more agents being “coupled” together, refers to a covalent or otherwise stable association between the two or more agents.
- a therapeutic agent may be coupled with an intracellular permeation enhancing agent via a covalent bond, a covalently tethered linker moiety, or non-covalently through ionic interactions or hydrogen bonding.
- One or more agents that are coupled together retain substantial their same independent functions and characteristics.
- the therapeutic agent when coupled to another agent may retain its same activity as if it were independent.
- cycle or “drug cycle” is meant the administration of repetitive dosing for a defined period of time, which may range from minute to hours to days to weeks to months or even years.
- cytokine is meant a hormone that acts locally and that modulates an individual's immune response.
- cytotoxic agent refers to any agent capable of destroying cells, preferably dividing cells such as cancer cells.
- detecting an assay performed to determine one or more characteristics of a sample, e.g. identifying the presence, absence or amount of the analyte to be detected.
- detection can include identification of a specific analyte in a sample or an activity of an agent in a sample.
- Detection can include the determination of the presence of nucleic acid, protein (e.g., antibody, cytokine, and the like) by PCR, immunoassay (e.g., ELISA), microscopy, pathogen challenge, and the like.
- the amount of analyte or activity detected in the sample can be none or below the level of detection of the assay or method.
- disease is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
- An exemplary disease is cancer.
- an “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, refer to an amount of an agent or compound that is sufficient to treat a disorder, e.g., a cancer. In some embodiments, the result is a reduction in and/or alleviation of the signs, symptoms, or causes of a disorder, or any other desired alteration of a biological system.
- an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disorder.
- An “effective amount” or therapeutically effective amount of an agent or combination of agents of the invention may also be that amount or dose that is effective to substantially shrink or destroy a tumor, or permit its surgical removal.
- An appropriate “effective” amount in any individual case is determined using any suitable technique, (e.g., a dose escalation study) and will depend on the judgment of the practitioner. However, suitable dosage ranges are readily determinable by one skilled in the art.
- More than one dose may be required to provide an effective dose. It is understood that an effective dose in one population may or may not be sufficient in all populations.
- the therapeutic agent in connection with the administration of a therapeutic agent, is “effective against” a disease or condition when administration in a clinically appropriate manner results in a beneficial effect for at least a statistically significant fraction of subjects, such as a prevention of disease onset, improvement of symptoms, a cure, a reduction in disease signs or symptoms, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or condition.
- growth refers to any tissue or organ that comprises a cellular mass considered to represent an abnormal proliferation. Such growths may be cancerous, non-cancerous, malignant, or non-malignant. If a growth comprises cancer, it may be a tumor. Such tumors may be solid or non-solid.
- an “immunoassay” is a detection method based on the specific binding of at least one antibody to an antigen, e.g., ELISA, RIA, western blot, and the like.
- immunogen refers to substances that can promote an immune response, e.g., an antibody based or cell mediated immune response, in at least one organism.
- immunogenic composition is meant a composition comprising a molecule capable of inducing or modulating an immune response in a subject. Such an immune response may be a prophylactic or therapeutic immune response.
- the immunogenic composition is a vaccine or T-cell agonist.
- immunotherapeutic agent refers to any agent, compound, or biologic which is capable of modulating the host's immune system.
- an immunotherapeutic agent is capable of causing a stimulation of the immune system against a tumor cell.
- inducing immunity is meant to refer to any immune response generated against an antigen.
- immunity is mediated by antibodies against an infectious agent, which is exhibited by a vertebrate (e.g., a human), that prevents or ameliorates an infection or reduces at least one symptom thereof.
- the immunogenic compositions of the invention can stimulate the production of antibodies that, for example, neutralize infectious agents, block infectious agents from entering cells, block replication of infectious agents, and/or protect host cells from infection and destruction.
- the term can also refer to an immune response that is mediated by T-lymphocytes and/or other white blood cells against an infectious agent, exhibited by a vertebrate (e.g., a human), that prevents or ameliorates an infection or reduces at least one symptom thereof.
- the term “into”, as used herein, refers to the successful penetration of a molecule through or within a cell membrane.
- a viral vector may be introduced into a solid tumor cell under conditions such that the tumor cell is transfected.
- a glycolipid may be introduced into a solid tumor cell under conditions such that the glycolipid becomes inserted into the cell's phospholipid bilayer membrane.
- an antigen—or a vector encoding the antigen— may be introduced into a solid tumor cell under conditions such that the glycolipid becomes inserted into the cell's phospholipid bilayer membrane.
- intracellular permeation enhancing agent refers to a compound, molecule, substance, or the like that increases the passage of a therapeutic agent across a cell membrane, e.g., a cell of a solid tumor, and thus, enables the exposure of the contents (e.g., proteins, DNA, cellular machinery) of intracellular environment to the therapeutic agent.
- isolated refers to any composition, molecule, or mixture that has undergone a laboratory purification procedure including, but not limited to, extraction, centrifugation, chromatographic separation (i.e., for example, thin layer chromatography or high performance liquid chromatography). Usually such a purification procedure provides an isolated composition, molecule, or mixture based upon physical, chemical, or electrical potential properties. Depending upon the choice of procedure an isolated composition, molecule, or mixture may contain other compositions, compounds or mixtures having similar chemical properties. For example, an isolated composition, molecule, or mixture may contain between 1-20%, 1-10%, or 1-5% of compositions or mixtures having similar chemical properties. In one embodiment, an isolated composition or mixture comprises a mixture of glycolipids free of cholesterol and phospholipids. In one embodiment, an isolated composition or mixture comprises glycolipids having from between 5-15 glycosidic linkages.
- the term “local” or “locally,” as in local administration or coadministration of one or more therapeutics, refers to the delivery of a therapeutic agent to a bodily site that is proximate or nearby the site of a tumor, adjacent or immediately nearby the site of the tumor, at the perimeter of or in contact with the tumor, or within or inside the tumor. Delivery of a therapeutic within the tumor may also be referred to as “intratumoral” administration. Local administration generally excludes systemic administration routes.
- nonresectable refers to any part of an organ or bodily structure that cannot be surgically removed.
- a “nonresectable tumor” may be a tumor physically unreachable by conventional surgical techniques or a tumor where its removal does not improve the overall cancer disease of the patient.
- nucleic acid as in a nucleic acid for delivery to a cell is understood by its usual meaning in the art as a polynucleotide or oligonucleotide which refers to a string of at least two base-sugar-phosphate combinations.
- Nucleotides are the monomeric units of nucleic acid polymers. The term includes deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in the form of an oligonucleotide messenger RNA, anti-sense, plasmid DNA, parts of a plasmid DNA, genetic material derived from a virus, and the like.
- Polynucleotides include nucleic acids of at least two monomers.
- Anti-sense polynucleotides are nucleic acids that interfere with the function of DNA or RNA.
- An siRNA or an shRNA is a double stranded RNA that inhibits or disrupts activity or translation, for example by promoting degradation of modifying splicing or processing of the cellular nucleic acid, e.g., mRNA, microRNA, and the like, to which it is targeted.
- siRNA and shRNA include any double stranded RNA molecule that can modulate the stability, translation, or splicing of an RNA to which at least one strand of the double stranded nucleic acid hybridizes.
- RNAs are well known in the art, see e.g., patent publications WO02/44321, WO/2003/099298, US 20050277610, US 20050244858; and U.S. Pat. Nos. 7,297,786, 7,560,438 and 7,056,704, all of which are incorporated herein by reference.
- Nucleic acid as used herein is understood to include non-natural nucleotides (not occurring in nature), for example: a derivative of natural nucleotides such as phosphothionates or peptide nucleic acids (such as those described in the patents and applications cited immediately above).
- a nucleic acid can be delivered to a cell in order to produce a cellular change that is therapeutic.
- the delivery of a nucleic acid or other genetic material for therapeutic purposes is gene therapy.
- the nucleic acid may express a protein or polypeptide, e.g., a protein that is missing or non-functional in the cell or subject.
- the nucleic acid may be single or double stranded, may be sense or anti-sense, and can be delivered to a cell as naked DNA, in combination with agents to promote nucleic acid uptake into a cell (e.g., transfection reagents), in the context of a viral vector, and the like.
- the nucleic acid can be targeted to a nucleic acid that is endogenous to the cell (mRNA or microRNA), or a heterologous nucleic acid (e.g., nucleic acid from a pathogen, such as a viral gene). Delivery of a nucleic acid means to transfer a nucleic acid from outside a subject to within the outer cell membrane of a cell in the subject.
- pharmaceutically acceptable refers to a material, (e.g., a carrier or diluent), which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic (i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained).
- phrases “pharmaceutically acceptable carrier, excipient, or diluent” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals.
- pharmaceutically acceptable means being approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopia, European Pharmacopia or other generally recognized pharmacopia for use in mammals, e.g., humans.
- the term “pharmaceutically effective regimen” refers to a systematic plan for the administration of one or more therapeutic agents, which includes aspects such as type of therapeutic agent, therapeutic agent concentrations, intratumoral enhancer concentrations, amounts or levels based on the tumor type, location or size, timing, and repetition, and any changes therein made during the course of the drug administration, which when administered is effective in treating a tumor and/or its metastasis. Such considerations depend on the judgment of the practitioner and are readily determinable by one skilled in the art.
- the term “proliferative disorder” refers to a disorder wherein the growth of a population of cells exceeds, and is uncoordinated with, that of the surrounding cells. In certain instances, a proliferative disorder leads to the formation of a tumor.
- the tumor is benign, pre-malignant, or malignant.
- the proliferative disorder is a pancreatic cancer. In some embodiments, the proliferative disorder is a pre-malignant growth on the pancreas.
- a “polypeptide” or “peptide” as used herein is understood as two or more independently selected natural or non-natural amino acids joined by a covalent bond (e.g., a peptide bond).
- a peptide can include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more natural or non-natural amino acids joined by peptide bonds.
- Polypeptides as described herein include full length proteins (e.g., fully processed proteins) as well as shorter amino acids sequences (e.g., fragments of naturally occurring proteins or synthetic polypeptide fragments).
- Ranges provided herein are understood to be shorthand for all of the values within the range.
- a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9.
- a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.
- reduces is meant a negative alteration of at least 10%, 25%, 50%, 75%, 100%, or any number therebetween.
- the term “regimen” refers to the various parameters that characterize how a drug or agent is administered, including, the dosage level, timing, and iterations, as well as the ratio of different drugs or agents to one another.
- pharmaceutically effective regimen refers to a particular regimen which provides a desired therapeutic result or effect, including substantial shrinkage and/or destruction of the tumor or cells that have metastasized therefrom.
- iterations refer to the general concept of repeating sets of administering one or more agents. For example, a combination of drug X and drug Y may be given (co-administered at or about at the same time and in any order) to a patient on a first day at dose Z.
- Drugs X and Y may then be administered (co-administered at or about at the same time and in any order) again at dose Z, or another dose, on a second day.
- the timing between the first and second days can be 1 day or anywhere up to several days, or a week, or several weeks, or months.
- the iterative administrations may also occur on the same day, separated by a specified number of minutes (e.g., 10 minutes, 20 minutes, 30 minutes or more) or hours (e.g., 1 hour, 2 hours, 4 hours, 6 hours, 12 hours).
- An effective dosing regimen may be determinable by those of ordinary skill in the art, e.g., prescribing physician, using standard practices.
- sample refers to a biological material that is isolated from its environment (e.g., blood or tissue from an animal, cells, or conditioned media from tissue culture).
- the sample is suspected of containing, or known to contain an analyte, such as an infectious agent or a protein of interest (e.g., antibody, cytokine, and the like).
- a sample can also be a partially purified fraction of a tissue or bodily fluid.
- a reference sample can be a “normal” sample, from a donor not having the disease or condition fluid, or from a normal tissue in a subject having the disease or condition, or an untreated subject (e.g., a subject not treated with the vaccine).
- a reference sample can also be taken at a “zero time point” prior to contacting the cell or subject with the agent or therapeutic intervention to be tested.
- the term “selectively” means tending to occur at a higher frequency in one population than in another population.
- Solid tumor refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancerous), or malignant (cancerous). Generally, a solid tumor connotes cancer of body tissues other than blood, bone marrow, or the lymphatic system.
- telomere binding By “specifically binds” is meant recognition and binding to a target (e.g., polypeptide, cell, and the like), but which does not substantially recognize and bind other molecules in a sample, for example, a biological sample.
- a target e.g., polypeptide, cell, and the like
- subject refers to any organism that is capable of developing a solid tumor.
- organisms include, but are not limited to, human, dog, cat, horse, cow, sheep, goat, mouse, rat, guinea pig, monkey, avian, reptiles etc.
- the term “substantially shrink or destroy” refers to where the size and/or mass of the tumor has been decreased or altogether eradicated or killed.
- the tumor may shrink by at least about 10%, or about 25%, or about 50%, or about 75%, or about 85%, or about 90%, or about by 95%, or by 99%, or more, or any number therebetween.
- the shrinkage is such that an inoperable tumor is sufficient to permit resection if desired.
- the concept of substantial shrinkage may also be referred to as “regression,” which refers to a diminution of a bodily growth, such as a tumor.
- Such a diminution may be determined by a reduction in measured parameters such as, but not limited to, diameter, mass (i.e., weight), or volume. This diminution by no means indicates that the size is completely reduced, only that a measured parameter is quantitatively less than a previous determination.
- substantially destroy a tumor
- this term may refer to either the substantial eradication of actual tumor cells or it may refer to substantially killing the tumor cells but where the cells are not removed or eradicated but remain in the body as dead cells and/or tissue.
- substantial eradication the concept refers to the complete cellular breakdown of a bodily growth, such as, for example, a solid tumor. Such destruction may involve intracellular apoptosis and/or macrophage phagocytosis such that the bodily growth is completely digested and eliminated from the body.
- a subject “suffering from or suspected of suffering from” a specific disease, condition, or syndrome has a sufficient number of risk factors or presents with a sufficient number or combination of signs or symptoms of the disease, condition, or syndrome such that a competent individual would diagnose or suspect that the subject was suffering from the disease, condition, or syndrome.
- Methods for identification of subjects suffering from or suspected of suffering from cancer is within the ability of those in the art.
- Subjects suffering from, and suspected of suffering from, a specific disease, condition, or syndrome are not necessarily two distinct groups.
- “susceptible to” or “prone to” or “predisposed to” a specific disease or condition and the like refers to an individual who based on genetic, environmental, health, and/or other risk factors is more likely to develop a disease or condition than the general population.
- An increase in likelihood of developing a disease may be an increase of about 10%, 20%, 50%, 100%, 150%, 200%, or more.
- targeting moiety is a moiety that is capable of enhancing the ability of a therapeutic agent, or other agent of the invention (e.g., an intracellular penetration enhancing agent or immunotherapeutic agent) to be targeted to, to bind with, or to enter, a target cell of the invention (e.g., a cancer tumor cell).
- targeting moieties are polypeptides, carbohydrates or lipids.
- targeting moieties are antibodies, antibody fragments or nobodies.
- targeting moieties include tumor targeting moieties, such as somatostatin (sst2), bombesin/GRP, luteinizing hormone-releasing hormone (LHRH), neuropeptide Y (NPY/Y1), neurotensin (NT1), vasoactive intestinal polypeptide (VIP/VPAC1) and cholecystokinin (CCK/CCK2).
- a targeting moiety is non-covalently associated with an agent of the invention.
- treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
- the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
- “To treat a cancer or a tumor” or “Treating a cancer or a tumor” in a mammal means one or more of alleviating a symptom of, correcting an underlying molecular or physiological disorder of, or reducing the frequency or severity of a pathological or deleterious physiological consequence of a cancer or a tumor in a subject.
- the deleterious physiological consequences of a cancer or a tumor can include uncontrolled proliferation, metastasis and invasion of other tissues, and suppression of an immune response.
- treatment of a tumor includes, but is not limited to, inhibiting tumor growth, inhibiting tumor cell proliferation, reducing tumor volume, or inhibiting the spread of tumor cells to other parts of the body (metastasis).
- ⁇ -gal epitopes refers to any molecule, or part of a molecule, with a terminal structure comprising Gal ⁇ 1-3Gal ⁇ 1-4G1cNAc-R, Gal ⁇ 1-3Gal ⁇ 1-3G1cNAc-R, or any carbohydrate chain with terminal Gal ⁇ 1-3Gal at the non-reducing end.
- glycolipids refers to any molecule with at least one carbohydrate chain linked to a ceramide, a fatty acid chain, or any other lipid.
- a glycolipid maybe referred to as a glycosphingolipid.
- ⁇ 1,3galactosyltransferase refers to any enzyme capable of synthesizing ⁇ -gal epitopes.
- anti-Gal binding epitope refers to any molecule or part of molecule that is capable of binding in vivo the natural anti-Gal antibody.
- ⁇ -ManCer refers to a ⁇ -mannosylceramide containing a sphingosine moiety and a fatty acid moiety having a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 49 carbon atoms, from about 18 to about 49 carbon atoms, from about 8 to about 15 carbon atoms, or from about 18 to about 30 carbon atoms.
- ⁇ -ManCer has the following structure:
- sphingosine as used herein means 2-amino-4-octadecene-1 ,3-diol, which is an 18-carbon amino alcohol with a hydrocarbon chain that forms a primary portion of ceramide molecules.
- ceramide as used herein, means one of a number of a class of sphingolipids, N-acyl derivatives with long chains of saturated or unsaturated fatty acids.
- the fatty acid moiety of ceramides can have carbon chain lengths from at least about eight carbons.
- the fatty acid moiety of ⁇ -ManCer can have anywhere from at least about eight carbons in length. For example, it can have a fatty acid moiety of between about 8 carbons to about 49 carbons in length, or for example, it can have a fatty acid moiety of between about 8 carbons to about 15 carbons in length.
- the ⁇ -ManCer can have a fatty acid moiety of between about 16 carbons and about 30 carbons in length.
- the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.
- Any therapeutic agents, compositions, or methods provided herein can be combined with one or more of any of the other therapeutic agents, compositions, and methods provided herein.
- FIG. 1 provides photos of bioluminescent images of s.c.i.d. mice with pancreatic BxPc-3 luciferase treated tumors.
- FIG. 2 is a photo of excised BxPC tumor tissue showing penetration by 50 microliters of enhancer with dye. 50 microliters of enhancer India ink solution was distributed in 2 minutes using a programmable syringe into a BxPc s.c.i.d. mouse tumor of approximately 500 mm 3 .
- FIG. 3 is a photo of excised BxPC tumor tissue with penetration by 100 microliters of enhancer with dye. 100 microliters of the enhancer India ink solution was distributed in 2 minutes using a programmable syringe pump into a BxPc-3 s.c.i.d. mouse tumor of approximately 500mm 3 .
- FIG. 4 is a graph showing the bioluminescence (BLI) readings for dosing groups in Example 8 from baseline to 72 hrs.
- FIG. 5 is a graph showing the relative change in bioluminescence (BLI) from baseline to 72 hours.
- FIG. 6 is a graph showing the bioluminescence (BLI) values from baseline to day 10 from Example10.
- FIG. 7 is a graph showing the relative bioluminescence (BLI) values from baseline to day 10 from Example 10.
- FIG. 8 is a graph showing the body weights changes from baseline to day 10 from Example 10
- FIG. 9 is a graph showing progression of tumor volume for 120 animals that were matched by tumor volume and placed into 12 groups with an initial, predose mean tumor volume per animal per group ranging from 341 mm 3 to 349 mm 3 .
- the line representing each group is referenced in the legend.
- FIG. 10 is a Kaplan-Meier plot showing the ability of exemplary intracellular formulations of the invention to extend animal life.
- FIGS. 11A-11C are plots depicting results of an exemplary study in which mice whose tumors regressed to less than 18 mm 3 were reinoculated with 1 ⁇ 10 6 CT26 mouse colon cancer cells.
- FIG. 11A shows progression of tumor growth over time for individual na ⁇ ve animals.
- FIG. 11B shows progression of tumor growth over time for individual, complete response, and IT-dosed animals only.
- FIG. 11C depicts mean tumor growth over time for an age matched control, a complete response animal dosed IT, and a complete response animal IT no outlier.
- the present invention provides new regional approaches to treating cancer.
- the invention is based, at least in part, on the discovery that traditional cancer therapeutic agents are surprisingly more effective when locally or regionally administered in combination with an intracellular penetration enhancing agent.
- the invention is also based on the discovery that administration of at least one immunotherapeutic agent further enhances the anti-cancer effects of the therapeutic agent and the intracellular penetration enhancing agent (e.g., reduced tumor growth and/or reduced tumor size).
- Additional methods for regional treatment of tumors include targeted delivery of chemotherapeutics to a cancerous region, without exposure to the rest of the body. See Collins, J. M., J. Clin. Oncol. 2:498-504 (1984); Markman, M., Semin. Oncolo. 12:38-42 (1985); and U.S. Patent Publication No. 2007/0196277; U.S. Pat. No. 4,619,913 October 1986; Jia, Y: Int J Nanomedicine. 2012;7:1697-708, Kim JI: Biomaterials. 2012 June; 33(19):4836-42; Hamstra, D A: J Neurooncol.
- novel regional cancer therapeutic and dosing methodology has been discovered that overcomes the limitations associated with current treatment methods.
- the novel therapeutic methods involve locally or regionally coadministering a therapeutic agent and an intracellular penetration enhancing agent to a subject, thereby achieving high concentrations of the therapeutic agent in the tumor cells.
- the delivery methods of the present invention minimize exposure of the rest of the body to the cytotoxic therapeutic agent.
- the novel therapeutic methods also involve administration of an immunotherapy agent.
- the immunotherapy agent which is administered before, during, or after delivery of the therapeutic and intracellular penetration enhancing agents, stimulates the immune system and enhances the anti-cancer effects of the therapeutic agent and the intracellular penetration enhancing agent.
- the invention provides methods for inducing an immune response in a subject.
- the methods involve administering an effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
- the subject has a tumor.
- the therapeutic agent and/or the intracellular permeation enhancing agent is locally or regionally administered to the subject.
- the invention provides methods for modulating an immune response in a subject.
- the methods involve administering an effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
- the subject has a tumor.
- the therapeutic agent and/or the intracellular permeation enhancing agent is locally or regionally administered to the subject.
- the invention provides methods treating a tumor in a subject.
- the methods involve locally or regionally coadministering to the subject a therapeutic agent and an intracellular permeation enhancing agent.
- the tumor can be a solid tumor. In yet other embodiments, the tumor has metastasized. In embodiments, the tumor is a carcinoma or sarcoma. In related embodiments, the tumor is a carcinoma or sarcoma of the skin, bone, muscle, breast, oral cavity, organ, kidney, liver, lung, gallbladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testes, ovaries, or uterus. In certain embodiments, the tumor is a carcinoma of the pancreas or colon.
- the therapeutic agent and/or the intracellular permeation enhancing agent can be administered intratumorally.
- the method can reduce the growth of the tumor, shrinks the tumor, or eradicates the tumor.
- the tumor shrinks by 5%, 10%, 25%, 50%, 75%, 85%, 90%, 95%, or 99% or more as compared to its original size.
- the methods can involve administering the therapeutic agent and/or the intracellular permeation enhancing agent on a first day and repeating the administration on one or more subsequent days.
- the therapeutic agent and the intracellular permeation enhancing agent are coadministered on the first day and administered again on one or more subsequent days.
- the first day and one or more subsequent days are separated by between 1 day and about 3 weeks.
- the therapeutic agent and the intracellular permeation enhancing agent are coadministered in a ratio of about 1:2, 1:4, 1:10, 1:20, 1:25, 1:50, 1:100, 1:200, or any ratio therebetween (weight ratio of therapeutic agent: intracellular permeation enhancing agent). It is further contemplated within the scope of the invention that the therapeutic agent and/or the intracellular permeation enhancing agent may be administered over the course of one or more cycles.
- the therapeutic agent and the intracellular permeation enhancing agent can be delivered simultaneously. In any of the above aspects or embodiments, the intracellular permeation enhancing agent can be administered before the therapeutic agent.
- the therapeutic agent is any anti-cancer therapeutic well known in the art. See, e.g., Anticancer Drugs: Design, Delivery and Pharmacology (Cancer Etiology, Diagnosis and Treatments) (eds. Spencer, P. & Holt, W.) (Nova Science Publishers, 2011); Clinical Guide to Antineoplastic Therapy: A Chemotherapy Handbook (ed. Gullatte) (Oncology Nursing Society, 2007); Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (eds. Polovich, M. et al.) (Oncology Nursing Society, 2009); Physicians' Cancer Chemotherapy Drug Manual 2012 (eds. Chu, E.
- the therapeutic agent is an anticancer agent.
- the anticancer can be any anticancer agent well known in the art, including, but not limited to, the chemotherapeutic agents described herein.
- the therapeutic agent is a therapeutic antibody.
- the therapeutic antibody can be any therapeutic antibody well known in the art, including, but not limited to, those described herein.
- the therapeutic agent is a therapeutic nucleic acid molecule.
- the therapeutic nucleic acid molecule can be any therapeutic nucleic acid molecule well known in the art.
- the therapeutic agent is a radioisotope.
- the radioisotope can be any radioisotope well known in the art.
- the therapeutic agent is a thymidylate synthase inhibitor.
- the therapeutic agent is a platinum compound.
- the therapeutic agent is a vinca drug.
- the therapeutic agent is a combination of two or more drug compounds.
- the methods involve administering a therapeutically effective amount of an immunotherapeutic agent.
- the immunotherapeutic agent may be any suitable means by which to trigger a further immune response that targets destruction of the cells of the tumor. Such targeting by the immune system may also allow the immune system to target tumor cells that have metastasized to other regions of the body.
- the immunotherapeutic agent enhances the immunomodulatory effects of the therapeutic agent and/or the intracellular permeation enhancing agent. In related embodiments, the immunotherapeutic agent further reduces the growth of the tumor or further shrinks the tumor.
- the immunotherapeutic agent can be administered before, during, or after the therapeutic agent and intracellular penetration enhancing agent have been administered. In embodiments, the immunotherapeutic agent is administered before the first administration of the therapeutic agent and the intracellular permeation enhancing agent. In embodiments, the immunotherapeutic agent is administered simultaneously with the first administration of the therapeutic agent and the intracellular permeation enhancing agent.
- the therapeutic agent and the immunotherapeutic agent can be administered in a ratio of about 1:2, 1:4, 1:10, 1:25, 1:50, 1:100, 1:200, or any ratio therebetween (weight ratio of therapeutic agent: immunotherapeutic agent).
- the intracellular permeation enhancing agent and the immunotherapeutic agent can be administered in a ratio of about 1:2, 1:4, 1:10, 1:20, 1:25, 1:50, 1:100, 1:100, or any ratio therebetween (weight ratio of intracellular permeation enhancing agent: immunotherapeutic agent).
- the immunotherapeutic agent can be administered intraperitoneally; locally or regionally; systemically (e.g. intravenously); or intratumorally.
- the therapeutic agent and the intracellular permeation enhancing agent can be coupled.
- the method can involve further administering a standard of care therapy to the subject.
- a standard of care therapy is surgery, radiation, systemic chemotherapy, or a combination thereof.
- administration of the therapeutic agent, the intracellular permeation enhancing agent, or the immunotherapeutic agent can be conducted with the aid of an imaging system.
- an imaging system may be used to calculate the volume of a given tumor so that a tumor volume-based dose of the agents of the invention may be calculated.
- an imaging system may be used to guide a needle to a specific site of injection within the tumor.
- the imaging system can be any imaging system well known in the art (see, e.g., The MD Anderson Manual of Medical Oncology (eds. Kantarjian, H. M.
- the imaging system is X-ray computed tomography (CT), fluoroscopy, magnetic resonance imaging (MRI), ultrasound, or positron emission tomography (PET)/computed tomography (CT).
- Suitable therapeutic agents include, but are not limited to, pharmaceutical drugs or compounds (i.e., small molecule drugs), therapeutic antibodies, therapeutic proteins or biologics (e.g., hormone therapies), and nucleic acid molecules (e.g., siRNAs).
- the therapeutic agent is an agent that has been shown to have cytotoxic properties against tumor cells.
- the therapeutic agent is an existing market-approved pharmaceutical drug or other market-approved composition for treating cancer using a conventional approach.
- chemotherapeutic agent includes chemical reagents that inhibit the growth of proliferating cells or tissues wherein the growth of such cells or tissues is undesirable.
- Chemotherapeutic agents are well known in the art, and any such agent is suitable for use in the present invention. See, e.g., Anticancer Drugs: Design, Delivery and Pharmacology (Cancer Etiology, Diagnosis and Treatments) (eds. Spencer, P. & Holt, W.) (Nova Science Publishers, 2011); Clinical Guide to Antineoplastic Therapy: A Chemotherapy Handbook (ed. Gullatte) (Oncology Nursing Society, 2007); Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (eds. Polovich, M.
- the pharmaceutical drug can be an alkylating agent.
- Alkylating agents directly damage DNA to prevent the cancer cell from reproducing. As a class of drugs, these agents are not phase-specific; in other words, they work in all phases of the cell cycle. Alkylating agents are used to treat many different cancers, including, but not limited to, leukemia, lymphoma, Hodgkin disease, multiple myeloma, sarcoma, as well as cancers of the lung, breast, and ovary.
- alkylating agents include, for example, nitrogen mustards (e.g., mechlorethamine, chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan), alkyl sulfonates (e.g., busulfan), triazines (e.g., dacarbazine (DTIC), temozolomide (Temodar), Nitrosoureas (including streptozocin, carmustine (BCNU), and lomustine), and ethylenimines (e.g., thiotepa and altretamine).
- nitrogen mustards e.g., mechlorethamine, chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan
- alkyl sulfonates e.g., busulfan
- triazines e.g., dacarbazine
- the invention contemplates any antimetabolite drug.
- Antimetabolites are a class of drugs that interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA. These agents damage cells during the S phase. They are commonly used to treat leukemias, cancers of the breast, ovary, and the intestinal tract, as well as other types of cancer.
- antimetabolites including, for example, 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), Capecitabine (Xeloda®), Cladribine, Clofarabine, Cytarabine (Ara-C®), Floxuridine, Fludarabine, Gemcitabine (Gemzar®), Hydroxyurea, Methotrexate, Pemetrexed (Alimta®), Pentostatin, and Thioguanine.
- 5-fluorouracil 6-mercaptopurine
- 6-MP Capecitabine
- Capecitabine Xeloda®
- Cladribine Clofarabine
- Cytarabine Cytarabine
- Gemcitabine Gemcitabine
- Hydroxyurea Methotrexate
- Pemetrexed Pemetrexed
- Pentostatin Pentostatin
- Thioguanine Thioguanine
- the invention also contemplates the use of an anti-tumor antibiotic, such as anthracyclines.
- Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in DNA replication. These drugs work in all phases of the cell cycle. They are widely used for a variety of cancers. A major consideration when giving these drugs is that they can permanently damage the heart if given in high doses. For this reason, lifetime dose limits are often placed on these drugs. Examples include Daunorubicin, Doxorubicin
- Anti-tumor antibiotics include, for example, Actinomycin-D, Bleomycin, and Mitomycin-C.
- topoisomerase inhibitors are also contemplated. These drugs interfere with enzymes called topoisomerases, which help separate the strands of DNA so they can be copied. They are used to treat certain leukemias, as well as lung, ovarian, gastrointestinal, and other cancers. Examples of topoisomerase I inhibitors include topotecan and irinotecan (CPT-11). Examples of topoisomerase II inhibitors include etoposide (VP-16) and teniposide. Mitoxantrone also inhibits topoisomerase II. Treatment with topoisomerase II inhibitors increases the risk of a second cancer—acute myelogenous leukemia (AML). With this type of drug, a secondary leukemia can be seen as early as 2 to 3 years after the drug is given.
- AML acute myelogenous leukemia
- the present invention also contemplates using therapeutic agents known as mitotic inhibitors.
- Mitotic inhibitors are often plant alkaloids and other compounds derived from natural products. They can stop mitosis or inhibit enzymes from making proteins needed for cell reproduction. These drugs work during the M phase of the cell cycle, but can damage cells in all phases. They are used to treat many different types of cancer including breast, lung, myelomas, lymphomas, and leukemias. These drugs are known for their potential to cause peripheral nerve damage, which can be a dose-limiting side effect.
- mitotic inhibitors examples include Taxanes (e.g., paclitaxel (Taxo®) and docetaxel (Taxotere®)), Epothilones (e.g., ixabepilone (Ixempra®)), Vinca alkaloids (e.g., vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®), and Estramustine (Emcyt®).
- Taxanes e.g., paclitaxel (Taxo®) and docetaxel (Taxotere®)
- Epothilones e.g., ixabepilone (Ixempra®
- Vinca alkaloids e.g., vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®)
- Estramustine Emcyt®
- the anti-cancer agents may also be corticosteroids.
- Steroids are natural hormones and hormone-like drugs that are useful in treating some types of cancer (lymphoma, leukemias, and multiple myeloma), as well as other illnesses. When these drugs are used to kill cancer cells or slow their growth, they are considered chemotherapy drugs.
- Corticosteroids are also commonly used as anti-emetics to help prevent nausea and vomiting caused by chemotherapy. They are used before chemotherapy to help prevent severe allergic reactions (hypersensitivity reactions), too. Examples include prednisone, methylprednisolone (e.g., Solumedrol®), and dexamethasone (e.g., Decadron®).
- the pharmaceutical agent is selected from the group consisting of: Abiraterone Acetate, Afatinib, Aldesleukin, Alemtuzumab, Alitretinoin, Altretamine, Amifostine, Aminoglutethimide Anagrelide, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, Azathioprine, Bendamustine, Bevacizumab, Bexarotine, Bicalutamide, Bleomycin, Bortezomib, Busulfan, Capecitabine, Carboplatin, Carmustine, Cetuximab, Chlorambucil, Cisplatin, Cladribine, Crizotinib, Cyclophosphamide, Cytarabine, dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, Denileukin diftitox, Decitabine, Docetaxel, Dexamethas
- the invention also contemplates any derivative form of the aforementioned pharmaceutical agents and therapeutic agents.
- Common derivatizations may include, for example, adding a chemical moiety to improve solubility and/or stability, or a targeting moiety, which allows more specific targeting of the molecule to a specific cell or region of the body.
- the pharmaceutical agents may also be formulated in any suitable combinations, wherein the drugs may either mixed in individual form or coupled together in a manner that retains the functionality of each drug.
- the drugs may also be derivatized to include a radioisotope or other cell-killing moiety to make the molecule even more effective at killing the cell.
- the drugs, or a portion thereof may be modified with fluorescence compound or other detectable labels which may allow tracking of the drug or agent in the body or within the tumor.
- the pharmaceutical drug or otherwise any of the aforementioned therapeutic agents may be provided in a precursor form such that they the drug only gains its activity or function after it has been processed in some manner, e.g., metabolized by a cell.
- Therapeutic antibodies contemplated by the present invention may include any isotype (IgA, IgG, IgE, IgM, or IgD) of an anti-cancer antibody or immune-active fragment or derivative thereof.
- Such fragments can include, for example, single-chain variable fragments (scFv), antigen-binding fragment (Fab), crystallizable fragment (Fc) modified to contain an antigen or epitope binding region, and domain antibodies.
- scFv single-chain variable fragments
- Fab antigen-binding fragment
- Fc crystallizable fragment
- Derivatized versions of therapeutic antibodies may include, for example, diabodies, nanobodies, and virtually any antibody-derived structure which contains or is engineered to contain an appropriate and effective antigen binding site.
- antibody-based anticancer therapies can include, for example, Abagovomab, Alacizumab pegol, Alemtuzumab, Altumomab pentetate (Hybri-ceaker), Amatuximab, Anatumomab mafenatox, anti-PD-1 antibodies, Apolizumab, Arcitumomab (CEA-Scan), Belimumab, Bevacizumab, Bivatuzumab mertansine, Blinatumomab, Brentuximab vedotin, Cantuzumab mertansine, Cantuzumab ravtansine, Capromab pendetide (Prostascint), Catumaxomab (Removab), Cetuximab (Erbitux), Citatuzumab communicatingox, Cixutumumab, Clivatuzumab tetraxet
- suitable biologics e.g., hormone therapy
- suitable biologics include hormone therapy.
- Drugs in this category can be sex hormones, or hormone-like drugs, that change the action or production of female or male hormones. They can be used to slow the growth of breast, prostate, and endometrial (uterine) cancers, which normally grow in response to natural hormones in the body.
- These cancer treatment hormones do not work in the same ways as standard chemotherapy drugs, but rather by preventing the cancer cell from using a hormone it requires for grow, or by preventing the body from making the hormones required for growth of the cancer.
- Such hormone therapies can include, for example, anti-estrogens (e.g., fulvestrant (Faslodex®), tamoxifen, and toremifene (Fareston®), Aromatase inhibitors (e.g., anastrozole (Arimidex), exemestane (Aromasin®), and letrozole (Femara®)), Progestins (e.g., megestrol acetate (Megace®)), Estrogens, Anti-androgens (e.g., bicalutamide (Casodex®), flutamide (Eulexin®), and nilutamde (Nilandron®)), and Gonadotropin-releasing hormone (GnRH) (aka luteinizing hormone-releasing hormone (LHRH) agonists or analogs, e.g., leuprolide (Lupron®) and goserelin (Zoladex®)).
- the invention also contemplates that cancer treatment may be effectuated using a nucleic acid molecule that targets a specified “target gene” that has a role in cancer.
- the effect of the nucleic acid molecule on the target gene may include gene silencing, mRNA destruction, or inhibited transcription, or the like, such that the level of expression and/or conversion of the target gene to an operable encoded polypeptide are substantially affected (up or down) such that the cancer is inhibited and/or destroyed by the agent.
- target gene refers to nucleic acid sequences (e.g., genomic DNAs or mRNAs) encoding a target protein, peptide, or polypeptide, or that encode for or are regulatory nucleic acids (e.g., a “target gene” for purpose of the instant invention can also be a miRNA or miRNA-encoding gene sequence) which have a role in cancer.
- a target gene for purpose of the instant invention can also be a miRNA or miRNA-encoding gene sequence
- target gene is also meant to include isoforms, mutants, polymorphisms, and splice variants of target genes.
- nucleic acid based agent any nucleic acid based agent well known in the art is suitable for use in the invention.
- exemplary types of nucleic acid based agents include, but are not limited to, single stranded ribonucleic acid agents (e.g., microRNAs), antisense-type oligonucleotide agents, double-stranded ribonucleic acid agents, and the like.
- interfering RNA can be assembled from two separate oligonucleotides, where one strand is the sense strand and the other is the antisense strand, wherein the antisense and sense strands are self-complementary (i.e., each strand comprises nucleotide sequence that is complementary to nucleotide sequence in the other strand; such as where the antisense strand and sense strand form a duplex or double stranded structure); the antisense strand comprises nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense strand comprises nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof.
- interfering RNA is assembled from a single oligonucleotide, where the self-complementary sense and antisense regions are linked by means of nucleic acid based or non-nucleic acid-based linker(s).
- the interfering RNA can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises a nucleotide sequence that is complementary to nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof.
- the interfering can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active siRNA molecule capable of mediating RNA interference.
- therapeutic nucleic acid molecules may be delivered in a delivery vehicle, such as a lipid vesicle or other polymer carrier material known in the art.
- a delivery vehicle such as a lipid vesicle or other polymer carrier material known in the art.
- additional lipid-based carrier systems which may be prepared with at least one modified cationic lipid of the invention
- suitable for use in the present invention include lipoplexes (see, e.g.,U.S. Patent Publication No. 20030203865; and Zhang et al., I Control Release, 100:165-180 (2004)), pH-sensitive lipoplexes (see, e.g., U.S. Patent Publication No.
- liposomes containing lipids derivatized with releasable hydrophilic polymers see, e.g., U.S. Patent Publication No. 2003/0031704
- lipid-entrapped nucleic acid see, e.g., PCT Publication Nos. WO 03/057190 and WO 03/059322
- lipid-encapsulated nucleic acid see, e.g., U.S. Patent Publication No. 2003/0129221; and U.S. Pat. No. 5,756,122
- other liposomal compositions see, e.g., U.S. Patent Publication Nos. 2003/0035829 and 2003/0072794; and U.S.
- any of the agents of the invention including pharmaceutical drugs, biologics, and therapeutic antibodies, may also be delivered via the above described carrier systems. All carrier systems may further be modified with a targeting moiety or the like in order to facilitate delivery of the composition to a target tumor of interest.
- the present invention utilizes platinum compounds as the therapeutic agent.
- Platinum containing compound have been used for several years as an effective treatment of several types of cancers.
- Platinum based compounds e.g., carboplatin, cisplatin, oxaliplatin
- IV intravenously
- Intravenous administration is generally used because the oral bioavailability of carboplatin alone is low (approximately 4%) and highly variable.
- Platinum based products potently kill fast dividing cells.
- administration of carboplatin by intravenous infusion results in drug throughout the body, killing healthy fast dividing cells including and especially bone marrow cells.
- Intravenous administration of carboplatin results in a dilute blood concentration of the drug reaching the tumor site. In addition, because of the dilute drug concentration there is poor penetration into the tumor cells.
- Carboplatin is a crystalline powder with the molecular formula of C 6 H 12 N 2 O 4 Pt and a molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5-7, whereas Cisplatin is soluble at approximately 1-2 mg/ML. These compounds are virtually insoluble in ethanol, acetone, and dimethylacetamide. They are currently administered only by intravenous infusion.
- the present invention employs thymidalate synthesis inhibitors.
- These agents include the agent 5-FU (fluorouracil), which has been in use against cancer for about 40 years.
- the compound acts in several ways, but principally as a thymidylate synthase inhibitor, interrupting the action of an enzyme which is a critical factor in the synthesis of the pyrimidine thymine-which is important in DNA replication.
- 5-FU fluorouracil
- 5-FU is not orally absorbed.
- Gemcitabine Gemcitabine
- these compounds are transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA and RNA, finally inducing cell cycle arrest and apoptosis by inhibiting the cell's ability to synthesize DNA.
- These compounds are typically S-phase specific drug and only active during certain cell cycles.
- these drugs have been shown to inhibit the activity of the exosome complex, an exoribonuclease complex of which the activity is essential for cell survival.
- the present invention is based, in part, on penetration agents, such as benzoate linked aliphatic acids, functionalized keto acids (e.g. oxo-6-phenylhexanoic acid), keto esters, modified acylated amino acids (e.g., sodium N-[8-2-(2-hyrodxybenzoyl) amino caprylate), to substantially enhance drug permeability or penetration into cancer cells to surprisingly increase and unexpectedly improve cancer cell killing.
- penetration agents such as benzoate linked aliphatic acids, functionalized keto acids (e.g. oxo-6-phenylhexanoic acid), keto esters, modified acylated amino acids (e.g., sodium N-[8-2-(2-hyrodxybenzoyl) amino caprylate), to substantially enhance drug permeability or penetration into cancer cells to surprisingly increase and unexpectedly improve cancer cell killing.
- penetration agents such as benzoate linked aliphatic acids, functionalized keto acids (e.g. oxo-6-phen
- the invention contemplates any suitable intracellular penetration enhancing agent, known or yet to be discovered or developed.
- a number of drug delivery companies have developed such compounds to increase cell penetration for purposes of delivery charged or macromolecule compounds to the blood stream by non inj ection methods.
- Such companies include Emisphere Technologies, Acrux Pharma Pty, Ltd., Oramed Pharmaceuticals, Apollo Life Sciences, Diabetology, and Unigene.
- these platforms were developed to achieve systemic delivery of therapeutics via conventional routes, such as, oral, buccal, pulmonary or dermal; however, none contemplated the present usage of such penetration enhancing agents in the manner described in conjunction with the present invention.
- the present invention is based on combining the delivery of an anticancer therapeutic with an intracellular penetration enhancing agent administered locally using advanced imaging techniques to set the dose and guide the administration prior to or at or at about the same time as the therapeutic agent to substantially enhance cellular membrane penetration of the locally-delivered anti-cancer agents.
- the method described herein involves a “penetration enhancer” or carrier that imparts improved cell transport.
- penetration enhancer or carrier that imparts improved cell transport.
- These molecules facilitate or enable the penetration and/or transport of therapeutic molecules across biological membranes into cells.
- This specific use for such penetration compounds such as those described in Emisphere Technologies' U.S. Pat. No. 5,650,386 (which is incorporated by reference in its entirety), has not previously been contemplated.
- the combination of permeation enhancers capable of facilitating intracellular transport of locally delivered anticancer agents was not previously considered or contemplated in the art.
- the present invention comprises 6-oxo-6-phenyl hexanoic acid as the intracellular penetration enhancing compound or a salt or analog thereof,
- a method for treating cancer e.g., a solid tumor
- a method for treating cancer comprising locally coadministering the above compound and an anticancer therapeutic agent in therapeutically effective amounts and in accordance with a regimen that is effective to cause substantial shrinkage of the tumor and/or destruction of the tumor.
- the intracellular penetration enhancing agent is modified amino acids, N48-(2-hydroxybenzoyl)aminooctanoic acid,
- the intracellular penetration enhancing compound is selected from any one of the compounds described in U.S. Pat. Nos. 4,764,381; 4,783,450; 4,885,174; 4,983,396; 5,045,553; 5,118,845; 5,219,877; 5,401,516; 5,451,410; 5,540,939; 5,443,841; 5,541,155; 5,578,323; 5,601,839; 5,601,846; 5,627,270; 5,629,020; 5,643,957; 5,650,386; 5,693,338; 5,693,769; 5,709,861; 5,714,167; 5,773,647; 5,766,633; 5,776,888; 5,792,451; 5,804,688; 5,863,944; 5,866,536; 5,876,710; 5,879,681; 5,820,881; 5,834,010; 5,840,340; 5,935,601; 5,939,381; 5,95
- Intracellular penetration enhancers in general have little to no known pharmacological activity themselves. These technologies, such as those described and shown above, make it possible to penetrate membranes to deliver a therapeutic agent without altering its chemical form or biological integrity. Such penetration enhancers have demonstrated significantly increased absorption of several different types of agents.
- the invention employs one or more immunotherapeutic agents to further enhance the tumor cell inhibitory and/or destructive effects imparted by the combination of the anticancer therapeutic agent with the intracellular penetration enhancing agent.
- the immunotherapeutic agent is delivered after the effects of the first two agents have set in, but the invention is not limited to this concept.
- the invention contemplates any administration regimen involving all three agents so long as the therapeutic benefits attributable to the each of the agents may occur. It is also contemplated within the scope of the invention that administration of the one or more immunotherapeutic agents have immunostimulatory activity that provides prophylaxis against further recurrence of a cancer. This immunostimulatory effect can be achieved when the agent is given intratumorally or intraperitoneally either with or without an intracellular penetration enhancer.
- an immunotherapeutic agent is a treatment that aims to use an individual's own immune system to fight cancer or disease. This may be accomplished by boosting the individual's own immune system or to provide supplemental pieces of an otherwise defective or deficient immune system.
- Immunotherapy is a form of biological therapy which can be used in the present invention supplement and/or enhance the effects of treating with the therapeutic agent/penetration enhancing treatment.
- immunotherapy There are generally two recognized forms of immunotherapy, which are referred to as active immunotherapies and passive immunotherapies.
- Active immunotherapies stimulate the body's own immune system to fight a disease.
- Passive immunotherapies use immune system components, such as antibodies, prepared outside the body, to enhance the body's immune response level.
- Immunotherapies may also work by targeting certain types of cells or antigens (specific immunotherapies) or they may work by more generally stimulating the immune system (non-specific immunotherapies, or sometimes referred to as adjuvants).
- immunotherapies contemplated by the invention include monoclonal antibody therapy (such as rituximab and alemtuzumab), non-specific immunotherapies and adjuvants (substances which boost the immune response such as interleukin-2 and interferon-alpha), immunomodulating drugs (such as thalidomide and lenalidomide), and cancer vaccines (e.g., NKT cell agonists, including but not limited to ⁇ -GalCer, ⁇ MannCer, or a-Gal glycolipids).
- monoclonal antibody therapy such as rituximab and alemtuzumab
- non-specific immunotherapies and adjuvants substances which boost the immune response such as interleukin-2 and interferon-alpha
- immunomodulating drugs such as thalidomide and lenalidomide
- cancer vaccines e.g., NKT cell agonists, including but not limited to ⁇ -GalCer, ⁇ MannCer, or
- immunotherapeutic agents which may also be referred to in same meaning as “immunomodulator” can include, for example, interleukins (e.g., IL-2, IL-7, or IL-12), certain other cytokines (e.g., interferons, growth colony stimulating factor (G-CSF), imiquimod), chemokines, and other types of agents, which can include antigens, epitopes, antibodies, monoclonal antibodies, or even a delivery vehicle to deliver one or more of these compounds, and may even also include recombinant immune system cells.
- Such immunotherapeutic agents can include recombinant forms, synthetic forms, and natural preparations (see D′Alessandro, N. et al., Cancer Therapy: Differentiation, Immunomodulation and Angiogenesis, New York: Springer-Verlag, 1993).
- the immunotherapeutic agent of the invention is a cancer vaccine that may include, for example, Ovalabumin, Neuvenge®, Oncophage, CimaVax-EGF, Mobilan, a-Gal glycolipids, adenovirus delivered vaccines, Celldex's CDX1307 and CDX1401; GRNVAC1, viral based vaccines, MVA-BN, PROSTVAC®, Advaxis'; ADXS11-001, ADXS31-001, ADXS31-164, BiovaxID, folate binding protein (E39), Granulocyte macrophage colony stimulating factor (GM-CSF) with and without E75 (NeuVax) or OncoVEX, trastuzumab, Ae-37, IMA901, SC1B1, Stimuvax, peptides that can elicit cytotoxic lymphocyte response, peptide vaccines including telomerase peptide vaccine (GV1001), survivin peptide, MUC1
- the immunotherapeutic agent takes advantage of the body's innate immune system and has the effect when introduced of triggering the innate immune response against the unwanted cancer or tumor.
- the present invention utilizes an immunotherapeutic agent that effectively converts the target tumor into a vaccine in situ (e.g., utilization of a NKT cell anti-tumor agent).
- this embodiment can involve generating autologous tumor-associated antigens (TAA) in treated patients.
- TAA tumor-associated antigens
- a-Gal glycolipids carry the carbohydrate ⁇ -gal epitope (Gal ⁇ 1-3 ⁇ 1-4G1cNac-R) which binds the most abundant naturally-occurring antibody in humans—the anti-Gal antibody.
- the anti-Gal antibody is present in high concentrations due to the continuous exposure to the ⁇ -Gal epitope due to its presence in bacteria.
- Human tissue does not contain natural ⁇ -Gal epitopes as that would cause an attack by the immune system on that tissue. Thus tumors are not vulnerable to attack by naturally occurring anti- ⁇ -Gal antibodies.
- the underlying inventive aspect is that ⁇ -Gal glycolipids injected as micelles insert into tumor cell membranes resulting in ⁇ -Gal epitope expression on tumor cells and thus the binding of the natural anti-Gal antibody. In this manner, the tumor itself becomes a vaccine in situ.
- the Ag-epitope/Gal Ab interaction activates complement and generates complement cleavage chemotactic factors that recruit antigen presenting cells (APC).
- APC antigen presenting cells
- the APC transport internalized TAA to regional lymph nodes, process and present the multiple TAA peptides for activation of tumor specific T cells.
- the T cells proliferate, leave the lymph nodes and circulate to seek and destroy the tumor and any micrometastases presenting the autologous TAA.
- the invention involves use of ⁇ -mannosylceramide ( ⁇ -ManCer) to treat patients.
- ⁇ -ManCer is an NKT agonist that promotes immunity against tumors and infectious agents through nitric oxide and TNF ⁇ dependent mechanisms.
- ⁇ -ManCer can also be used with ⁇ -GalCer to synergistically enhance the effects of ⁇ -GalCer.
- the ⁇ -ManCer can contain a sphingosine moiety and a fatty acid moiety having a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 49 carbon atoms, from about 18 to about 49 carbon atoms, from about 8 to about 15 carbon atoms, or from about 18 to about 30 carbon atoms.
- ⁇ -ManCer has the following structure:
- the present invention comprises locally co-administering an anticancer therapeutic agent and an intracellular penetration enhancing agent in therapeutically effective amounts and in accordance with a regimen that results in substantial shrinkage and/or destruction of a target tumor.
- the method of the invention further comprises enhancing the effects of the therapeutic agent and the intracellular penetration enhancing agent by administering an immunotherapeutic agent.
- the treatment results in substantial shrinkage and/or destruction of tumor cells, any micrometastases or metastasized cells that have relocated to other parts of the body.
- the immunotherapeutic agent is a cancer vaccine that causes the tumor to function as an in situ vaccine, e.g., introduction of the a-gal epitopes into the tumor.
- the immunotherapeutic agents of the invention may be achieved using any suitable approach, including by local or regional administration of the agent at, near, or within the tumor or micrometastases.
- the agent may also be delivered, where suitable, via gene therapy.
- the antibody-inducing antigen may be introduced by injecting or otherwise directly administering a genetic vector or otherwise nucleic acid molecule capable of expressing the desired antigen in the tumor.
- the antigens themselves may also be directly administered into the targettissue.
- the present invention contemplates treating a broad range of diseases, including tumors of all types, locations, sizes, and characteristics.
- the method of the invention is suitable for treating, for example, pancreatic cancer and colon cancer.
- cancers any type of cancer may be treatable by the present invention, including the following cancers:
- Bile duct cancer extrahepatic
- GIST Gastrointestinal stromal tumor
- Germ cell tumor extracranial, extragonadal, or ovarian
- Kidney cancer (renal cell cancer)
- Leukemia acute lymphoblastic (also called acute lymphocytic leukemia)
- Leukemia acute myeloid (also called acute myelogenous leukemia)
- Chronic lymphocytic also called chronic lymphocytic leukemia
- Chronic myelogenous also called chronic myeloid leukemia
- Non-Hodgkin an old classification of all lymphomas except Hodgkin's
- Lymphoma Primary Central Nervous System
- Ovarian epithelial cancer (Surface epithelial-stromal tumor)
- Renal cell carcinoma kidney cancer
- T-Cell lymphoma T-Cell lymphoma, cutaneous—see Mycosis Fungoides and Sézary syndrome
- cancers are classified by the type of cell that the tumor cell resembles and is therefore presumed to be the origin of the tumor. These types include:
- cancers are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ or tissue of origin as the root.
- cancers of the liver parenchyma arising from malignant epithelial cells is called hepatocarcinoma
- a malignancy arising from primitive liver precursor cells is called a hepatoblastoma
- a cancer arising from fat cells is called a liposarcoma.
- the English organ name is used.
- the most common type of breast cancer is called ductal carcinoma of the breast.
- the adjective ductal refers to the appearance of the cancer under the microscope, which suggests that it has originated in the milk ducts.
- Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root.
- a benign tumor of smooth muscle cells is called a leiomyoma (the common name of this frequently occurring benign tumor in the uterus is fibroid).
- a suffix the common name of this frequently occurring benign tumor in the uterus is fibroid.
- some types of cancer also use the -oma suffix, examples including melanoma and seminoma.
- Some types of cancer are named for the size and shape of the cells under a microscope, such as giant cell carcinoma, spindle cell carcinoma, and small cell carcinoma.
- the present invention generally can treat all forms of the above cancers.
- the method of the invention advantageously may treat solid tumors arising in any tissue of the body including, but not limited to, the skin, bone, muscle, breast, organ, kidney, liver, lung, gallbladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testes, ovaries, or uterus.
- the present invention generally also may treat all forms of the above cancers and where the cancer is at any stage.
- cancer severity is staged (I to IV) with survival prognosis in stage III and IV often being low for several cancer types.
- the present invention also may be effective against tumors that arise from metastasis of another source or primary tumor.
- the metastasized sites may be visible tumors, or may also be at the level of single cells, or micrometastases.
- the present invention is directed to a method for treating a pancreatic tumor or metastasized pancreatic tumor.
- the present invention is directed to a method for treating a colon tumor or metastasized colon tumor.
- Reduction of tumor growth means a measurable decrease in growth of the tumor of at least about 0.01-fold (for example 0.01, 0.1, 1, 3, 4, 5, 10, 100, 1000-fold or more) or decrease by at least about 0.01% (for example 0.01, 0.1, 1, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99 or 100%) as compared to the growth measured over time prior to treatment as defined herein.
- Full eradication of the tumor may also be achieved through methods of the invention. Eradication refers elimination of the tumor. The tumor is considered to be eliminated when it is no longer detectable using detection methods known in the art (e.g., imaging).
- the invention provides pharmaceutical compositions for use in any of the methods described herein.
- the pharmaceutical compositions contain a therapeutic agent, an intracellular permeation enhancing agent, and/or an immunotherapeutic agent.
- the pharmaceutical compositions include a pharmaceutically acceptable carrier.
- pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
- carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
- Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, olive oil, gel (e.g., hydrogel), and the like.
- Saline is a preferred carrier when the pharmaceutical composition is administered intravenously.
- Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers particularly for inj ectable solutions.
- Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.
- the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
- Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
- suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin, the contents of which are hereby incorporated by reference in its entirety.
- Such compositions will generally contain a therapeutically effective amount of the therapeutic agent, the intracellular permeation enhancing agent, and/or the immunotherapeutic agent, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
- the formulation should suit the mode of administration.
- the therapeutic agent, the intracellular permeation enhancing agent or their combination, and/or the immunotherapeutic agent are administered locally as an immediate release or controlled release composition, for example by controlled dissolution and/or the diffusion of the active substance.
- Dissolution or diffusion controlled release can be achieved by incorporating the active substance into an appropriate matrix.
- a controlled release matrix may include one or more of shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
- the matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
- the controlled release matrix is a hydrogel.
- a hydrogel is a three-dimensional, hydrophilic or amphiphilic polymeric network capable of taking up large quantities of water.
- the networks are composed of homopolymers or copolymers, which are insoluble due to the presence of covalent chemical or physical (e.g., ionic, hydrophobic interactions, entanglements) crosslinks.
- the crosslinks provide the network structure and physical integrity.
- Hydrogels exhibit a thermodynamic compatibility with water that allows them to swell in aqueous media.
- the chains of the network are connected in such a fashion that pores exist and that a substantial fraction of these pores are of dimensions between 1 nm and 1000nm.
- the hydrogels can be prepared by crosslinking hydrophilic biopolymers or synthetic polymers.
- hydrogels formed from physical or chemical crosslinking of hydrophilic biopolymers include but are not limited to, hyaluronans, chitosans, alginates, collagen, dextran, pectin, carrageenan, polylysine, gelatin, agarose, (meth)acrylate-oligolactide-PEO-oligolactide-(meth)acrylate, poly(ethylene glycol) (PEO), poly(propyleneglycol) (PPO), PEO-PPO-PEO copolymers (Pluronics), poly(phosphazene), poly(methacrylates), poly(N-vinylpyrrolidone), PL(G)A-PEO-PL(G)A copolymers, poly(ethylene imine), and the like.
- the amount of the pharmaceutical composition of the invention which will be effective in the treatment or prevention of a solid tumor may depend on the nature of the tumor and can be determined by standard clinical techniques, including imaging techniques.
- in vitro assays may optionally be employed to help identify optimal dosage ranges.
- the precise dose to be employed in the formulation may also depend on the route of administration, and the seriousness of the tumor, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
- the therapeutic agents, intracellular permeation enhancing agents, immunotherapeutic agents, or compositions containing these agents are administered in a manner compatible with the dosage formulation, and in such amount as may be therapeutically affective, protective andimmunogenic.
- the agents and/or compositions may be administered through different routes, including, but not limited to, oral, parenteral, buccal and sublingual, rectal, aerosol, nasal, intramuscular, subcutaneous, intradermal, and topical.
- parenteral as used herein includes, for example, intraocular, subcutaneous, intraperitoneal, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional, and intracranial inj ection, or other infusion techniques.
- administration of the therapeutic agents and/or the intracellular permeation enhancing agent is delivered locally or regionally (e.g., intratumorally).
- the agents and/or compositions formulated according to the present invention are formulated and delivered in a manner to evoke a systemic immune response.
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers.
- Formulations suitable for administration include aqueous and non-aqueous sterile solutions, which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, immediately prior to use.
- sterile liquid carrier for example, water
- Extemporaneous solutions and suspensions may be prepared from sterile powders, granules and tablets commonly used by one of ordinary skill in the art.
- agents and/or compositions may be administered in different forms, including, but not limited to, solutions, emulsions and suspensions, microspheres, particles, microparticles, nanoparticles, liposomes, and the like.
- the agents and/or compositions are administered in a manner compatible with the dosage formulation, and in such amount as may be therapeutically effective, immunogenic and protective.
- the quantity to be administered depends on the subject to be treated, including, for example, the size of the tumor, the stage of the disease, and the capacity of the individual's immune system to synthesize antibodies and/or to produce a cell-mediated immune response.
- Precise amounts of active ingredients required to be administered depend on the judgment of the practitioner. However, suitable dosage ranges are readily determinable by one skilled in the art and may be of the order of micrograms to milligrams of the active ingredient(s) per dose.
- the dosage may also depend on the route of administration and may vary according to the size of the host.
- the agents and/or compositions should be administered to a subject in an amount effective to stimulate a protective immune response in the subject.
- Specific dosage and treatment regimens for any particular subject may depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease (including tumor size), condition or symptoms, the subject's disposition to the disease, condition or symptoms, method of administration, and the judgment of the treating physician. Actual dosages can be readily determined by one of ordinary skill in the art.
- Exemplary unit dosage formulations are those containing a dose or unit, or an appropriate fraction thereof, of the administered ingredient. It should be understood that in addition to the ingredients mentioned herein, the formulations of the present invention may include other agents commonly used by one of ordinary skill in the art.
- a therapeutically effective dosage should produce a serum concentration of compound of from about 0.1 ng/ml to about 50-100 ⁇ g/ml.
- the pharmaceutical compositions typically provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day.
- dosages for systemic administration to a human patient can range from 1-10 ⁇ g/kg, 20-80 ⁇ g/kg, 5-50 ⁇ g/kg, 75-150 ⁇ g/kg, 100-500 ⁇ g/kg, 250-750 ⁇ g/kg, 500-1000 ⁇ g/kg, 1-10 mg/kg, 5-50 mg/kg, 25-75 mg/kg, 50-100 mg/kg, 100-250 mg/kg, 50-100 mg/kg, 250-500 mg/kg, 500-750 mg/kg, 750-1000 mg/kg, 1000-1500 mg/kg, 1500-2000 mg/kg, 5 mg/kg, 20 mg/kg, 50 mg/kg, 100 mg/kg, 500 mg/kg, 1000 mg/kg, 1500 mg/kg, or 2000 mg/kg.
- Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 5000 mg, for example from about 100 to about 2500 mg of the compound or a combination of essential ingredients per dosage unit form.
- a therapeutically effective amount of the present compounds in dosage form usually ranges from slightly less than about 0.025 mg/kg/day to about 2.5 g/kg/day, preferably about 0.1 mg/kg/day to about 100 mg/kg/day of the patient or considerably more, depending upon the compound used, the condition or infection treated and the route of administration, although exceptions to this dosage range may be contemplated by the present invention.
- intracellular permeation compounds according to the present invention may be administered intratumorally in amounts ranging from about 0.5 mg/ml of dosing solution to about 50 mg/ml.
- intracellular permeation compounds according to the present invention may be administered intratumorally in amounts ranging from about 10 mg/ml to about 30 mg/ml.
- the dosage of the intracellular permeation compound(s) may depend on the type of cancer being treated, the particular compound used, the therapeutic agent, and other clinical factors and conditions of the patient and the route of administration. It is to be understood that the present invention has application for both human and veterinary use.
- the agents and/or compositions are administered in one or more doses as required to achieve the desired effect.
- the agents and/or compositions may be administered in 1, 2, 3, 4, 5, or more doses.
- the doses may be separated by any period of time, for example hours, days, weeks, months, and years.
- the agents and/or compositions can be formulated as liquids or dry powders, or in the form of microspheres.
- the agents and/or compositions may be stored at temperatures of from about ⁇ 100° C. to about 25° C. depending on the duration of storage.
- the agents and/or compositions may also be stored in a lyophilized state at different temperatures including room temperature.
- the agents and/or compositions may be sterilized through conventional means known to one of ordinary skill in the art. Such means include, but are not limited to, filtration.
- the composition may also be combined with bacteriostatic agents to inhibit bacterial growth.
- a preparation may contain from about 0.1% to about 95% active compound (w/w), from about 20% to about 80% active compound, or from any percentage therebetween.
- the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form.
- the pharmaceutical carriers may be in the form of a sterile liquid preparation, for example, as a sterile aqueous or oleaginous suspension.
- a sterile liquid preparation for example, as a sterile aqueous or oleaginous suspension.
- acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono-or diglycerides.
- Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
- surfactants such as TWEEN® or SPAN® and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- the agents and/or compositions can be delivered in an exosomal delivery system.
- Exosomes are small membrane vesicles that are released into the extracellular environment during fusion of multivesicular bodies with plasma membrane. Exosomes are secreted by various cell types including hematopoietic cells, normal epithelial cells and even some tumor cells. Exosomes are known to carry MHC class I, various costimulatory molecules and some tetraspanins. Recent studies have shown the potential of using native exosomes as immunologic stimulants.
- the agents and/or compositions provided herein can contain nanoparticles having at least one or more agents linked thereto, e.g., linked to the surface of the nanoparticle.
- a composition typically includes many nanoparticles with each nanoparticle having at least one or more agents linked thereto.
- Nanoparticles can be colloidal metals.
- a colloidal metal includes any water-insoluble metal particle or metallic compound dispersed in liquid water.
- a colloid metal is a suspension of metal particles in aqueous solution. Any metal that can be made in colloidal form can be used, including gold, silver, copper, nickel, aluminum, zinc, calcium, platinum, palladium, and iron.
- Nanoparticles are used, e.g., prepared from HAuC14.
- Nanoparticles can be any shape and can range in size from about 1 nm to about 10 nm in size, e.g., about 2 nm to about 8 nm, about 4 to about 6 nm, or about 5 nm in size.
- Methods for making colloidal metal nanoparticles, including gold colloidal nanoparticles from HAuCl 4 are known to those having ordinary skill in the art. For example, the methods described herein as well as those described elsewhere (e.g., US Pat. Publication Nos. 2001/005581; 2003/0118657; and 2003/0053983, which are hereby incorporated by reference) are useful guidance to make nanoparticles.
- a nanoparticle can have two, three, four, five, six, or more active agents linked to its surface.
- many molecules of active agents are linked to the surface of the nanoparticle at many locations. Accordingly, when a nanoparticle is described as having, for example, two active agents linked to it, the nanoparticle has two active agents, each having its own unique molecular structure, linked to its surface.
- one molecule of an active agent can be linked to the nanoparticle via a single attachment site or via multiple attachment sites.
- An active agent can be linked directly or indirectly to a nanoparticle surface.
- the active agent can be linked directly to the surface of a nanoparticle or indirectly through an intervening linker.
- a linker can be an aliphatic chain including at least two carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms), and can be substituted with one or more functional groups including ketone, ether, ester, amide, alcohol, amine, urea, thiourea, sulfoxide, sulfone, sulfonamide, and disulfide functionalities.
- a linker can be any thiol-containing molecule. Reaction of a thiol group with the gold results in a covalent sulfide (-S-) bond.
- the nanoparticle is linked to a targeting agent/moiety.
- a targeting functionality can allow nanoparticles to accumulate at the target at higher concentrations than in other tissues.
- a targeting molecule can be one member of a binding pair that exhibits affinity and specificity for a second member of a binding pair.
- an antibody or antibody fragment therapeutic agent can target a nanoparticle to a particular region or molecule of the body (e.g., the region or molecule for which the antibody is specific) while also performing a therapeutic function.
- a receptor or receptor fragment can target a nanoparticle to a particular region of the body, e.g., the location of its binding pair member.
- Other therapeutic agents such as small molecules can similarly target a nanoparticle to a receptor, protein, or other binding site having affinity for the therapeutic agent.
- compositions of this invention comprise one or more additional therapeutic or prophylactic agents
- the therapeutic/enhancing/immunotherapy agent and the additional agent should be present at dosage levels of between about 0.1 to 100%, or between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
- the additional agents may be administered separately, as part of a multiple dose regimen, from the agents of this invention. Alternatively, those additional agents may be part of a single dosage form, mixed together with the agents of this invention in a single composition.
- the administration of the agents and/or compositions of the invention elicits an immune response against an immunogen, e.g., a cancer antigen.
- an immunogen e.g., a cancer antigen.
- the dose can be adjusted within this range based on, e.g., the subject's age, the subject's health and physical condition, the capacity of the subject's immune system to produce an immune response, the subject's body weight, the subject's sex, diet, time of administration, the degree of protection desired, and other clinical factors.
- Those in the art can also readily address parameters such as biological half-life, bioavailability, route of administration, and toxicity when formulating the agents and/or compositions of the invention.
- Preparation of dosing solution 1 167mg of NaOH were dissolved into 20 ML of de-ionized water to create a sodium hydroxide solution of 0.21 molar. Eighty (80) mgs of 6-Oxo-6-phenylhexanoic acid (obtained from Rieke Metals, Lincoln Nebr.) were weighed out and dissolved into 2 ML of the 0.21 Normal sodium hydroxide solution. In a separate container 6.2 mg of cis-Diaminodichloroplatinum (obtained from Tocris Bioscience, Elisville Mo.) were dissolved into 2.5 ML of de-ionized water. Each material was vortexed for 1 minute and sonicated for 15 minutes.
- Preparation of dosing solution 3 137mg of NaOH were dissolved into 20 ML of de-ionized water to create a sodium hydroxide solution of 0.16 molar. Eighty (80) microliters of 2-ethylhexyl 2-hydroxybenzoate (obtained from Chem Pacific, Baltimore Maryland) were weighed out and mixed with 2 ML of the 0.16 Normal sodium hydroxide solution. In a separate container 6.2 mg of cis-Diaminodichloroplatinum (obtained from Tocris Bioscience, Elisville Mo.) were dissolved into 2.5 ML of de-ionized water. Each material was vortexed for 1 minute and sonicated for 15 minutes.
- dosing solution 4 Eighty (80) microliters of 2-ethylhexyl 2-hydroxybenzoate (obtained from ChemPacific, Baltimore Maryland) were weighed out and mixed with 2 ML of the 0.16 Normal sodium hydroxide solution as described in example 3. In a separate container 20 mg cis-Diammine(1,1-cyclobutanedicarboxylato) platinum (Sigma Aldrich C2538) were dissolved into 2.5 ML of de-ionized water. Each material was vortexed for 1 minute and sonicated for 15 minutes.
- BxPC-3-luc2 cells were inoculated into the right flank of 32 female C.B-17 scid mice. Tumor growth was monitored once or twice weekly by caliper measurements until tumor size reached ⁇ 500mm 3 . Twenty-four mice with tumors of the appropriate size were selected for dosing. Each selected animal was numbered on their tail and ear tagged with the same number. The final groupings are noted in Table 1.
- the tumor size of each animal was measured by caliper and the animals divided into four groups such that the average tumor volume (using the caliper measure) for each group was similar.
- the groupings are shown in Table 2.
- the animals were then injected with luciferase 3 to obtain a tumor bioluminescence measurement (BLI) using a Xenogen photonic instrument (Xenogen became a division of Caliper Life Sciences).
- the four groups were then assigned to a treatment regimen.
- Group one was treated intratumorally with 100 microliters of enhancer 6-oxo-6 phenylhexanoic acid prepared as a sodium salt at pH approximately 7.0 and concentration of 13.3 mg/ML.
- Group two was treated with 100 microliters of cisplatin administered intravenously into the tail artery in a buffered solution at concentration of 1.2 mg/ml.
- Group three was treated intratumorally with 100 microliters of cisplatin in a buffered solution at a dose of approximately 0.45 mg/ml.
- Group 4 was administered intratumorally 100 microliters of the sodium salt form of enhancer 6-oxo-6 phenylhexanoic acid prepared with a final concentration of 13.3 mg/ml combined with cisplatin at a final concentration of 0.45 mg/ml.
- BLI readings for the animals administered from Example 7 were taken at six hours post dosing, 24 hours post dosing, and 72 hours post dosing. Caliper measurements of the tumors for the animals in all groups were taken pre-dose and 72 hours post dose. Results comparing baseline, 6 hour, 24 hour and 72 hour BLI time-points for the animals are shown in FIG. 4 .
- the animals described in example 7 were administered a second set of treatments following a measurement of their tumor bioluminescence at 72 hours.
- Group one was treated intratumorally with 100 microliters of enhancer 6-oxo-6 phenylhexanoic acid prepared as a sodium salt at pH approximately 7.0 and concentration of 13.3 mg/ML.
- Group two was treated with 100 microliters cisplatin administered intravenously into the tail artery as a buffered solution at concentration of 1.2 mg/ml.
- Group three was treated intratumorally with 100 microliters of cisplatin in a buffered solution at a dose of approximately 1.2 mg/ml.
- Group 4 was administered intratumorally 100 microliters of the sodium salt form of enhancer 6-oxo-6 phenylhexanoic acid prepared with a final concentration of 13.3 mg/ml combined with cisplatin at a final concentration of 1.2 mg/ml.
- BLI values of these cisplatin intratumoral doses were evaluated through day 3 of the study. Relative values of BLI results through day 3 are shown in FIG. 5 .
- the animals described in example 7 were administered a third set of treatments following a measurement of their tumor bioluminescence at 7 and 10 days post baseline.
- the doses administered for the third treatment to each group (1 to 4) were identical to those administered in in the second treatment described in Example 9.
- BLI values over the entire study are shown in FIG. 6 .
- Relative change in BLI values over the entire study are shown in FIG. 7 .
- FIG. 8 shows the changes in body weight from baseline to day 10.
- Formulations were prepared for dosing.
- An example is that of group 7 which is as follows: 11.8 mgs of sodium hydroxide pellets were dissolved in 6.0 mls of water. The solution was sonicated for 2 to 3 minutes. 80 mgs of 8-[(2-hydroxybenzoyl)amino]octanoic acid was added to the 6.0 mls of sodium hydroxide solution prepared above, and sonicated for 2 minutes. 2.0 ml of a solution of Tween 80 from a prepared stock solution (0.8mgs of Tween 80/ml) was added to the 6 mls of enhancer salt solution.
- Colon CT26 cells were inoculated into the flank of over 120 female balb/c immune competent mice. Tumor growth was monitored once or twice weekly by caliper measurements until the largest tumor reached ⁇ 500mm 3 . After sixteen days 120 mice with tumors were selected for inclusion in the study. Each selected animal was numbered and tagged with the corresponding number. The animals were then matched by tumor volume and placed into 12 groups with a mean tumor volume per animal per group ranging from 341 mm 3 to 349 mm 3 . Animals were treated with 1 of 12 different regimens and classified as Group 1-12, respectively, based on the identifying characteristics enumerated in Table 3.
- Treatment Regimen 2 Dosed in the same formulation Treatment Regimen 1 with Regimen 1 Group n Enhancer Agent Vehicle mg/animal Route Schedule Agent Vehicle mg/animal Route Schedule 1 # 10 No Treatment — — — — No Treatment — — — — 2 10 Sodium 8 cyclohexyl-8oxo- 0.3 it 2/1/3 Cisplatin 0.05 it 2/1/3 octanoate 3 10 Sodium 8 cyclohexyl-8oxo- 1 it 2/1/3 Cisplatin 0.15 it 2/1/3 octanoate 4 * 10 Sodium 8 cyclohexyl-8oxo- 1 it 2/1/3 Cisplatin 0.05 it 2/1/3 octanoate 5 10 Sodium 8 cyclohexyl-8oxo- 3 it 2/1/3 Cisplatin 0.15 it 2/1/3 octanoate 6 10 Sodium 8-[(2- 0.3 it 2/1/3 Cisplatin 0.05 it 2/1/3 hydroxybenzoyl)
- FIG. 9 depicts tumor volume over time for each of the 12 Groups analyzed by the study.
- FIG. 10 shows several intracellular formulations were able to show a significant extension of animal life versus control groups, and an overall survival benefit versus no treatment and also versus animals given drug alone systemically.
- Exemplary formulations according to an illustrative embodiment of the invention are shown in Table 4.
- FIGS. 11A-C show that 90% of the animals that had a complete response were fully immunized against recurrence of the cancer.
- the top figure (a) is the 10 animals from the control group.
- the second figure (b) are the animals that had shown a complete response in the study describe in example 12.
- the bottom figure (c) are the mean values and standard error of the means for the two groups.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Birds (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Dermatology (AREA)
- Dispersion Chemistry (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Apparatus For Radiation Diagnosis (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
Abstract
The invention provides a method for treating cancer using a coadministration strategy that combines local codelivery of a therapeutic agent and an intracellular penetration enhancing agent, and optionally in further combination with local administration of an immunotherapeutic agent, such as a cancer vaccine or NKT agonist. The invention also provides a method for treating cancer using an intracellular penetration enhancing agent. The methods of the invention aim to substantially kill and/or destroy the target tumor cells, as well as those cancerous cells that have metastasized to other parts of the body.
Description
- This application is a continuation of U.S. Ser. No. 15/441,907 filed Feb. 24, 2017, which is a continuation of U.S. Ser. No. 15/052,326, filed Feb. 24, 2016, now U.S. Pat. No. 9,636,406, which is a continuation of U.S. Ser. No. 14/280,036, filed May 16, 2014, now U.S. Pat. No. 9,351,997, which is a continuation of PCT/US2013/05984, filed Sep. 15, 2013, which claims priority to, and the benefit of, U.S. Ser. No. 61/779,509, filed Mar. 13, 2013, U.S. Ser. No. 61/707,733, filed Sep. 28, 2012, and U.S. Ser. No. 61/703,890, filed Sep. 21, 2012. Each of these applications is hereby incorporated by reference in their entirety.
- The present invention relates to novel methods for treating cancer. The methods involve treating a carcinoma or sarcoma using a coadministration strategy that combines local codelivery of a therapeutic agent and an intracellular penetration enhancing agent, optionally in combination with at least one additional therapeutic agent (e.g., local or systemic administration of an immunotherapeutic agent). The methods of the invention reduce the growth, shrink, and/or eradicate a target tumor, as well as those cancerous cells that have metastasized to other parts of the body.
- It is currently believed that cancer cells routinely arise in our bodies but are continuously destroyed by a healthy immune system. It is thought that cancer tumors form when the immune system fails to destroy these routinely formed diseased cells. The word “cancer” is used to describe a number of diseases in which there is uncontrolled division of abnormal cells. Cancer may initially arise in virtually any tissue or organ in the body and forms as a result of a complex interaction of both innate genetic factors and environmental factors, such as one's diet or exposure to radiation, toxins, and the like. Despite advances in medicine and the understanding of the molecular basis of cancer, the exact causes of any given type of cancer are largely unknown, especially in a particular individual. Given this lack of knowledge, it is not surprising that it remains highly difficult to find effective cancer treatments.
- Finding effective treatments is also made challenging because cancer often develops resistance to various therapeutic strategies. In addition, effective means for treating cancer become an even greater challenge in view of the capacity for certain types of cancers to spread from their primary source. This process, called metastasis, enables cancer cells to spread to other vital parts of the body through the blood and lymph systems. Some experts estimate that only a single cell in a million can survive long enough to help form a metastatic tumor. These odds are thought to be attributable to the challenges metastasized cells face in the destination tissue, including lodging in the destination tissue, overcoming local immune defenses, and acquiring their own blood supply and nutrients through the process of angiogenesis. Nevertheless, metastasis remains a key reason why effective cancer treatments are difficult to develop.
- Existing cancer therapies today include multiple different ablation techniques such as surgical procedures; cryogenic or heat methods on the tissue, ultrasound, radiofrequency, and radiation; chemical methods such as pharmaceuticals, cytotoxic agents, monoclonal antibodies; or transarterial chemo immobilization (TACE), and combinations thereof pursuant to specific regimens based on the specific type and stage of cancer under treatment. However, these therapies are associated with substantially high costs. In addition, current treatment options are highly invasive, are associated with significant toxicities, and result in an overall poor quality of life for patients.
- Standard of care cancer therapies typically couple surgical removal of the affected tissue with chemotherapy or radiation treatments. Standard approaches for administering chemotherapeutics are through the blood, e.g., systemic delivery, which can be achieved by various routes such as intravenous and/or gastrointestinal delivery. However, toxicity is a major drawback associated with systemically delivered chemotherapeutic drugs. Standard of care surgical treatments also introduce problems, including dislodgement of cancer cells into the blood and/or lymph systems, which results in the opportunity for cancer cells to metastasize to other sites in the body and cause additional tumors to form.
- When surgery is not possible, the accepted treatment for cancer is to use radiation or chemotherapy. But survival rates for inoperable cancer are low when compared to the survival rate for cancers that are surgically removed prior to chemotherapy or radiation.
- Regional chemotherapy represents a recent advance in the chemotherapeutic treatment of cancer. This approach involves delivering the chemotherapeutic agent directly to the tumor, e.g., proximal to, adjacent to, or intratumorally, as opposed to introducing the toxic agent into the bloodstream. One goal of regional chemotherapy is to minimize the toxic side effects typically associated with systemic chemotherapeutic administration.
- However, regional chemotherapeutic approaches generally have not been satisfactory. A general problem with chemotherapy—including regional chemotherapy—is that cancer cells are highly resistant to penetration by chemotherapeutic agents. For example, certain platinum compounds are mainly taken into cancer cells by an active transport process using the CTR1 pathway (see Holzer et al. Molecular Pharmacology 70:1390-1394 (2006)). In addition, chemotherapeutic agents generally are delivered by the blood, they should be soluble in the blood, making them generally water soluble. Water soluble materials such as chemotherapeutic agents do not effectively pass through lipid cell membranes passively, and thus, are not readily deliverable to the intracellular space of cancer cells especially at low concentrations. Further, once inside, tumor cells have mechanisms and various processes designed to excrete the chemotherapeutic agents. For example, tumor cells are able to rid themselves of chemical agents using glutathione and/or metallothioneins complexing and have innate DNA repair mechanisms to overcome chemotherapies.
- Certain cancer tumors resemble the body's tissue and thus diminish the immune system's otherwise innate ability to identify and kill them. Several cancer-fighting technologies (e.g., cancer vaccines) aim to stimulate the immune system against cancerous cells. Although one such product is currently approved for use (PROVENGE® by Dendreon Corporation, which is used against prostate cancer), the success of cancer vaccines has been limited. As tumor cells are derived from the individual with cancer, tumor cells are very similar to a person's own cells. The immune system's ability to mount an attack on the tumor cell is hindered because the tumor cell displays few, if any, antigens that are foreign to that individual. In addition, a tumor can have many different types of cells in it. Each cell type has different cell-surface antigens, again thwarting attack by the immune system. Moreover, tumors can secrete cytokines that directly inhibit immune activity. Finally, depending on disease stage, the tumor may be too advanced (e.g., bulky) for the vaccine to be effective. These, as well as other factors, are why tumors may lack sufficient amounts of antigens (or targets) needed to stimulate a sufficient immune system.
- That said, it is generally the case that if cancer is detected early, the standard treatments against cancer can be highly effective. However, even when the best results are obtained, such treatments are invasive, toxic and damaging to the body and mentally demanding on the patient. If cancer is detected in late stage, few treatments offer the patient much hope of long term survival.
- Thus, there continues to be a need in the art to identify and develop new cancer-fighting strategies that are more effective at treating disease, and which present lower costs to individuals and society in general.
- There is disclosed herein a method for treating cancer. In aspects, the invention provides methods for effectively treating a solid tumor by locally coadministering (e.g., proximally, locally, directly into, and the like) a combination of a therapeutic agent (e.g., a small molecule, pharmaceutical drug, antibody, and the like) together with an intracellular penetration enhancing agent. The therapeutic agent and the intracellular penetration enhancing agent are administered in amounts and/or in a regimen that results in substantial tumor shrinkage and/or destruction. The exact administration regimen may vary, including that the agents may be delivered at the same time or concomitant with one another (e.g., same injection), or at different times and in any order. In addition, the administration regimen may involve multiple repetitions or rounds of administration, wherein the agents are delivered in the same or different fashions multiple times in a single day or on separate days.
- Administration of repetitive dosing for a defined period of time is often referred to as a drug cycle. The methods described may also involve multiple drug cycles. The methods may also vary depending on the tumor type. The method of the invention also involves enhancing the treatment effects of the therapeutic agent and intracellular penetration enhancing agent by coupling their local administration with the administration of an immune-stimulating agent, such as a cancer vaccine or T-cell agonist, which may be delivered prior to, at or at about the same time, or subsequent to the therapeutic and intracellular penetration enhancing agents. In embodiments, the therapeutic agent may be a combination of two or more agents selected from the group consisting of a chemotherapeutic agent, an antibody, and a nucleic acid molecule.
- In one embodiment, the method of the invention can also be thought of as a two-phase therapeutic approach. In the first phase, a subject is locally coadministered both a therapeutic agent and an intracellular penetration enhancing agent in accordance with an effective dosing regimen. For example, the agents may be delivered at the same time, or at approximately the same time, to a bodily location that is in the same region as the target tumor, or which is at the perimeter of the target tumor, or which is within (intratumoral) the tumor itself. The intracellular penetration enhancing agent surprisingly and unexpectedly results in a substantially high increase in drug permeability of the therapeutic agent into the tumor cells. In the second phase, which can overlap, precede, or succeed the first phase, an immune-stimulating agent, such as a cancer vaccine, CD4 or NKT cell stimulating agent or combination of agents, is administered locally to the subject. However, it was unexpectedly found that the intracellular penetration agent in combination with certain cytotoxic drug agents elicits an immune response when administered intratumorally, even in the absence of additional immune stimulating agents. The invention also provides formulations for use in treating cancer in accordance with the methods of the invention. The formulations combine, separately or together, a therapeutic agent and an intracellular penetration enhancing agent. Such formulations may be administered locally or regionally, or intratumorally to a tumor in a subject. In certain embodiments, the invention provides formulations that further combine, separately or together, a therapeutic agent, an intracellular penetration enhancing agent, and an immunotherapeutic agent, e.g., a cancer vaccine. Such formulations may be administered locally or regionally, or intratumorally to a tumor in a subject.
- Accordingly, in aspects, the invention provides methods for treating a subject in need thereof (e.g., a subject with one or more tumors) with an effective amount of a therapeutic agent and an intracellular permeation enhancing agent. In embodiments, administration of the intracellular permeation agent increases the likelihood of effectiveness of the therapeutic agent. In related embodiments, administration of the intracellular permeation agent increases the likelihood of effectiveness of the therapeutic agent by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more (or any number therebetween) as compared to treatment without the intracellular permeation agent.
- In another aspect, the invention provides methods for reducing the side effects of a therapeutic agent. In embodiments, the methods involve administering an effective amount of the therapeutic agent and an intracellular permeation enhancing agent to a subject (e.g., a subject with a tumor).
- In yet another aspect, the invention provides methods for destroying cancerous cells within a subject (e.g., a subject with one or more tumors). In embodiments, the methods involve administering an effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
- In a further aspect, the invention provides methods for treating a tumor in a subject. In embodiments, the methods involve administering an effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
- In other aspects, the invention provides methods for inhibiting growth of a tumor in a subject. In embodiments, the methods involve administering an effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
- In any of the above aspects and embodiments, the therapeutic agent can be locally, regionally, or systemically administered to the subject.
- In any of the above aspects and embodiments, the intracellular permeation enhancing agent can be locally or regionally administered to the subject.
- In embodiments, the methods involve locally or regionally coadministering to the subject a therapeutic agent and an intracellular permeation enhancing agent.
- In embodiments, the tumor is a solid tumor. In some embodiments, the tumor has metastasized.
- In embodiments, the tumor is a carcinoma or sarcoma. In related embodiments, the tumor is a carcinoma or sarcoma of the skin, bone, muscle, breast, oral cavity, colon, organ, kidney, liver, lung, gallbladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testes, ovaries, or uterus. In certain embodiments, the tumor is a carcinoma of the pancreas, colon, or liver.
- In embodiments, the therapeutic agent is administered intratumorally and/or the intracellular permeation enhancing agent is administered intratumorally. In some embodiments, the therapeutic agent is administered systemically and the intracellular permeation enhancing agent is administered intratumorally.
- In any of the above aspects and embodiments, the methods may reduce the growth of the one or more tumors, shrink the one or more tumors, or eradicate the one or more tumors. For example, the tumor mass does not increase. In certain embodiments, the tumor shrinks by 10%, 25%, 50%, 75%, 85%, 90%, 95%, or 99% or more (or any number therebetween) as compared to its original mass.
- In any of the above aspects and embodiments, the methods may prevent tumor metastasis.
- In any of the above aspects and embodiments, the effective amount of the therapeutic agent can be selected based on the volume and type of the tumor.
- In any of the above aspects and embodiments, the effective amount of the intracellular permeation enhancing agent and/or drug agent can be selected based on the volume and type of the tumor.
- In embodiments, the methods involve administering the therapeutic agent on a first day and repeating the administration on one or more subsequent days. In related embodiments, the first day and one or more subsequent days are separated by between 1 day and about 3 weeks.
- In embodiments, the methods involve administering the intracellular permeation enhancing agent on a first day and repeating the administration on one or more subsequent days. In related embodiments, the first day and one or more subsequent days are separated by between 1 day and about 3 weeks. In another embodiment, the intracellular permeation enhancing agent may be administered between 3 and 5 days consecutively or with one day of rest within the period.
- In certain embodiments, the methods involve coadministering the therapeutic agent and the intracellular permeation enhancing agent on the first day and repeating the administration on one or more subsequent days. In related embodiments, the first day and one or more subsequent days are separated by between 1 day and about 3 weeks.
- In some embodiments, the therapeutic agent and the intracellular permeation enhancing agent are coadministered in a ratio of about 1:2, 1:4, 1:10, 1:20, 1:25, 1:50, 1:100, or 1:200 (weight ratio of therapeutic agent: intracellular permeation enhancing agent).
- In some embodiments, the intracellular permeation enhancing agent is administered at a concentration of between about 0.5 mgs per ml and about 50 mgs per ml. In still other embodiments, the intracellular permeation enhancing agent is administered at a concentration of between about 10 mgs per ml and about 30 megs per ml.
- In certain embodiments, the therapeutic agent and the intracellular permeation enhancing agent are delivered simultaneously in a single formulation or simultaneously in separate formulations. In other embodiments, the intracellular permeation enhancing agent is administered before the therapeutic agent.
- In any of the above aspects and embodiments, the therapeutic agent can be an anticancer agent.
- In some embodiments, the anticancer agent is a chemotherapeutic agent (e.g., Abiraterone Acetate, Afatinib, Aldesleukin, Alemtuzumab, Alitretinoin, Altretamine, Amifostine, Aminoglutethimide Anagrelide, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, Azathioprine, Bendamustine, Bevacizumab, Bexarotine, Bicalutamide, Bleomycin, Bortezomib, Busulfan, Capecitabine, Carboplatin, Carmustine, Cetuximab, Chlorambucil, Cisplatin, Cladribine, Crizotinib, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, Denileukin diftitox, Decitabine, Docetaxel, Dexamethasone, Doxifluridine, Doxorubicin, Epirubicin, Epoetin Alpha, Epothilone, Erlotinib, Estramustine, Etinostat, Etoposide, Everolimus, Exemestane, Filgrastim, Floxuridine, Fludarabine, Fluorouracil, Fluoxymesterone, Flutamide, folate linked alkaloids, Gefitinib, Gemcitabine, Gemtuzumab ozogamicin, GM-CT-01, Goserelin, Hexamethylmelamine, Hydroxyureas, Ibritumomab, Idarubicin, Ifosfamide, Imatinib, Interferon alpha, Interferon beta, Irinotecan, Ixabepilone, Lapatinib, Leucovorin, Leuprolide, Lenalidomide, Letrozole, Lomustine, Mechlorethamine, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Nelarabine, Nilotinib, Nilutamide, Octreotide, Ofatumumab, Oprelvekin, Oxaliplatin, Paclitaxel, Panitumumab, Pemetrexed, Pentostatin, polysaccharide galectin inhibitors, Procarbazine, Raloxifene, Retinoic acids, Rituximab, Romiplostim, Sargramostim, Sorafenib, Streptozocin, Sunitinib, Tamoxifen, Temsirolimus, Temozolamide, Teniposide, Thalidomide, Thioguanine, Thiotepa, Tioguanine, Topotecan, Toremifene, Tositumomab, Trametinib, Trastuzumab, Tretinoin, Valrubicin, VEGF inhibitors and traps, Vinblastine, Vincristine, Vindesine, Vinorelbine, Vintafolide (EC145), Vorinostat, a salt thereof, or any combination of the foregoing.
- In other embodiments, the therapeutic agent is a therapeutic antibody or a combination of two or more therapeutic antibodies (e.g., Abagovomab, Alacizumab pegol, Alemtuzumab, Altumomab pentetate (Hybri-ceaker), Amatuximab, Anatumomab mafenatox, anti-PD-1 antibodies, Apolizumab, Arcitumomab (CEA-Scan), Belimumab, Bevacizumab, Bivatuzumab mertansine, Blinatumomab, Brentuximab vedotin, Cantuzumab mertansine, Cantuzumab ravtansine, Capromab pendetide (Prostascint), Catumaxomab (Removab), Cetuximab (Erbitux), Citatuzumab bogatox, Cixutumumab, Clivatuzumab tetraxetan (hPAM4-Cide), Conatumumab, Dalotuzumab, Denosumab, Drozitumab, Edrecolomab (Panorex), Enavatuzumab, Gemtuzumab, Ibritumomab tiuxetan, Ipilimumab (MDX-101), Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, or any combination thereof).
- In yet another embodiment, the therapeutic agent is a nucleic acid molecule. For example, the nucleic acid molecule can be an interfering RNA (e.g., RNAi or shRNA), a gene therapy expression vector, or a gene silencing vector.
- In certain embodiments, the therapeutic agent is a radioisotope.
- In certain embodiments, the therapeutic agent is a thymidylate synthase inhibitor. In certain embodiments, the therapeutic agent is a platinum compound.
- In certain embodiments, the therapeutic agent is a vinca alkaloid agent.
- In any of the above aspects and embodiments, the intracellular permeation enhancing agent can be a chemical compound that enhances passive transport of the therapeutic compound into a cell.
- In embodiments, the intracellular permeation enhancing agent is a functionalized ketoacid, 6-Oxo-6-phenylhexanoic acid, 8-Oxo-8-phenyloctanoic acid, 8-(2,5-Dichlorophenyl)-8-oxooctanoic acid, a functionalized ketoester or aldehyde, a modified amino acid, modified amino acids, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, N-[8-(2-hydroxybenzoyl)aminodecanoic acid, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-[4-(4-chloro-2hydroxybenzoyl)amino]butanoic acid, 2-ethylhexyl 2-hydroxybenzoate, 5-Cyclohexyl-5-oxovaleric acid, 6-Cyclohexyl-6-oxohexanoic acid, 7-Cyclohexyl-7-oxoheptanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, 4-Cyclopentyl-4-oxobutyric acid, 5-Cyclopentyl-5-oxovaleric acid, 6-Cyclopentyl-6-oxohexanoic acid, 7-Cyclopentyl-7-oxoheptanoic acid, 8-Cyclopentyl-8-oxooctanoic acid, 4-Cyclobutyl-4-oxobutyric acid, 5-Cyclobutyl-5-oxovaleric acid, 6-Cyclobutyl-6-oxohexanoic acid, 7-Cyclobutyl-7-oxoheptanoic acid, 8-Cyclobutyl-8-oxooctanoic acid, 4-Cyclopropyl-4-oxobutyric acid, 5-Cyclopropyl-5-oxovaleric acid, 6-Cyclopropyl-6-oxohexanoic acid, 7-Cyclopropyl-7-oxoheptanoic acid, 8-Cyclopropyl-8-oxooctanoic acid, 8-[(3-methylcyclohexyl)oxy]octanoic acid, 7-[(3-methylcyclohexyl)oxy]heptanoic acid, 6-[(3-methylcyclohexyl)oxy]hexanoic acid, 5-[(3-methylcyclohexyl)oxy]pentanoic acid, 4-[(3-methylcyclohexyl)oxy]butanoic acid, 3-[(3-methylcyclohexyl)oxy]propanoic acid, octisalate, a diketopiperazines, saponin, an acylcarnitine, an alkanoylcholine, a taurodihydrofusidate, a sulphoxide, an oxazolidinone, a pyrrolidone, an alcohol or alkanol, a benzoic acid, a glycol, a surfactant, a terpene, a functionally effective salt of any of the foregoing, a derivative of any of the foregoing, or combinations thereof.
- In some embodiments, the intracellular permeation enhancing agent is 6-Oxo-6-phenylhexanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, a functionally effective salt of any of the foregoing, a derivative of any of the foregoing, or any combination thereof.
- In certain embodiments, the therapeutic agent is cisplatin or other platinum agent (e.g., satraplatin, pcioplatin, nedaplatin, triplatin, carboplatin or oxaplatin), and wherein the intracellular permeation enhancing agent is 6-oxo-6 phenylhexanoic acid, N-8-(2-hydroxybenzoyl)aminooctanoic acid, a salt or derivative of any of the foregoing, or any combination thereof.
- In embodiments, the above methods further involve administering a therapeutically effective amount of an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is a cancer vaccine, hormone, epitope, cytokine, tumor antigen, CD4 cell stimulator, NKT cell agonist, or adjuvant. For example, the immunotherapeutic agent can be an interferon, interleukin, tumor necrosis factor, ovalabumin, Neuvenge®, Oncophage, CimaVax-EGF, Mobilan, a-Gal glycolipid, α-Galactosylceramide (α-GalCer), β-mannosylceramide (β-ManCer), adenovirus delivered vaccines, Celldex's CDX1307 and CDX1401; GRNVAC1, viral based vaccines, MVA-BN, PROSTVAC®, Advaxis'; ADXS11-001, ADXS31-001, ADXS31-164, BiovaxID, folate binding protein (E39), Granulocyte macrophage colony stimulating factor (GM-CSF) with and without E75 (NeuVax) or OncoVEX, trastuzumab, Ae-37, IMA901, SC1B1, Stimuvax, peptides that can elicit cytotoxic lymphocyte response, peptide vaccines including telomerase peptide vaccine (GV1001), survivin peptide, MUC1 peptide, ras peptide, TARP 29-37-9V Peptide epitope enhanced peptide, DNA Vector pPRA-PSM with synthetic peptides E-PRA and E-PSM; Ad.p53 DC vaccine, NY-ESO-1 Plasmid DNA (pPJV7611), genetically modified allogeneic (human) tumor cells for the expression of IL-1, IL-7, GM-CSF, CD80 or CD154, HyperAcute(R)-Pancreatic cancer vaccine (HAPa-1 and HAPa-2 components), Melaxin (autologous dendritoma vaccine) and BCG, GVAX (CG8123), CD40 ligand and IL-2 gene modified autologous skin fibroblasts and tumor cells, ALVAC-hB7.1, Vaximm Gmbh's VXM01, Immunovative Therapies' AlloStim-7, ProstAtak™, TG4023 (MVA-FCU1), Antigenic's HSPPC-96, Immunovaccine Technologies' DPX-0907 which consists of specific HLA-A2-restricted peptides, a universal T Helper peptide, a polynucleotide adjuvant, a liposome and Montanide (ISA51 VG), GSK2302032A, Memgen's ISF35, Avax's OVax: Autologous, DNP-Modified Ovarian vaccine, Theratope®, Ad100-gp96Ig-HLA Al, Bioven's recombinant Human rEGF-P64K/Montanide vaccine, TARP 29-37, or Dendreon's DN24-02.
- In certain embodiments, the immunotherapeutic agent is an α-Gal glycolipid.
- In certain embodiments, the immunotherapeutic agent is a β-ManCer comprising a sphingosine moiety and a fatty acid moiety comprising a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 49 carbon atoms. In related embodiments, the fatty acid moiety comprises a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 15 carbon atoms. In other related embodiments, the fatty acid moiety comprises a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 18 to about 30 carbon atoms. The β-ManCer comprises the following structure:
- In the above embodiments, the immunotherapeutic agent enhances the therapeutic effects of the therapeutic agent. For example, the immunotherapeutic agent further reduces the growth of the tumor or further shrinks the tumor.
- In some embodiments, the immunotherapeutic agent is administered after administration of the therapeutic agent and the intracellular permeation enhancing agent. In other embodiments, the immunotherapeutic agent is administered simultaneously with the first administration of the therapeutic agent and the intracellular permeation enhancing agent.
- In embodiments, the immunotherapeutic agent is administered locally, regionally, or systemically. For example, the immunotherapeutic agent can be administered intraperitoneally. The immunotherapeutic agent can also be administered intratumorally.
- In any of the above aspects and embodiments, the therapeutic agent and the intracellular permeation enhancing agent can be coupled.
- In aspects, the above methods can further involve administering a standard of care therapy to the subject. In embodiments, the standard of care therapy is surgery, radiation, radio frequency, cryogenic, ultranoic ablation, systemic chemotherapy, or a combination thereof.
- In any of the above aspects and embodiments, administration of the therapeutic agent, the intracellular permeation enhancing agent, or the immunotherapeutic agent can be conducted with the aid of an imaging system (e.g., X-ray computed tomography (CT), fluoroscopy, magnetic resonance imaging (MRI), ultrasound, or positron emission tomography (PET)/computed tomography (CT)).
- In other aspects, the invention includes methods of imaging one or more tumors with an imaging system selected from the group consisting of X-ray computed tomography (CT), fluoroscopy, magnetic resonance imaging (MRI), ultrasound, and positron emission tomography (PET)/computed tomography (CT), determining the volume of the one or more tumors; and calculating, based on the determined tumor volume, a therapeutically effective tumor-specific dose amount of the therapeutic agent and the intracellular permeation enhancing agent. In certain embodiments, each or some of the one or more tumors may be intratumorally co-administered with the therapeutically effective tumor-specific dose of the therapeutic agent and the intracellular permeation enhancing agent calculated for that tumor.
- In any of the above aspects and embodiments, the subject can be a mammal (e.g., human, dog, cat, horse, cow, sheep, goat, pig, mouse, rat, guinea pig, or monkey).
- The invention also features methods of treating a subject in need thereof (e.g., a subject having a tumor) with an effective amount of an intracellular permeation enhancing agent.
- In some aspects, the invention provides methods for destroying cancerous cells within a subject (e.g., a subject having a tumor). In embodiments, the methods involve administering an effective amount of an intracellular permeation enhancing agent.
- In certain aspects, the invention provides methods for treating a tumor in a subject. In embodiments, the methods involve administering an effective amount of an intracellular permeation enhancing agent.
- In certain aspects, the invention provides methods for inhibiting growth of a tumor in a subject. In embodiments, the methods involve administering an effective amount of an intracellular permeation enhancing agent.
- In any of the above aspects and embodiments, the intracellular permeation enhancing agent can be locally or regionally administered to the subject.
- In embodiments, the tumor is a solid tumor. In some embodiments, the tumor has metastasized.
- In embodiments, the tumor is a carcinoma or sarcoma. In related embodiments, the tumor is a carcinoma or sarcoma of the skin, bone, muscle, breast, oral cavity, organ, kidney, liver, lung, gallbladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testes, ovaries, or uterus. In certain embodiments, the tumor is a carcinoma or sarcoma of the pancreas.
- In embodiments, the intracellular permeation enhancing agent is administered intratumorally.
- In the above aspects and embodiments, the methods may reduce the growth of the tumor, shrinks the tumor, or eradicates the tumor. For example, the tumor mass does not increase. In certain embodiments, the tumor shrinks by 10%, 25%, 50%, 75%, 85%, 90%, 95%, or 99% or more (or any number therebetween) as compared to its original mass.
- In the above aspects and embodiments, the methods may prevent tumor metastasis. In any of the above aspects and embodiments, the effective amount of the intracellular permeation enhancing agent can be selected based on the volume and type of the tumor.
- In embodiments, the methods involve administering the intracellular permeation enhancing agent on a first day and repeating the administration on one or more subsequent days. In related embodiments, the first day and one or more subsequent days are separated by between 1 day and about 3 weeks.
- In the above aspects and embodiments, the intracellular permeation enhancing agent can be a chemical compound that enhances passive transport of the therapeutic compound into a cell.
- In embodiments, the intracellular permeation enhancing agent is a functionalized ketoacid, 6-Oxo-6-phenylhexanoic acid, 8-Oxo-8-phenyloctanoic acid, 8-(2,5-Dichlorophenyl)-8-oxooctanoic acid, a functionalized ketoester or aldehyde, a modified amino acid, modified amino acids, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, N-[8-(2-hydroxybenzoyl)aminodecanoic acid, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-[4-(4-chloro-2hydroxybenzoyl)amino]butanoic acid, 2-ethylhexyl 2-hydroxybenzoate, 5-Cyclohexyl-5-oxovaleric acid, 6-Cyclohexyl-6-oxohexanoic acid, 7-Cyclohexyl-7-oxoheptanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, 4-Cyclopentyl-4-oxobutyric acid, 5-Cyclopentyl-5-oxovaleric acid, 6-Cyclopentyl-6-oxohexanoic acid, 7-Cyclopentyl-7-oxoheptanoic acid, 8-Cyclopentyl-8-oxooctanoic acid, 4-Cyclobutyl-4-oxobutyric acid, 5-Cyclobutyl-5-oxovaleric acid, 6-Cyclobutyl-6-oxohexanoic acid, 7-Cyclobutyl-7-oxoheptanoic acid, 8-Cyclobutyl-8-oxooctanoic acid, 4-Cyclopropyl-4-oxobutyric acid, 5-Cyclopropyl-5-oxovaleric acid, 6-Cyclopropyl-6-oxohexanoic acid, 7-Cyclopropyl-7-oxoheptanoic acid, 8-Cyclopropyl-8-oxooctanoic acid, 84(3-methylcyclohexyl)oxy]octanoic acid, 7-[(3-methylcyclohexyl)oxy]heptanoic acid, 6-[(3-methylcyclohexyl)oxy]hexanoic acid, 5-[(3-methylcyclohexyl)oxy]pentanoic acid, 4-[(3-methylcyclohexyl)oxy]butanoic acid, 3-[(3-methylcyclohexyl)oxy]propanoic acid, octisalate, adiketopiperazines, saponin, an acylcarnitine, an alkanoylcholine, a taurodihydrofusidate, a sulphoxide, an oxazolidinone, a pyrrolidone, an alcohol or alkanol, a benzoic acid, a glycol, a surfactant, a terpene or a functionally effective salt, derivative or combination thereof.
- In some embodiments, the intracellular permeation enhancing agent is 6-Oxo-6-phenylhexanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, or a functionally effective salt or derivative thereof.
- In the above aspects and embodiments, the subject can be a mammal (e.g., human, dog, cat, horse, cow, sheep, goat, pig, mouse, rat, guinea pig, or monkey).
- The invention further features pharmaceutical compositions for conducting the method described herein. In embodiments, the composition is optimized for intratumoral administration. In other embodiments, the intracellular permeation enhancing agent and the therapeutic agent are coadministered intratumorally. These and other embodiments are disclosed or are obvious from and encompassed by, the following detailed description.
- Definitions and Use of Terms
- The present invention may be understood more readily by reference to the following detailed description of the invention and the Examples included therein. Before the present methods and techniques are disclosed and described, it is to be understood that this invention is not limited to specific analytical or synthetic methods as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.
- By “agent” or “therapeutic agent” is meant any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof.
- By “ameliorate” is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease or a symptom thereof.
- By “analog” is meant a molecule that is not identical, but has analogous functional or structural features. For example, a polypeptide analog retains the biological activity of a corresponding naturally-occurring polypeptide, while having certain biochemical modifications that enhance the analog's function relative to a naturally occurring polypeptide. Such biochemical modifications could increase the analog's protease resistance, membrane permeability, or half-life, without altering, for example, ligand binding. An analog may include an unnatural amino acid.
- As used herein “an interfering RNA” refers to any double stranded or single stranded RNA sequence, capable—either directly or indirectly (i.e., upon conversion)—of inhibiting or down regulating gene expression by mediating RNA interference. Interfering RNA includes but is not limited to small interfering RNA (“siRNA”) and small hairpin RNA (“shRNA”). “RNA interference” refers to the selective degradation of a sequence-compatible messenger RNA transcript.
- As used herein “an shRNA” (small hairpin RNA) refers to an RNA molecule comprising an antisense region, a loop portion and a sense region, wherein the sense region has complementary nucleotides that base pair with the antisense region to form a duplex stem. Following post-transcriptional processing, the small hairpin RNA is converted into a small interfering RNA by a cleavage event mediated by the enzyme Dicer, which is a member of the RNase III family.
- As used herein “an RNAi” (RNA interference) refers to a post-transcriptional silencing mechanism initiated by small double-stranded RNA molecules that suppress expression of genes with sequence homology.
- As used herein “anti-tumor therapy” refers to any therapy to decrease tumor growth or metastasis, including surgery, radiation, and/or chemotherapy.
- As used herein, “changed as compared to a control” sample or subject is understood as having a level of the analytic or diagnostic or therapeutic indicator to be detected at a level that is statistically different than a sample from a normal, untreated, or control sample. Control samples include, for example, cells in culture, one or more laboratory test animals, or one or more human subjects. Methods to select and test control samples are within the ability of those in the art. An analytic substance can be a naturally occurring substance that is characteristically expressed or produced by the cell or organism (e.g., antibodies, pathogenic peptides or particles, and the like) or a substance produced by a reporter construct (e.g, β-galactosidase or luciferase). Depending on the method used for detection the amount and measurement of the change can vary. Determination of statistical significance is within the ability of those skilled in the art.
- As used herein, the term “co-administering,” or “co-administration,” and the like refers to the act of administering two or more agents (e.g., a therapeutic agent with a penetration enhancer), compounds, therapies, or the like, at or about the same time. The order or sequence of administering the different agents of the invention, e.g., chemotherapeutics, intracellular permeation enhancing agents, or immunotherapeutic agents, may vary and is not confined to any particular sequence. Co-administering may also refer to the situation where two or more agents are administered to different regions of the body or via different delivery schemes, e.g., where a first agent is administered systemically and a second agent is administered intratumorally, or where a first agent is administered intratumorally and a second agent is administering systemically into the blood or proximally to the tumor. Co-administering may also refer to two or more agents administered via the same delivery scheme, e.g., where a first agent is administered intratumorally and a second agent is administered intratumorally.
- As used herein, the terms “comprises,” “comprising,” “containing” and “having” and the like are open-ended as defined by U.S. Patent law and can mean “includes,” “including,” and the like; “consisting essentially of” or “consists essentially” likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.
- “Contacting a cell” is understood herein as providing an agent to a cell e.g., a cell to be treated in culture, ex vivo, or in an animal, such that the agent can interact with the cell (e.g., cell to be treated), potentially be taken up by the cell, and have an effect on the cell. The agent (e.g., an adjuvant) can be delivered to the cell directly (e.g., by addition of the agent to culture medium or by injection into the cell, tissue, or tumor of interest), or by delivery to the organism by a topical or parenteral route of administration for delivery to the cell by vascular, lymphatic, or other means. One of ordinary skill in the art will readily understand that administration of a therapeutic agent to a subject involves contacting the therapeutic agent with a cell, tumor, or tissue of the subject.
- As used herein, the term “coupled,” as in reference to two or more agents being “coupled” together, refers to a covalent or otherwise stable association between the two or more agents. For example, a therapeutic agent may be coupled with an intracellular permeation enhancing agent via a covalent bond, a covalently tethered linker moiety, or non-covalently through ionic interactions or hydrogen bonding. One or more agents that are coupled together retain substantial their same independent functions and characteristics. For example, the therapeutic agent when coupled to another agent may retain its same activity as if it were independent.
- By “cycle” or “drug cycle” is meant the administration of repetitive dosing for a defined period of time, which may range from minute to hours to days to weeks to months or even years.
- By “cytokine” is meant a hormone that acts locally and that modulates an individual's immune response.
- As used herein, a “cytotoxic agent” refers to any agent capable of destroying cells, preferably dividing cells such as cancer cells.
- As used herein, “detecting”, “detection” and the like are understood that an assay performed to determine one or more characteristics of a sample, e.g. identifying the presence, absence or amount of the analyte to be detected. For example, detection can include identification of a specific analyte in a sample or an activity of an agent in a sample. Detection can include the determination of the presence of nucleic acid, protein (e.g., antibody, cytokine, and the like) by PCR, immunoassay (e.g., ELISA), microscopy, pathogen challenge, and the like. The amount of analyte or activity detected in the sample can be none or below the level of detection of the assay or method.
- By “disease” is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. An exemplary disease is cancer.
- The terms “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, refer to an amount of an agent or compound that is sufficient to treat a disorder, e.g., a cancer. In some embodiments, the result is a reduction in and/or alleviation of the signs, symptoms, or causes of a disorder, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disorder. An “effective amount” or therapeutically effective amount of an agent or combination of agents of the invention may also be that amount or dose that is effective to substantially shrink or destroy a tumor, or permit its surgical removal. An appropriate “effective” amount in any individual case is determined using any suitable technique, (e.g., a dose escalation study) and will depend on the judgment of the practitioner. However, suitable dosage ranges are readily determinable by one skilled in the art.
- More than one dose may be required to provide an effective dose. It is understood that an effective dose in one population may or may not be sufficient in all populations. Thus, in connection with the administration of a therapeutic agent, the therapeutic agent is “effective against” a disease or condition when administration in a clinically appropriate manner results in a beneficial effect for at least a statistically significant fraction of subjects, such as a prevention of disease onset, improvement of symptoms, a cure, a reduction in disease signs or symptoms, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or condition.
- By “enhances” is meant a positive alteration of at least 10%, 25%, 50%, 75%, 100%, or any number therebetween.
- As used herein, the term “growth” refers to any tissue or organ that comprises a cellular mass considered to represent an abnormal proliferation. Such growths may be cancerous, non-cancerous, malignant, or non-malignant. If a growth comprises cancer, it may be a tumor. Such tumors may be solid or non-solid.
- As used herein, an “immunoassay” is a detection method based on the specific binding of at least one antibody to an antigen, e.g., ELISA, RIA, western blot, and the like.
- As used herein “immunogen”, “immunogenic”, and the like refer to substances that can promote an immune response, e.g., an antibody based or cell mediated immune response, in at least one organism.
- By “immunogenic composition” is meant a composition comprising a molecule capable of inducing or modulating an immune response in a subject. Such an immune response may be a prophylactic or therapeutic immune response. In embodiments, the immunogenic composition is a vaccine or T-cell agonist.
- As used herein, the term “immunotherapeutic agent” refers to any agent, compound, or biologic which is capable of modulating the host's immune system. For example, an immunotherapeutic agent is capable of causing a stimulation of the immune system against a tumor cell.
- As used herein “inducing immunity” is meant to refer to any immune response generated against an antigen. In embodiments, immunity is mediated by antibodies against an infectious agent, which is exhibited by a vertebrate (e.g., a human), that prevents or ameliorates an infection or reduces at least one symptom thereof. The immunogenic compositions of the invention can stimulate the production of antibodies that, for example, neutralize infectious agents, block infectious agents from entering cells, block replication of infectious agents, and/or protect host cells from infection and destruction. The term can also refer to an immune response that is mediated by T-lymphocytes and/or other white blood cells against an infectious agent, exhibited by a vertebrate (e.g., a human), that prevents or ameliorates an infection or reduces at least one symptom thereof. The term “into”, as used herein, refers to the successful penetration of a molecule through or within a cell membrane. For example, a viral vector may be introduced into a solid tumor cell under conditions such that the tumor cell is transfected. In another example, a glycolipid may be introduced into a solid tumor cell under conditions such that the glycolipid becomes inserted into the cell's phospholipid bilayer membrane. In yet another example, an antigen—or a vector encoding the antigen—may be introduced into a solid tumor cell under conditions such that the glycolipid becomes inserted into the cell's phospholipid bilayer membrane.
- As used herein, the term “intracellular permeation enhancing agent” refers to a compound, molecule, substance, or the like that increases the passage of a therapeutic agent across a cell membrane, e.g., a cell of a solid tumor, and thus, enables the exposure of the contents (e.g., proteins, DNA, cellular machinery) of intracellular environment to the therapeutic agent.
- The term “isolated”, as used herein, refers to any composition, molecule, or mixture that has undergone a laboratory purification procedure including, but not limited to, extraction, centrifugation, chromatographic separation (i.e., for example, thin layer chromatography or high performance liquid chromatography). Usually such a purification procedure provides an isolated composition, molecule, or mixture based upon physical, chemical, or electrical potential properties. Depending upon the choice of procedure an isolated composition, molecule, or mixture may contain other compositions, compounds or mixtures having similar chemical properties. For example, an isolated composition, molecule, or mixture may contain between 1-20%, 1-10%, or 1-5% of compositions or mixtures having similar chemical properties. In one embodiment, an isolated composition or mixture comprises a mixture of glycolipids free of cholesterol and phospholipids. In one embodiment, an isolated composition or mixture comprises glycolipids having from between 5-15 glycosidic linkages.
- As used herein, the term “local” or “locally,” as in local administration or coadministration of one or more therapeutics, refers to the delivery of a therapeutic agent to a bodily site that is proximate or nearby the site of a tumor, adjacent or immediately nearby the site of the tumor, at the perimeter of or in contact with the tumor, or within or inside the tumor. Delivery of a therapeutic within the tumor may also be referred to as “intratumoral” administration. Local administration generally excludes systemic administration routes.
- The term “nonresectable”, as used herein, refers to any part of an organ or bodily structure that cannot be surgically removed. For example, a “nonresectable tumor” may be a tumor physically unreachable by conventional surgical techniques or a tumor where its removal does not improve the overall cancer disease of the patient.
- As used herein, “nucleic acid” as in a nucleic acid for delivery to a cell is understood by its usual meaning in the art as a polynucleotide or oligonucleotide which refers to a string of at least two base-sugar-phosphate combinations. Nucleotides are the monomeric units of nucleic acid polymers. The term includes deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in the form of an oligonucleotide messenger RNA, anti-sense, plasmid DNA, parts of a plasmid DNA, genetic material derived from a virus, and the like. Polynucleotides include nucleic acids of at least two monomers. Anti-sense polynucleotides are nucleic acids that interfere with the function of DNA or RNA. An siRNA or an shRNA is a double stranded RNA that inhibits or disrupts activity or translation, for example by promoting degradation of modifying splicing or processing of the cellular nucleic acid, e.g., mRNA, microRNA, and the like, to which it is targeted. As used herein, siRNA and shRNA include any double stranded RNA molecule that can modulate the stability, translation, or splicing of an RNA to which at least one strand of the double stranded nucleic acid hybridizes. RNAs are well known in the art, see e.g., patent publications WO02/44321, WO/2003/099298, US 20050277610, US 20050244858; and U.S. Pat. Nos. 7,297,786, 7,560,438 and 7,056,704, all of which are incorporated herein by reference. Nucleic acid as used herein is understood to include non-natural nucleotides (not occurring in nature), for example: a derivative of natural nucleotides such as phosphothionates or peptide nucleic acids (such as those described in the patents and applications cited immediately above). A nucleic acid can be delivered to a cell in order to produce a cellular change that is therapeutic. The delivery of a nucleic acid or other genetic material for therapeutic purposes is gene therapy. The nucleic acid may express a protein or polypeptide, e.g., a protein that is missing or non-functional in the cell or subject. The nucleic acid may be single or double stranded, may be sense or anti-sense, and can be delivered to a cell as naked DNA, in combination with agents to promote nucleic acid uptake into a cell (e.g., transfection reagents), in the context of a viral vector, and the like. The nucleic acid can be targeted to a nucleic acid that is endogenous to the cell (mRNA or microRNA), or a heterologous nucleic acid (e.g., nucleic acid from a pathogen, such as a viral gene). Delivery of a nucleic acid means to transfer a nucleic acid from outside a subject to within the outer cell membrane of a cell in the subject.
- “Obtaining” is understood herein as manufacturing, purchasing, synthesizing, isolating, purifying, or otherwise coming into possession of
- The term “pharmaceutically acceptable” as used herein, refers to a material, (e.g., a carrier or diluent), which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic (i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained).
- The phrase “pharmaceutically acceptable carrier, excipient, or diluent” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals. As used herein, the term “pharmaceutically acceptable” means being approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopia, European Pharmacopia or other generally recognized pharmacopia for use in mammals, e.g., humans.
- As used herein, the term “pharmaceutically effective regimen” refers to a systematic plan for the administration of one or more therapeutic agents, which includes aspects such as type of therapeutic agent, therapeutic agent concentrations, intratumoral enhancer concentrations, amounts or levels based on the tumor type, location or size, timing, and repetition, and any changes therein made during the course of the drug administration, which when administered is effective in treating a tumor and/or its metastasis. Such considerations depend on the judgment of the practitioner and are readily determinable by one skilled in the art.
- As used herein, the term “proliferative disorder” refers to a disorder wherein the growth of a population of cells exceeds, and is uncoordinated with, that of the surrounding cells. In certain instances, a proliferative disorder leads to the formation of a tumor. In some embodiments, the tumor is benign, pre-malignant, or malignant. In some embodiments, the proliferative disorder is a pancreatic cancer. In some embodiments, the proliferative disorder is a pre-malignant growth on the pancreas.
- A “polypeptide” or “peptide” as used herein is understood as two or more independently selected natural or non-natural amino acids joined by a covalent bond (e.g., a peptide bond). A peptide can include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more natural or non-natural amino acids joined by peptide bonds. Polypeptides as described herein include full length proteins (e.g., fully processed proteins) as well as shorter amino acids sequences (e.g., fragments of naturally occurring proteins or synthetic polypeptide fragments).
- Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.
- By “reduces” is meant a negative alteration of at least 10%, 25%, 50%, 75%, 100%, or any number therebetween.
- By “reference” is meant a standard or control condition.
- As used herein, the term “regimen” refers to the various parameters that characterize how a drug or agent is administered, including, the dosage level, timing, and iterations, as well as the ratio of different drugs or agents to one another. The term “pharmaceutically effective regimen” refers to a particular regimen which provides a desired therapeutic result or effect, including substantial shrinkage and/or destruction of the tumor or cells that have metastasized therefrom. The term “iterations” refer to the general concept of repeating sets of administering one or more agents. For example, a combination of drug X and drug Y may be given (co-administered at or about at the same time and in any order) to a patient on a first day at dose Z. Drugs X and Y may then be administered (co-administered at or about at the same time and in any order) again at dose Z, or another dose, on a second day. The timing between the first and second days can be 1 day or anywhere up to several days, or a week, or several weeks, or months. The iterative administrations may also occur on the same day, separated by a specified number of minutes (e.g., 10 minutes, 20 minutes, 30 minutes or more) or hours (e.g., 1 hour, 2 hours, 4 hours, 6 hours, 12 hours). An effective dosing regimen may be determinable by those of ordinary skill in the art, e.g., prescribing physician, using standard practices.
- A “sample” as used herein refers to a biological material that is isolated from its environment (e.g., blood or tissue from an animal, cells, or conditioned media from tissue culture). In embodiments, the sample is suspected of containing, or known to contain an analyte, such as an infectious agent or a protein of interest (e.g., antibody, cytokine, and the like). A sample can also be a partially purified fraction of a tissue or bodily fluid. A reference sample can be a “normal” sample, from a donor not having the disease or condition fluid, or from a normal tissue in a subject having the disease or condition, or an untreated subject (e.g., a subject not treated with the vaccine). A reference sample can also be taken at a “zero time point” prior to contacting the cell or subject with the agent or therapeutic intervention to be tested.
- As used herein, the term “selectively” means tending to occur at a higher frequency in one population than in another population.
- As used herein, a “solid tumor” refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancerous), or malignant (cancerous). Generally, a solid tumor connotes cancer of body tissues other than blood, bone marrow, or the lymphatic system.
- By “specifically binds” is meant recognition and binding to a target (e.g., polypeptide, cell, and the like), but which does not substantially recognize and bind other molecules in a sample, for example, a biological sample.
- The term “subject”, as used herein, refers to any organism that is capable of developing a solid tumor. Such organisms include, but are not limited to, human, dog, cat, horse, cow, sheep, goat, mouse, rat, guinea pig, monkey, avian, reptiles etc.
- As used herein, the term “substantially shrink or destroy” refers to where the size and/or mass of the tumor has been decreased or altogether eradicated or killed. In the case of tumor shrinkage, the tumor may shrink by at least about 10%, or about 25%, or about 50%, or about 75%, or about 85%, or about 90%, or about by 95%, or by 99%, or more, or any number therebetween. In embodiments, the shrinkage is such that an inoperable tumor is sufficient to permit resection if desired. The concept of substantial shrinkage may also be referred to as “regression,” which refers to a diminution of a bodily growth, such as a tumor. Such a diminution may be determined by a reduction in measured parameters such as, but not limited to, diameter, mass (i.e., weight), or volume. This diminution by no means indicates that the size is completely reduced, only that a measured parameter is quantitatively less than a previous determination.
- In the case of “substantially destroy” a tumor, this term may refer to either the substantial eradication of actual tumor cells or it may refer to substantially killing the tumor cells but where the cells are not removed or eradicated but remain in the body as dead cells and/or tissue. In the case of substantial eradication, the concept refers to the complete cellular breakdown of a bodily growth, such as, for example, a solid tumor. Such destruction may involve intracellular apoptosis and/or macrophage phagocytosis such that the bodily growth is completely digested and eliminated from the body.
- A subject “suffering from or suspected of suffering from” a specific disease, condition, or syndrome has a sufficient number of risk factors or presents with a sufficient number or combination of signs or symptoms of the disease, condition, or syndrome such that a competent individual would diagnose or suspect that the subject was suffering from the disease, condition, or syndrome. Methods for identification of subjects suffering from or suspected of suffering from cancer is within the ability of those in the art. Subjects suffering from, and suspected of suffering from, a specific disease, condition, or syndrome are not necessarily two distinct groups.
- As used herein, “susceptible to” or “prone to” or “predisposed to” a specific disease or condition and the like refers to an individual who based on genetic, environmental, health, and/or other risk factors is more likely to develop a disease or condition than the general population. An increase in likelihood of developing a disease may be an increase of about 10%, 20%, 50%, 100%, 150%, 200%, or more.
- As used herein, the term “targeting moiety” is a moiety that is capable of enhancing the ability of a therapeutic agent, or other agent of the invention (e.g., an intracellular penetration enhancing agent or immunotherapeutic agent) to be targeted to, to bind with, or to enter, a target cell of the invention (e.g., a cancer tumor cell). In certain embodiments, targeting moieties are polypeptides, carbohydrates or lipids. Optionally, targeting moieties are antibodies, antibody fragments or nobodies. Exemplary targeting moieties include tumor targeting moieties, such as somatostatin (sst2), bombesin/GRP, luteinizing hormone-releasing hormone (LHRH), neuropeptide Y (NPY/Y1), neurotensin (NT1), vasoactive intestinal polypeptide (VIP/VPAC1) and cholecystokinin (CCK/CCK2). In certain embodiments, a targeting moiety is non-covalently associated with an agent of the invention.
- As used herein, the terms “treatment”, “treating”, and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. “To treat a cancer or a tumor” or “Treating a cancer or a tumor” in a mammal means one or more of alleviating a symptom of, correcting an underlying molecular or physiological disorder of, or reducing the frequency or severity of a pathological or deleterious physiological consequence of a cancer or a tumor in a subject. By way of example, and not by limitation, the deleterious physiological consequences of a cancer or a tumor can include uncontrolled proliferation, metastasis and invasion of other tissues, and suppression of an immune response. Thus, treatment of a tumor includes, but is not limited to, inhibiting tumor growth, inhibiting tumor cell proliferation, reducing tumor volume, or inhibiting the spread of tumor cells to other parts of the body (metastasis).
- The term “α-gal epitopes”, as used herein, refers to any molecule, or part of a molecule, with a terminal structure comprising Galα1-3Galβ1-4G1cNAc-R, Gal α 1-3Galβ1-3G1cNAc-R, or any carbohydrate chain with terminal Galα 1-3Gal at the non-reducing end.
- The term “glycolipids”, as used herein, refers to any molecule with at least one carbohydrate chain linked to a ceramide, a fatty acid chain, or any other lipid. Alternatively, a glycolipid maybe referred to as a glycosphingolipid.
- The term “α1,3galactosyltransferase” as used herein, refers to any enzyme capable of synthesizing α-gal epitopes.
- The term “anti-Gal binding epitope”, as used herein, refers to any molecule or part of molecule that is capable of binding in vivo the natural anti-Gal antibody.
- The term “β-ManCer” refers to a β-mannosylceramide containing a sphingosine moiety and a fatty acid moiety having a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 49 carbon atoms, from about 18 to about 49 carbon atoms, from about 8 to about 15 carbon atoms, or from about 18 to about 30 carbon atoms. In embodiments, β-ManCer has the following structure:
- The term “sphingosine” as used herein means 2-amino-4-octadecene-1 ,3-diol, which is an 18-carbon amino alcohol with a hydrocarbon chain that forms a primary portion of ceramide molecules.
- The term “ceramide” as used herein, means one of a number of a class of sphingolipids, N-acyl derivatives with long chains of saturated or unsaturated fatty acids. The fatty acid moiety of ceramides can have carbon chain lengths from at least about eight carbons. In embodiments, the fatty acid moiety of β-ManCer can have anywhere from at least about eight carbons in length. For example, it can have a fatty acid moiety of between about 8 carbons to about 49 carbons in length, or for example, it can have a fatty acid moiety of between about 8 carbons to about 15 carbons in length. In other embodiments, the β-ManCer can have a fatty acid moiety of between about 16 carbons and about 30 carbons in length.
- As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a gene” is a reference to one or more genes and includes equivalents thereof known to those skilled in the art, and so forth.
- Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive.
- Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.
- The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
- Other definitions appear in context throughout this disclosure.
- Any therapeutic agents, compositions, or methods provided herein can be combined with one or more of any of the other therapeutic agents, compositions, and methods provided herein.
- The following detailed description, given by way of example, but not intended to limit the invention solely to the specific embodiments described, may best be understood in conjunction with the accompanying drawings.
-
FIG. 1 provides photos of bioluminescent images of s.c.i.d. mice with pancreatic BxPc-3 luciferase treated tumors. -
FIG. 2 is a photo of excised BxPC tumor tissue showing penetration by 50 microliters of enhancer with dye. 50 microliters of enhancer India ink solution was distributed in 2 minutes using a programmable syringe into a BxPc s.c.i.d. mouse tumor of approximately 500 mm3. -
FIG. 3 is a photo of excised BxPC tumor tissue with penetration by 100 microliters of enhancer with dye. 100 microliters of the enhancer India ink solution was distributed in 2 minutes using a programmable syringe pump into a BxPc-3 s.c.i.d. mouse tumor of approximately 500mm3. -
FIG. 4 is a graph showing the bioluminescence (BLI) readings for dosing groups in Example 8 from baseline to 72 hrs. -
FIG. 5 is a graph showing the relative change in bioluminescence (BLI) from baseline to 72 hours. -
FIG. 6 is a graph showing the bioluminescence (BLI) values from baseline today 10 from Example10. -
FIG. 7 is a graph showing the relative bioluminescence (BLI) values from baseline today 10 from Example 10. -
FIG. 8 is a graph showing the body weights changes from baseline today 10 from Example 10 -
FIG. 9 is a graph showing progression of tumor volume for 120 animals that were matched by tumor volume and placed into 12 groups with an initial, predose mean tumor volume per animal per group ranging from 341 mm3 to 349 mm3. The line representing each group is referenced in the legend. -
FIG. 10 is a Kaplan-Meier plot showing the ability of exemplary intracellular formulations of the invention to extend animal life. -
FIGS. 11A-11C are plots depicting results of an exemplary study in which mice whose tumors regressed to less than 18 mm3 were reinoculated with 1×106 CT26 mouse colon cancer cells.FIG. 11A shows progression of tumor growth over time for individual naïve animals.FIG. 11B shows progression of tumor growth over time for individual, complete response, and IT-dosed animals only.FIG. 11C depicts mean tumor growth over time for an age matched control, a complete response animal dosed IT, and a complete response animal IT no outlier. - The present invention provides new regional approaches to treating cancer.
- The invention is based, at least in part, on the discovery that traditional cancer therapeutic agents are surprisingly more effective when locally or regionally administered in combination with an intracellular penetration enhancing agent. The invention is also based on the discovery that administration of at least one immunotherapeutic agent further enhances the anti-cancer effects of the therapeutic agent and the intracellular penetration enhancing agent (e.g., reduced tumor growth and/or reduced tumor size).
- Methods of Treatment
- Surgery remains a most effective means of cancer treatment; however, many tumors are inoperable or have metastasized (e.g., only twenty percent of pancreatic cancers are resectable). In addition, despite ablation (i.e., removal of all surrounding healthy tissue), surgery itself often leaves residual tumor cells at the site or causes cells to escape into the systemic system. These free cells often lead to the formation of additional tumors either locally or distally to the original tumor site.
- Additional methods for regional treatment of tumors include targeted delivery of chemotherapeutics to a cancerous region, without exposure to the rest of the body. See Collins, J. M., J. Clin. Oncol. 2:498-504 (1984); Markman, M., Semin. Oncolo. 12:38-42 (1985); and U.S. Patent Publication No. 2007/0196277; U.S. Pat. No. 4,619,913 October 1986; Jia, Y: Int J Nanomedicine. 2012;7:1697-708, Kim JI: Biomaterials. 2012 June; 33(19):4836-42; Hamstra, D A: J Neurooncol. 2005 July; 73(3):225-38, McArdle Harwood Academic Publishers 2000 ISBN 90-5702-436-5). In this way the normal side effects of chemotherapy, such as nausea, vomiting, hair-loss, and infection can be reduced. Unfortunately, these regional chemotherapeutic approaches have had limited success, if any, in improving outcomes.
- As described in detail herein, a novel regional cancer therapeutic and dosing methodology has been discovered that overcomes the limitations associated with current treatment methods. The novel therapeutic methods involve locally or regionally coadministering a therapeutic agent and an intracellular penetration enhancing agent to a subject, thereby achieving high concentrations of the therapeutic agent in the tumor cells. The delivery methods of the present invention minimize exposure of the rest of the body to the cytotoxic therapeutic agent. The novel therapeutic methods also involve administration of an immunotherapy agent. The immunotherapy agent, which is administered before, during, or after delivery of the therapeutic and intracellular penetration enhancing agents, stimulates the immune system and enhances the anti-cancer effects of the therapeutic agent and the intracellular penetration enhancing agent.
- In aspects, the invention provides methods for inducing an immune response in a subject. The methods involve administering an effective amount of a therapeutic agent and an intracellular permeation enhancing agent. In embodiments, the subject has a tumor. In embodiments, the therapeutic agent and/or the intracellular permeation enhancing agent is locally or regionally administered to the subject.
- In aspects, the invention provides methods for modulating an immune response in a subject. The methods involve administering an effective amount of a therapeutic agent and an intracellular permeation enhancing agent. In embodiments, the subject has a tumor. In embodiments, the therapeutic agent and/or the intracellular permeation enhancing agent is locally or regionally administered to the subject.
- In aspects, the invention provides methods treating a tumor in a subject. The methods involve locally or regionally coadministering to the subject a therapeutic agent and an intracellular permeation enhancing agent.
- In any of the above aspects or embodiments, the tumor can be a solid tumor. In yet other embodiments, the tumor has metastasized. In embodiments, the tumor is a carcinoma or sarcoma. In related embodiments, the tumor is a carcinoma or sarcoma of the skin, bone, muscle, breast, oral cavity, organ, kidney, liver, lung, gallbladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testes, ovaries, or uterus. In certain embodiments, the tumor is a carcinoma of the pancreas or colon.
- In any of the above aspects or embodiments, the therapeutic agent and/or the intracellular permeation enhancing agent can be administered intratumorally.
- In any of the above aspects or embodiments, the method can reduce the growth of the tumor, shrinks the tumor, or eradicates the tumor. In related embodiments, the tumor shrinks by 5%, 10%, 25%, 50%, 75%, 85%, 90%, 95%, or 99% or more as compared to its original size.
- In any of the above aspects or embodiments, the methods can involve administering the therapeutic agent and/or the intracellular permeation enhancing agent on a first day and repeating the administration on one or more subsequent days. In related embodiments, the therapeutic agent and the intracellular permeation enhancing agent are coadministered on the first day and administered again on one or more subsequent days. In yet further related embodiments, the first day and one or more subsequent days are separated by between 1 day and about 3 weeks. In related embodiments, the therapeutic agent and the intracellular permeation enhancing agent are coadministered in a ratio of about 1:2, 1:4, 1:10, 1:20, 1:25, 1:50, 1:100, 1:200, or any ratio therebetween (weight ratio of therapeutic agent: intracellular permeation enhancing agent). It is further contemplated within the scope of the invention that the therapeutic agent and/or the intracellular permeation enhancing agent may be administered over the course of one or more cycles.
- In any of the above aspects or embodiments, the therapeutic agent and the intracellular permeation enhancing agent can be delivered simultaneously. In any of the above aspects or embodiments, the intracellular permeation enhancing agent can be administered before the therapeutic agent.
- In any of the above aspects or embodiments, the therapeutic agent is any anti-cancer therapeutic well known in the art. See, e.g., Anticancer Drugs: Design, Delivery and Pharmacology (Cancer Etiology, Diagnosis and Treatments) (eds. Spencer, P. & Holt, W.) (Nova Science Publishers, 2011); Clinical Guide to Antineoplastic Therapy: A Chemotherapy Handbook (ed. Gullatte) (Oncology Nursing Society, 2007); Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (eds. Polovich, M. et al.) (Oncology Nursing Society, 2009); Physicians' Cancer Chemotherapy Drug Manual 2012 (eds. Chu, E. & DeVita, Jr., V. T.) (Jones & Bartlett Learning, 2011); DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology (eds. DeVita, Jr., V. T. et al.) (Lippincott Williams & Wilkins, 2011); and Clinical Radiation Oncology (eds. Gunderson, L. L. & Tepper, J. E.) (Saunders) (2011), the contents of which are hereby incorporated by references in their entirety.
- In certain embodiments, the therapeutic agent is an anticancer agent. The anticancer can be any anticancer agent well known in the art, including, but not limited to, the chemotherapeutic agents described herein.
- In yet other embodiments, the therapeutic agent is a therapeutic antibody. The therapeutic antibody can be any therapeutic antibody well known in the art, including, but not limited to, those described herein.
- In embodiments, the therapeutic agent is a therapeutic nucleic acid molecule. The therapeutic nucleic acid molecule can be any therapeutic nucleic acid molecule well known in the art.
- In embodiments, the therapeutic agent is a radioisotope. The radioisotope can be any radioisotope well known in the art.
- In embodiments, the therapeutic agent is a thymidylate synthase inhibitor.
- In embodiments, the therapeutic agent is a platinum compound.
- In embodiments, the therapeutic agent is a vinca drug.
- In other embodiments, the therapeutic agent is a combination of two or more drug compounds.
- In any of the above aspects or embodiments, the methods involve administering a therapeutically effective amount of an immunotherapeutic agent. The immunotherapeutic agent may be any suitable means by which to trigger a further immune response that targets destruction of the cells of the tumor. Such targeting by the immune system may also allow the immune system to target tumor cells that have metastasized to other regions of the body.
- In embodiments, the immunotherapeutic agent enhances the immunomodulatory effects of the therapeutic agent and/or the intracellular permeation enhancing agent. In related embodiments, the immunotherapeutic agent further reduces the growth of the tumor or further shrinks the tumor.
- The immunotherapeutic agent can be administered before, during, or after the therapeutic agent and intracellular penetration enhancing agent have been administered. In embodiments, the immunotherapeutic agent is administered before the first administration of the therapeutic agent and the intracellular permeation enhancing agent. In embodiments, the immunotherapeutic agent is administered simultaneously with the first administration of the therapeutic agent and the intracellular permeation enhancing agent.
- In any of the above aspects or embodiments, the therapeutic agent and the immunotherapeutic agent can be administered in a ratio of about 1:2, 1:4, 1:10, 1:25, 1:50, 1:100, 1:200, or any ratio therebetween (weight ratio of therapeutic agent: immunotherapeutic agent).
- In any of the above aspects or embodiments, the intracellular permeation enhancing agent and the immunotherapeutic agent can be administered in a ratio of about 1:2, 1:4, 1:10, 1:20, 1:25, 1:50, 1:100, 1:100, or any ratio therebetween (weight ratio of intracellular permeation enhancing agent: immunotherapeutic agent).
- In any of the above aspects or embodiments, the immunotherapeutic agent can be administered intraperitoneally; locally or regionally; systemically (e.g. intravenously); or intratumorally.
- In any of the above aspects or embodiments, the therapeutic agent and the intracellular permeation enhancing agent can be coupled.
- In any of the above aspects or embodiments, the method can involve further administering a standard of care therapy to the subject. In embodiments, the standard of care therapy is surgery, radiation, systemic chemotherapy, or a combination thereof.
- In any of the above aspects or embodiments, administration of the therapeutic agent, the intracellular permeation enhancing agent, or the immunotherapeutic agent can be conducted with the aid of an imaging system. For example, an imaging system may be used to calculate the volume of a given tumor so that a tumor volume-based dose of the agents of the invention may be calculated. Additionally, it is contemplated within the scope of the invention that such an imaging system may be used to guide a needle to a specific site of injection within the tumor. The imaging system can be any imaging system well known in the art (see, e.g., The MD Anderson Manual of Medical Oncology (eds. Kantarjian, H. M. et al.) (McGraw-Hill Professional, 2011), the contents of which are hereby incorporated by reference in their entirety), and methods for using an imaging system to aid in the administration of a therapeutic agent, an intracellular permeation enhancing agent, or an immunotherapeutic agent are also well known in the art (see, e.g., Majumder, S. et al., Expert Rev. Gastroenterol Hepatol. 6:95-103 (2012); Liu, F. et al., J. Thorac. Oncol. 5:879-84 (2010); Schmuecking, M. etal., Int. J. Radiat. Biol. 85:814-24 (2009); Zhao, B. etal., Radiology 252:263-72 (2009); Thrall, M. M. et al., Gynecol. Oncol. 105:17-22 (2007); Bogoni. L. et al., Br. J. Radiol. 1:557-62 (2005); Bluemke, D. A. et al., Radiographics 17:303-13 (1997); Arimoto, T., Cancer 72:2383-8 (1993); Feyerabend, T. et al., Strahlenther Onkol. 166:405-10 (1990); and Lee, N., IEEE Reviews 2:136-146 (2009), the contents of which are hereby incorporated by reference in their entirety). In embodiments, the imaging system is X-ray computed tomography (CT), fluoroscopy, magnetic resonance imaging (MRI), ultrasound, or positron emission tomography (PET)/computed tomography (CT).
- Therapeutic Agents
- The present invention contemplates any therapeutic agent suitable for use in the methods described herein (e.g., any type of anti-cancer agent to treat cancer). Suitable therapeutic agents include, but are not limited to, pharmaceutical drugs or compounds (i.e., small molecule drugs), therapeutic antibodies, therapeutic proteins or biologics (e.g., hormone therapies), and nucleic acid molecules (e.g., siRNAs).
- In embodiments, the therapeutic agent is an agent that has been shown to have cytotoxic properties against tumor cells. In related embodiments, the therapeutic agent is an existing market-approved pharmaceutical drug or other market-approved composition for treating cancer using a conventional approach.
- The “chemotherapeutic agent” includes chemical reagents that inhibit the growth of proliferating cells or tissues wherein the growth of such cells or tissues is undesirable. Chemotherapeutic agents are well known in the art, and any such agent is suitable for use in the present invention. See, e.g., Anticancer Drugs: Design, Delivery and Pharmacology (Cancer Etiology, Diagnosis and Treatments) (eds. Spencer, P. & Holt, W.) (Nova Science Publishers, 2011); Clinical Guide to Antineoplastic Therapy: A Chemotherapy Handbook (ed. Gullatte) (Oncology Nursing Society, 2007); Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (eds. Polovich, M. et al.) (Oncology Nursing Society, 2009); Physicians' Cancer Chemotherapy Drug Manual 2012 (eds. Chu, E. & DeVita, Jr., V. T.) (Jones & Bartlett Learning, 2011); DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology (eds. DeVita, Jr., V. T. et al.) (Lippincott Williams & Wilkins, 2011); and Clinical Radiation Oncology (eds. Gunderson, L. L. & Tepper, J. E.) (Saunders) (2011), the contents of which are hereby incorporated by references in their entirety.
- In one embodiment, the pharmaceutical drug can be an alkylating agent. Alkylating agents directly damage DNA to prevent the cancer cell from reproducing. As a class of drugs, these agents are not phase-specific; in other words, they work in all phases of the cell cycle. Alkylating agents are used to treat many different cancers, including, but not limited to, leukemia, lymphoma, Hodgkin disease, multiple myeloma, sarcoma, as well as cancers of the lung, breast, and ovary. Examples of alkylating agents include, for example, nitrogen mustards (e.g., mechlorethamine, chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan), alkyl sulfonates (e.g., busulfan), triazines (e.g., dacarbazine (DTIC), temozolomide (Temodar), Nitrosoureas (including streptozocin, carmustine (BCNU), and lomustine), and ethylenimines (e.g., thiotepa and altretamine). In addition, platinum drugs (e.g., cisplatin, carboplatin, and oxalaplatin) are often considered alkylating agents because they kill cancer cells in a similar way. The invention contemplates all of these drugs, or combinations thereof.
- In another embodiment, the invention contemplates any antimetabolite drug. Antimetabolites are a class of drugs that interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA. These agents damage cells during the S phase. They are commonly used to treat leukemias, cancers of the breast, ovary, and the intestinal tract, as well as other types of cancer. Examples of antimetabolites, including, for example, 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), Capecitabine (Xeloda®), Cladribine, Clofarabine, Cytarabine (Ara-C®), Floxuridine, Fludarabine, Gemcitabine (Gemzar®), Hydroxyurea, Methotrexate, Pemetrexed (Alimta®), Pentostatin, and Thioguanine.
- The invention also contemplates the use of an anti-tumor antibiotic, such as anthracyclines. Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in DNA replication. These drugs work in all phases of the cell cycle. They are widely used for a variety of cancers. A major consideration when giving these drugs is that they can permanently damage the heart if given in high doses. For this reason, lifetime dose limits are often placed on these drugs. Examples include Daunorubicin, Doxorubicin
- (Adriamycin®), Epirubicin, and Idarubicin. Other anti-tumor antibiotics include, for example, Actinomycin-D, Bleomycin, and Mitomycin-C.
- Also contemplated are topoisomerase inhibitors. These drugs interfere with enzymes called topoisomerases, which help separate the strands of DNA so they can be copied. They are used to treat certain leukemias, as well as lung, ovarian, gastrointestinal, and other cancers. Examples of topoisomerase I inhibitors include topotecan and irinotecan (CPT-11). Examples of topoisomerase II inhibitors include etoposide (VP-16) and teniposide. Mitoxantrone also inhibits topoisomerase II. Treatment with topoisomerase II inhibitors increases the risk of a second cancer—acute myelogenous leukemia (AML). With this type of drug, a secondary leukemia can be seen as early as 2 to 3 years after the drug is given.
- The present invention also contemplates using therapeutic agents known as mitotic inhibitors. Mitotic inhibitors are often plant alkaloids and other compounds derived from natural products. They can stop mitosis or inhibit enzymes from making proteins needed for cell reproduction. These drugs work during the M phase of the cell cycle, but can damage cells in all phases. They are used to treat many different types of cancer including breast, lung, myelomas, lymphomas, and leukemias. These drugs are known for their potential to cause peripheral nerve damage, which can be a dose-limiting side effect. Examples of mitotic inhibitors include Taxanes (e.g., paclitaxel (Taxo®) and docetaxel (Taxotere®)), Epothilones (e.g., ixabepilone (Ixempra®)), Vinca alkaloids (e.g., vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®), and Estramustine (Emcyt®).
- The anti-cancer agents may also be corticosteroids. Steroids are natural hormones and hormone-like drugs that are useful in treating some types of cancer (lymphoma, leukemias, and multiple myeloma), as well as other illnesses. When these drugs are used to kill cancer cells or slow their growth, they are considered chemotherapy drugs. Corticosteroids are also commonly used as anti-emetics to help prevent nausea and vomiting caused by chemotherapy. They are used before chemotherapy to help prevent severe allergic reactions (hypersensitivity reactions), too. Examples include prednisone, methylprednisolone (e.g., Solumedrol®), and dexamethasone (e.g., Decadron®).
- In certain embodiments, the pharmaceutical agent is selected from the group consisting of: Abiraterone Acetate, Afatinib, Aldesleukin, Alemtuzumab, Alitretinoin, Altretamine, Amifostine, Aminoglutethimide Anagrelide, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, Azathioprine, Bendamustine, Bevacizumab, Bexarotine, Bicalutamide, Bleomycin, Bortezomib, Busulfan, Capecitabine, Carboplatin, Carmustine, Cetuximab, Chlorambucil, Cisplatin, Cladribine, Crizotinib, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, Denileukin diftitox, Decitabine, Docetaxel, Dexamethasone, Doxifluridine, Doxorubicin, Epirubicin, Epoetin Alpha, Epothilone, Erlotinib, Estramustine, Etinostat, Etoposide, Everolimus, Exemestane, Filgrastim, Floxuridine, Fludarabine, Fluorouracil, Fluoxymesterone, Flutamide, folate linked alkaloids, Gefitinib, Gemcitabine, Gemtuzumab ozogamicin, GM-CT-01, Goserelin, Hexamethylmelamine, Hydroxyureas, Ibritumomab, Idarubicin, Ifosfamide, Imatinib, Interferon alpha, Interferon beta, Irinotecan, Ixabepilone, Lapatinib, Leucovorin, Leuprolide, Lenalidomide, Letrozole, Lomustine, Mechlorethamine, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Nelarabine, Nilotinib, Nilutamide, Octreotide, Ofatumumab, Oprelvekin, Oxaliplatin, Paclitaxel, Panitumumab, Pemetrexed, Pentostatin, polysaccharide galectin inhibitors, Procarbazine, Raloxifene, Retinoic acids, Rituximab, Romiplostim, Sargramostim, Sorafenib, Streptozocin, Sunitinib, Tamoxifen, Temsirolimus, Temozolamide, Teniposide, Thalidomide, Thioguanine, Thiotepa, Tioguanine, Topotecan, Toremifene, Tositumomab, Trametinib, Trastuzumab, Tretinoin, Valrubicin, VEGF inhibitors and traps, Vinblastine, Vincristine, Vindesine, Vinorelbine, Vintafolide (EC145), Vorinostat, and their functionally effective derivatives, pegylated forms, salts, polymorphisms, chiral forms and combinations thereof.
- The invention also contemplates any derivative form of the aforementioned pharmaceutical agents and therapeutic agents. Common derivatizations may include, for example, adding a chemical moiety to improve solubility and/or stability, or a targeting moiety, which allows more specific targeting of the molecule to a specific cell or region of the body. The pharmaceutical agents may also be formulated in any suitable combinations, wherein the drugs may either mixed in individual form or coupled together in a manner that retains the functionality of each drug. The drugs may also be derivatized to include a radioisotope or other cell-killing moiety to make the molecule even more effective at killing the cell. In addition, the drugs, or a portion thereof, may be modified with fluorescence compound or other detectable labels which may allow tracking of the drug or agent in the body or within the tumor. The pharmaceutical drug or otherwise any of the aforementioned therapeutic agents may be provided in a precursor form such that they the drug only gains its activity or function after it has been processed in some manner, e.g., metabolized by a cell.
- Therapeutic antibodies contemplated by the present invention may include any isotype (IgA, IgG, IgE, IgM, or IgD) of an anti-cancer antibody or immune-active fragment or derivative thereof. Such fragments can include, for example, single-chain variable fragments (scFv), antigen-binding fragment (Fab), crystallizable fragment (Fc) modified to contain an antigen or epitope binding region, and domain antibodies. Derivatized versions of therapeutic antibodies may include, for example, diabodies, nanobodies, and virtually any antibody-derived structure which contains or is engineered to contain an appropriate and effective antigen binding site.
- Examples of antibody-based anticancer therapies that may be utilized by the invention can include, for example, Abagovomab, Alacizumab pegol, Alemtuzumab, Altumomab pentetate (Hybri-ceaker), Amatuximab, Anatumomab mafenatox, anti-PD-1 antibodies, Apolizumab, Arcitumomab (CEA-Scan), Belimumab, Bevacizumab, Bivatuzumab mertansine, Blinatumomab, Brentuximab vedotin, Cantuzumab mertansine, Cantuzumab ravtansine, Capromab pendetide (Prostascint), Catumaxomab (Removab), Cetuximab (Erbitux), Citatuzumab bogatox, Cixutumumab, Clivatuzumab tetraxetan ( hPAM4-Cide), Conatumumab, Dalotuzumab, Denosumab, Drozitumab, Edrecolomab (Panorex), Enavatuzumab, Gemtuzumab, Ibritumomab tiuxetan, Ipilimumab (MDX-101), Ofatumumab, Panitumumab, Rituximab, Tositumomab, and Trastuzumab.
- The invention also contemplates any suitable biologic, e.g., hormone therapy, that can be used to treat cancer. In one non-limiting example, suitable biologics that may be used include hormone therapy. Drugs in this category can be sex hormones, or hormone-like drugs, that change the action or production of female or male hormones. They can be used to slow the growth of breast, prostate, and endometrial (uterine) cancers, which normally grow in response to natural hormones in the body. These cancer treatment hormones do not work in the same ways as standard chemotherapy drugs, but rather by preventing the cancer cell from using a hormone it requires for grow, or by preventing the body from making the hormones required for growth of the cancer. Such hormone therapies can include, for example, anti-estrogens (e.g., fulvestrant (Faslodex®), tamoxifen, and toremifene (Fareston®), Aromatase inhibitors (e.g., anastrozole (Arimidex), exemestane (Aromasin®), and letrozole (Femara®)), Progestins (e.g., megestrol acetate (Megace®)), Estrogens, Anti-androgens (e.g., bicalutamide (Casodex®), flutamide (Eulexin®), and nilutamde (Nilandron®)), and Gonadotropin-releasing hormone (GnRH) (aka luteinizing hormone-releasing hormone (LHRH) agonists or analogs, e.g., leuprolide (Lupron®) and goserelin (Zoladex®)).
- The invention also contemplates that cancer treatment may be effectuated using a nucleic acid molecule that targets a specified “target gene” that has a role in cancer. The effect of the nucleic acid molecule on the target gene may include gene silencing, mRNA destruction, or inhibited transcription, or the like, such that the level of expression and/or conversion of the target gene to an operable encoded polypeptide are substantially affected (up or down) such that the cancer is inhibited and/or destroyed by the agent. The term “target gene” refers to nucleic acid sequences (e.g., genomic DNAs or mRNAs) encoding a target protein, peptide, or polypeptide, or that encode for or are regulatory nucleic acids (e.g., a “target gene” for purpose of the instant invention can also be a miRNA or miRNA-encoding gene sequence) which have a role in cancer. In certain embodiments, the term “target gene” is also meant to include isoforms, mutants, polymorphisms, and splice variants of target genes.
- Any nucleic acid based agent well known in the art is suitable for use in the invention. Exemplary types of nucleic acid based agents include, but are not limited to, single stranded ribonucleic acid agents (e.g., microRNAs), antisense-type oligonucleotide agents, double-stranded ribonucleic acid agents, and the like.
- Methods for constructing therapeutic nucleic acids are well known in the art. For example, interfering RNA can be assembled from two separate oligonucleotides, where one strand is the sense strand and the other is the antisense strand, wherein the antisense and sense strands are self-complementary (i.e., each strand comprises nucleotide sequence that is complementary to nucleotide sequence in the other strand; such as where the antisense strand and sense strand form a duplex or double stranded structure); the antisense strand comprises nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense strand comprises nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof.
- Alternatively, interfering RNA is assembled from a single oligonucleotide, where the self-complementary sense and antisense regions are linked by means of nucleic acid based or non-nucleic acid-based linker(s). The interfering RNA can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises a nucleotide sequence that is complementary to nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The interfering can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active siRNA molecule capable of mediating RNA interference.
- Methods for administering/delivering therapeutic nucleic acids are well known in the art. For example, therapeutic nucleic acid molecules may be delivered in a delivery vehicle, such as a lipid vesicle or other polymer carrier material known in the art. Non-limiting examples of additional lipid-based carrier systems (which may be prepared with at least one modified cationic lipid of the invention) suitable for use in the present invention include lipoplexes (see, e.g.,U.S. Patent Publication No. 20030203865; and Zhang et al., I Control Release, 100:165-180 (2004)), pH-sensitive lipoplexes (see, e.g., U.S. Patent Publication No. 2002/0192275), reversibly masked lipoplexes (see, e.g., U.S. Patent Publication Nos. 2003/0180950), cationic lipid-based compositions (see, e.g., U.S. Pat. No. 6,756,054; and U.S. Patent Publication No. 2005/0234232), cationic liposomes (see, e.g., U.S. Patent Publication Nos. 2003/0229040, 2002/0160038, and 2002/0012998; U.S. Pat. No. 5,908,635; and PCT Publication No. WO 01/72283), anionic liposomes (see, e.g., U.S. Patent Publication No. 2003/0026831), pH-sensitiveliposomes (see, e.g., U.S. Patent Publication No. 2002/0192274; and AU 2003/210303), antibody-coated liposomes (see, e.g., U.S. Patent Publication No. 2003/0108597; and PCT Publication No. WO 00/50008), cell-type specific liposomes (see, e.g., U.S. Patent Publication No. 2003/0198664), liposomes containing nucleic acid and peptides (see, e.g., U.S. Pat. No. 6,207,456), liposomes containing lipids derivatized with releasable hydrophilic polymers (see, e.g., U.S. Patent Publication No. 2003/0031704), lipid-entrapped nucleic acid (see, e.g., PCT Publication Nos. WO 03/057190 and WO 03/059322), lipid-encapsulated nucleic acid (see, e.g., U.S. Patent Publication No. 2003/0129221; and U.S. Pat. No. 5,756,122), other liposomal compositions (see, e.g., U.S. Patent Publication Nos. 2003/0035829 and 2003/0072794; and U.S. Pat. No. 6,200,599), stabilized mixtures of liposomes and emulsions (see, e.g., EP1304160), emulsion compositions (see, e.g., U.S. Pat. No. 6,747,014), and nucleic acid micro-emulsions (see, e.g., U.S. Patent Publication No. 2005/0037086).
- If suitable, any of the agents of the invention, including pharmaceutical drugs, biologics, and therapeutic antibodies, may also be delivered via the above described carrier systems. All carrier systems may further be modified with a targeting moiety or the like in order to facilitate delivery of the composition to a target tumor of interest.
- In an embodiment, the present invention utilizes platinum compounds as the therapeutic agent. Platinum containing compound have been used for several years as an effective treatment of several types of cancers. Platinum based compounds (e.g., carboplatin, cisplatin, oxaliplatin) are anti-neoplastic agents administered by physicians intravenously (IV) to treat various cancers. Intravenous administration is generally used because the oral bioavailability of carboplatin alone is low (approximately 4%) and highly variable. Platinum based products potently kill fast dividing cells. However, administration of carboplatin by intravenous infusion results in drug throughout the body, killing healthy fast dividing cells including and especially bone marrow cells. Intravenous administration of carboplatin results in a dilute blood concentration of the drug reaching the tumor site. In addition, because of the dilute drug concentration there is poor penetration into the tumor cells.
- Upon entering the cancer cells these compounds damage the DNA and cause cross links in the strands, thereby preventing future DNA production, which ultimately results in cancer cell death. This effect is apparently cell-cycle nonspecific. When given intravenously, platinum can cause severe blood disorders (e.g., anemia bone marrow suppression) resulting in infection or bleeding problems. The major route of elimination of the two main platinum compounds is renal excretion. Cisplatin and carboplatin are generic, platinum-based chemotherapeutic agents and widely available. The chemical name for carboplatin is platinum, diammine [1,1-cyclobutane-dicarboxylato (2-)-0,0]-(SP-4-2). Carboplatin is a crystalline powder with the molecular formula of C6H12N2O4Pt and a molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5-7, whereas Cisplatin is soluble at approximately 1-2 mg/ML. These compounds are virtually insoluble in ethanol, acetone, and dimethylacetamide. They are currently administered only by intravenous infusion.
- In another embodiment, the present invention employs thymidalate synthesis inhibitors. These agents include the agent 5-FU (fluorouracil), which has been in use against cancer for about 40 years. The compound acts in several ways, but principally as a thymidylate synthase inhibitor, interrupting the action of an enzyme which is a critical factor in the synthesis of the pyrimidine thymine-which is important in DNA replication. 5-FU is not orally absorbed. Currently the best treatment therapy for pancreatic cancer is a course of therapy using Gemcitabine (Gemzar).
- As a pyrimidine analogue, these compounds are transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA and RNA, finally inducing cell cycle arrest and apoptosis by inhibiting the cell's ability to synthesize DNA. These compounds are typically S-phase specific drug and only active during certain cell cycles. In addition to being incorporated in DNA and RNA, these drugs have been shown to inhibit the activity of the exosome complex, an exoribonuclease complex of which the activity is essential for cell survival.
- Intracellular Penetration Enhancing Agents
- The present invention is based, in part, on penetration agents, such as benzoate linked aliphatic acids, functionalized keto acids (e.g. oxo-6-phenylhexanoic acid), keto esters, modified acylated amino acids (e.g., sodium N-[8-2-(2-hyrodxybenzoyl) amino caprylate), to substantially enhance drug permeability or penetration into cancer cells to surprisingly increase and unexpectedly improve cancer cell killing. Thus, in one aspect, the present invention provides a method for treating cancer by locally or regionally coadministering a combination of a therapeutic agent, such as those described above, together with an intracellular penetration enhancing agent in amounts and in a manner that results in substantial tumor shrinkage and/or destruction.
- The invention contemplates any suitable intracellular penetration enhancing agent, known or yet to be discovered or developed.
- A number of drug delivery companies have developed such compounds to increase cell penetration for purposes of delivery charged or macromolecule compounds to the blood stream by non inj ection methods. Such companies include Emisphere Technologies, Acrux Pharma Pty, Ltd., Oramed Pharmaceuticals, Apollo Life Sciences, Diabetology, and Unigene. Generally, these platforms were developed to achieve systemic delivery of therapeutics via conventional routes, such as, oral, buccal, pulmonary or dermal; however, none contemplated the present usage of such penetration enhancing agents in the manner described in conjunction with the present invention.
- It will be appreciated that conventional means for delivering active agents are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, or the target itself. Biologically or chemically active agents are particularly vulnerable to such barriers. In the delivery to animals of biologically active or chemically active pharmacological and therapeutic agents, physical and chemical barriers are imposed by the body. Examples of physical barriers are the skin and various organ membranes that are traversed before reaching a target, and examples of chemical barriers include, but are not limited to, variations in pH, lipid bilayers, and degrading enzymes. The cellular membrane also represents an important barrier having a significant effect on the effectiveness of drug delivery.
- The present invention is based on combining the delivery of an anticancer therapeutic with an intracellular penetration enhancing agent administered locally using advanced imaging techniques to set the dose and guide the administration prior to or at or at about the same time as the therapeutic agent to substantially enhance cellular membrane penetration of the locally-delivered anti-cancer agents.
- Accordingly, in one aspect of the invention, the method described herein involves a “penetration enhancer” or carrier that imparts improved cell transport. These molecules facilitate or enable the penetration and/or transport of therapeutic molecules across biological membranes into cells. This specific use for such penetration compounds, such as those described in Emisphere Technologies' U.S. Pat. No. 5,650,386 (which is incorporated by reference in its entirety), has not previously been contemplated. In other words, the combination of permeation enhancers capable of facilitating intracellular transport of locally delivered anticancer agents was not previously considered or contemplated in the art.
- In one embodiment, the present invention comprises 6-oxo-6-phenyl hexanoic acid as the intracellular penetration enhancing compound or a salt or analog thereof,
- in a method for treating cancer, e.g., a solid tumor, comprising locally coadministering the above compound and an anticancer therapeutic agent in therapeutically effective amounts and in accordance with a regimen that is effective to cause substantial shrinkage of the tumor and/or destruction of the tumor.
- In other embodiments, the intracellular penetration enhancing agent is modified amino acids, N48-(2-hydroxybenzoyl)aminooctanoic acid,
- N-[8-(2-hydroxybenzoyl)aminodecanoic acid, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-[4-(4-chloro-2hydroxybenzoyl)amino]butanoic acid, 8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic acid (4-MOAC), 8-Oxo-8-phenyloctanoic acid, 8-(2,5-Dichlorophenyl)-8-oxooctanoic acid, 2-ethylhexyl 2-hydroxybenzoate, 5-Cyclohexyl-5-oxoyaleric acid, 6-Cyclohexyl-6-oxohexanoic acid, 7-Cyclohexyl-7-oxoheptanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, 4-Cyclopentyl-4-oxobutyric acid, 5-Cyclopentyl-5-oxovaleric acid, 6-Cyclopentyl-6-oxohexanoic acid, 7-Cyclopentyl-7-oxoheptanoic acid, 8-Cyclopentyl-8-oxooctanoic acid, 4-Cyclobutyl-4-oxobutyric acid, 5-Cyclobutyl-5-oxovaleric acid, 6-Cyclobutyl-6-oxohexanoic acid, 7-Cyclobutyl-7-oxoheptanoic acid, 8-Cyclobutyl-8-oxooctanoic acid, 4-Cyclopropyl-4-oxobutyric acid, 5-Cyclopropyl-5-oxovaleric acid, 6-Cyclopropyl-6-oxohexanoic acid, 7-Cyclopropyl-7-oxoheptanoic acid, 8-Cyclopropyl-8-oxooctanoic acid, 8-[(3-methylcyclohexyl)oxy]octanoic acid, 7-[(3-methylcyclohexyl)oxy]heptanoic acid, 6-[(3-methylcyclohexyl)oxy]hexanoic acid, 5-[(3-methylcyclohexyl)oxy]pentanoic acid, 4-[(3-methylcyclohexyl)oxy]butanoic acid, 3-[(3-methylcyclohexyl)oxy]propanoic acid and other pharmaceutically acceptable salts thereof, as well as octyl salicylate or, octisalate, Diketopiperazines, saponin, Acylcarnitines, Alkanoylcholines, taurodihydrofusidate, sulphoxides, Oxazolidinones, pyrrolidones, alcohols and alkanols, benzoic acid, glycols, surfactants, terpenes or their functionally effective salts, derivatives or combinations thereof.
- In yet further embodiments, the intracellular penetration enhancing compound is selected from any one of the compounds described in U.S. Pat. Nos. 4,764,381; 4,783,450; 4,885,174; 4,983,396; 5,045,553; 5,118,845; 5,219,877; 5,401,516; 5,451,410; 5,540,939; 5,443,841; 5,541,155; 5,578,323; 5,601,839; 5,601,846; 5,627,270; 5,629,020; 5,643,957; 5,650,386; 5,693,338; 5,693,769; 5,709,861; 5,714,167; 5,773,647; 5,766,633; 5,776,888; 5,792,451; 5,804,688; 5,863,944; 5,866,536; 5,876,710; 5,879,681; 5,820,881; 5,834,010; 5,840,340; 5,935,601; 5,939,381; 5,955,503; 5,990,166; 5,958,457; 5,965,121; 5,972,387; 5,976,569; 5,989,539; 6,001,347; 6,051,258; 6,051,561; 6,060,513; 6,071,510; 6,090,958; 6,099,856; 6,100,298; 6,180,140; 6,221,367; 6,242,495; 6,245,359; 6,313,088; 6,331,318; 6,333,046; 6,344,213; 6,358,504; 6,395,774; 6,413,550; 6,428,780; 6,461,643; 6,525,020; 6,610,329; 6,623,731; 6,627,228; 6,642,411; 6,646,162; 6,663,887; 6,663,898; 6,693,208; 6,699,467; 6,673,574; 6,818,226; 6,846,844; 6,906,030; 6,916,489; 6,916,789; 6,960,355; 6,972,300; 6,991,798; 7,005,141; 7,067,119; 7,071,214; 7,084,279; 7,115,663; 7,125,910; 7,129,274; 7,138,546; 7,151,191; 7,186,414; 7,208,483; 7,217,703; 7,268,214; 7,276,534; 7,279,597; 7,297,794; 7,351,741; 7,384,982; 7,387,789; 7,390,834; 7,485,321; 7,491,796; 7,495,030; 7,553,872; 7,638,599; 7,670,626; 7,700,775; 7,727,558; 7,744,910; 7,820,722; 7,893,297; 7,951,971; 7,977,506; 8,003,697; 8,017,727; 8,026,392; 8,088,734; and RE35,862, each of which is hereby incorporated by reference.
- Intracellular penetration enhancers in general have little to no known pharmacological activity themselves. These technologies, such as those described and shown above, make it possible to penetrate membranes to deliver a therapeutic agent without altering its chemical form or biological integrity. Such penetration enhancers have demonstrated significantly increased absorption of several different types of agents.
- Immunotherapeutic Agents
- In another aspect, the invention employs one or more immunotherapeutic agents to further enhance the tumor cell inhibitory and/or destructive effects imparted by the combination of the anticancer therapeutic agent with the intracellular penetration enhancing agent. For example, the immunotherapeutic agent is delivered after the effects of the first two agents have set in, but the invention is not limited to this concept. The invention contemplates any administration regimen involving all three agents so long as the therapeutic benefits attributable to the each of the agents may occur. It is also contemplated within the scope of the invention that administration of the one or more immunotherapeutic agents have immunostimulatory activity that provides prophylaxis against further recurrence of a cancer. This immunostimulatory effect can be achieved when the agent is given intratumorally or intraperitoneally either with or without an intracellular penetration enhancer.
- Those skilled in the art will appreciate that an immunotherapeutic agent is a treatment that aims to use an individual's own immune system to fight cancer or disease. This may be accomplished by boosting the individual's own immune system or to provide supplemental pieces of an otherwise defective or deficient immune system.
- Immunotherapy is a form of biological therapy which can be used in the present invention supplement and/or enhance the effects of treating with the therapeutic agent/penetration enhancing treatment. There are generally two recognized forms of immunotherapy, which are referred to as active immunotherapies and passive immunotherapies. Active immunotherapies stimulate the body's own immune system to fight a disease. Passive immunotherapies use immune system components, such as antibodies, prepared outside the body, to enhance the body's immune response level. Immunotherapies may also work by targeting certain types of cells or antigens (specific immunotherapies) or they may work by more generally stimulating the immune system (non-specific immunotherapies, or sometimes referred to as adjuvants). Some examples of immunotherapies contemplated by the invention include monoclonal antibody therapy (such as rituximab and alemtuzumab), non-specific immunotherapies and adjuvants (substances which boost the immune response such as interleukin-2 and interferon-alpha), immunomodulating drugs (such as thalidomide and lenalidomide), and cancer vaccines (e.g., NKT cell agonists, including but not limited to α-GalCer, βMannCer, or a-Gal glycolipids).
- Accordingly, immunotherapeutic agents, which may also be referred to in same meaning as “immunomodulator” can include, for example, interleukins (e.g., IL-2, IL-7, or IL-12), certain other cytokines (e.g., interferons, growth colony stimulating factor (G-CSF), imiquimod), chemokines, and other types of agents, which can include antigens, epitopes, antibodies, monoclonal antibodies, or even a delivery vehicle to deliver one or more of these compounds, and may even also include recombinant immune system cells. Such immunotherapeutic agents can include recombinant forms, synthetic forms, and natural preparations (see D′Alessandro, N. et al., Cancer Therapy: Differentiation, Immunomodulation and Angiogenesis, New York: Springer-Verlag, 1993).
- In certain embodiments, the immunotherapeutic agent of the invention is a cancer vaccine that may include, for example, Ovalabumin, Neuvenge®, Oncophage, CimaVax-EGF, Mobilan, a-Gal glycolipids, adenovirus delivered vaccines, Celldex's CDX1307 and CDX1401; GRNVAC1, viral based vaccines, MVA-BN, PROSTVAC®, Advaxis'; ADXS11-001, ADXS31-001, ADXS31-164, BiovaxID, folate binding protein (E39), Granulocyte macrophage colony stimulating factor (GM-CSF) with and without E75 (NeuVax) or OncoVEX, trastuzumab, Ae-37, IMA901, SC1B1, Stimuvax, peptides that can elicit cytotoxic lymphocyte response, peptide vaccines including telomerase peptide vaccine (GV1001), survivin peptide, MUC1 peptide, ras peptide, TARP 29-37-9V Peptide epitope enhanced peptide, DNA Vector pPRA-PSM with synthetic peptides E-PRA and E-PSM; Ad.p53 DC vaccine, NY-ESO-1 Plasmid DNA (pPJV7611), genetically modified allogeneic (human) tumor cells for the expression of IL-1, IL-7, GM-CSF, CD80 or CD154, HyperAcute(R)-Pancreatic cancer vaccine (HAPa-1 and HAPa-2 components), Melaxin (autologous dendritoma vaccine) and BCG, GVAX (CG8123), CD40 ligand and IL-2 gene modified autologous skin fibroblasts and tumor cells, ALVAC-hB7.1, Vaximm Gmbh's VXM01, Immunovative Therapies' AlloStim-7, ProstAtak™ TG4023 (MVA-FCU1), Antigenic's HSPPC-96, Immunovaccine Technologies' DPX-0907 which consists of specific HLA-A2-restricted peptides, a universal T Helper peptide, a polynucleotide adjuvant, a liposome and Montanide (ISA51 VG), GSK2302032A, Memgen's ISF35, Avax's OVax: Autologous, DNP-Modified Ovarian vaccine, Theratope®, Ad100-gp96Ig-HLA Al, Bioven's recombinant Human rEGF-P64K/Montanide vaccine, TARP 29-37, or Dendreon's DN24-02.
- In another embodiment, the immunotherapeutic agent takes advantage of the body's innate immune system and has the effect when introduced of triggering the innate immune response against the unwanted cancer or tumor. In one embodiment in particular, the present invention utilizes an immunotherapeutic agent that effectively converts the target tumor into a vaccine in situ (e.g., utilization of a NKT cell anti-tumor agent).
- For example, this embodiment can involve generating autologous tumor-associated antigens (TAA) in treated patients. a-Gal glycolipids carry the carbohydrate α-gal epitope (Galα1-3β1-4G1cNac-R) which binds the most abundant naturally-occurring antibody in humans—the anti-Gal antibody. The anti-Gal antibody is present in high concentrations due to the continuous exposure to the α-Gal epitope due to its presence in bacteria. Human tissue does not contain natural α-Gal epitopes as that would cause an attack by the immune system on that tissue. Thus tumors are not vulnerable to attack by naturally occurring anti-α-Gal antibodies. The underlying inventive aspect is that α-Gal glycolipids injected as micelles insert into tumor cell membranes resulting in α-Gal epitope expression on tumor cells and thus the binding of the natural anti-Gal antibody. In this manner, the tumor itself becomes a vaccine in situ. The Ag-epitope/Gal Ab interaction activates complement and generates complement cleavage chemotactic factors that recruit antigen presenting cells (APC). The APC transport internalized TAA to regional lymph nodes, process and present the multiple TAA peptides for activation of tumor specific T cells. The T cells proliferate, leave the lymph nodes and circulate to seek and destroy the tumor and any micrometastases presenting the autologous TAA.
- The technology has been demonstrated to be highly effective in vivo. Intratumoral injection of a-gal epitopes linked to lipids in a knock-out mouse model (i.e. α-gal epitope absent mice) with developed adenocarcinoma tumors of significant size have demonstrated regression of the tumors and prevention of distal metastasis. In addition, a dose ranging, human clinical study (ND filed) that administered GMP produced a-Gal lipids to 11 patients with late state adenocarcinomas demonstrated the safety of the system and an increased life expectancy for a number of patients including those with pancreatic adenocarcinoma. Additional descriptive support of this immunotherapeutic agent can be found in U.S. Patent No. 7,820,628, which is incorporated by reference in its entirety.
- In another embodiment, the invention involves use of β-mannosylceramide (β-ManCer) to treat patients. β-ManCer is an NKT agonist that promotes immunity against tumors and infectious agents through nitric oxide and TNFαdependent mechanisms. β-ManCer can also be used with α-GalCer to synergistically enhance the effects of α-GalCer. The β-ManCer can contain a sphingosine moiety and a fatty acid moiety having a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 49 carbon atoms, from about 18 to about 49 carbon atoms, from about 8 to about 15 carbon atoms, or from about 18 to about 30 carbon atoms. In related embodiments, β-ManCer has the following structure:
- Additional descriptive support of this immunotherapeutic agent can be found in International Patent Application No. PCT/US2011/028024, which is incorporated by reference in its entirety.
- Accordingly, in one aspect, the present invention comprises locally co-administering an anticancer therapeutic agent and an intracellular penetration enhancing agent in therapeutically effective amounts and in accordance with a regimen that results in substantial shrinkage and/or destruction of a target tumor. The method of the invention further comprises enhancing the effects of the therapeutic agent and the intracellular penetration enhancing agent by administering an immunotherapeutic agent. The treatment results in substantial shrinkage and/or destruction of tumor cells, any micrometastases or metastasized cells that have relocated to other parts of the body. In an embodiment, the immunotherapeutic agent is a cancer vaccine that causes the tumor to function as an in situ vaccine, e.g., introduction of the a-gal epitopes into the tumor.
- Introduction of the immunotherapeutic agents of the invention, e.g., a cancer vaccine (e.g., T-cell agonists), may be achieved using any suitable approach, including by local or regional administration of the agent at, near, or within the tumor or micrometastases. The agent may also be delivered, where suitable, via gene therapy. For example, in the case of a cancer vaccine that involves introducing a particular antibody-inducing antigen in a tumor, the antibody-inducing antigen may be introduced by injecting or otherwise directly administering a genetic vector or otherwise nucleic acid molecule capable of expressing the desired antigen in the tumor. The antigens themselves may also be directly administered into the targettissue.
- Target Cancers
- The present invention contemplates treating a broad range of diseases, including tumors of all types, locations, sizes, and characteristics. For example, the method of the invention is suitable for treating, for example, pancreatic cancer and colon cancer.
- In other embodiments, virtually any type of cancer may be treatable by the present invention, including the following cancers:
- Acute myeloid leukemia
- Adrenocortical carcinoma
- AIDS-related cancers
- AIDS-related lymphoma
- Anal cancer
- Appendix cancer
- Astrocytoma, childhood cerebellar or cerebra
- Basal cell carcinoma
- Bile duct cancer, extrahepatic
- Bladder cancer
- Bone cancer, Osteosarcoma/Malignant fibrous histiocytoma
- Brainstemglioma
- Brain tumor
- Brain tumor, cerebellar astrocytoma
- Brain tumor, cerebral astrocytoma/malignant glioma
- Brain tumor, ependymoma
- Brain tumor, medulloblastoma
- Brain tumor, supratentorial primitive neuroectodermal tumors
- Brain tumor, visual pathway and hypothalamic glioma
- Breast cancer
- Bronchial adenomas/carcinoids
- Burkitt lymphoma
- Carcinoid tumor, childhood
- Carcinoid tumor, gastrointestinal
- Carcinoma of unknown primary
- Central nervous system lymphoma, primary
- Cerebellar astrocytoma, childhood
- Cerebral astrocytoma/Malignantglioma, childhood
- Cervical cancer
- Childhood cancers
- Chronic lymphocytic leukemia
- Chronic myelogenous leukemia
- Chronic myeloproliferative disorders
- Colon Cancer
- Cutaneous T-cell lymphoma
- Desmoplastic small round cell tumor
- Endometrial cancer
- Ependymoma
- Esophageal cancer
- Ewing's sarcoma in the Ewing family of tumors
- Extracranial germ cell tumor, Childhood
- Extragonadal Germ cell tumor
- Extrahepatic bile duct cancer
- Eye Cancer, Intraocular melanoma
- Eye Cancer, Retinoblastoma
- Gallbladder cancer
- Gastric (Stomach) cancer
- Gastrointestinal Carcinoid Tumor
- Gastrointestinal stromal tumor (GIST)
- Germ cell tumor: extracranial, extragonadal, or ovarian
- Gestational trophoblastic tumor
- Glioma of the brain stem
- Glioma, Childhood Cerebral Astrocytoma
- Glioma, Childhood Visual Pathway and Hypothalamic
- Gastric carcinoid
- Hairy cell leukemia
- Head and neck cancer
- Heart cancer
- Hepatocellular (liver) cancer
- Hodgkin lymphoma
- Hypopharyngeal cancer
- Hypothalamic and visual pathway glioma, childhood
- Intraocular Melanoma
- Islet Cell Carcinoma (Endocrine Pancreas)
- Kaposi sarcoma
- Kidney cancer (renal cell cancer)
- Laryngeal Cancer
- Leukemias
- Leukemia, acute lymphoblastic (also called acute lymphocytic leukemia)
- Leukemia, acute myeloid (also called acute myelogenous leukemia)
- Leukemia, chronic lymphocytic (also called chronic lymphocytic leukemia)
- Leukemia, chronic myelogenous (also called chronic myeloid leukemia)
- Leukemia, hairy cell
- Lip and Oral Cavity Cancer
- Liposarcoma
- Liver Cancer (Primary)
- Lung Cancer, Non-Small Cell
- Lung Cancer, Small Cell
- Lymphomas
- Lymphoma, AIDS-related
- Lymphoma, Burkitt
- Lymphoma, cutaneous T-Cell
- Lymphoma, Hodgkin
- Lymphomas, Non-Hodgkin (an old classification of all lymphomas except Hodgkin's)
- Lymphoma, Primary Central Nervous System
- Macroglobulinemia, Waldenstrom
- Malignant Fibrous Histiocytoma ofBone/Osteosarcoma
- Medulloblastoma, Childhood
- Melanoma
- Melanoma, Intraocular (Eye)
- Merkel Cell Carcinoma
- Mesothelioma, Adult Malignant
- Mesothelioma, Childhood
- Metastatic Squamous Neck Cancer with Occult Primary
- Mouth Cancer
- Multiple Endocrine Neoplasia Syndrome, Childhood
- Multiple Myeloma/Plasma Cell Neoplasm
- Mycosis Fungoides
- Myelodysplastic Syndromes
- Myelodysplastic/Myeloproliferative Diseases
- Myelogenous Leukemia, Chronic
- Myeloid Leukemia, Adult Acute
- Myeloid Leukemia, Childhood Acute
- Myeloma, Multiple (Cancer of the Bone-Marrow)
- Myeloproliferative Disorders, Chronic
- Nasal cavity and paranasal sinus cancer
- Nasopharyngeal carcinoma
- Neuroblastoma
- Non-Hodgkin lymphoma
- Non-small cell lung cancer
- Oral Cancer
- Oropharyngeal cancer
- Osteosarcoma/malignant fibrous histiocytoma of bone
- Ovarian cancer
- Ovarian epithelial cancer (Surface epithelial-stromal tumor)
- Ovarian germ cell tumor
- Ovarian low malignant potential tumor
- Pancreatic cancer
- Pancreatic cancer, islet cell
- Paranasal sinus and nasal cavity cancer
- Parathyroid cancer
- Penile cancer
- Pharyngeal cancer
- Pheochromocytoma
- Pineal astrocytoma
- Pineal germinoma
- Pineoblastoma and supratentorial primitive neuroectodermal tumors, childhood
- Pituitary adenoma
- Plasma cell neoplasia/Multiple myeloma
- Pleuropulmonary blastoma
- Primary central nervous system lymphoma
- Prostate cancer
- Rectal cancer
- Renal cell carcinoma (kidney cancer)
- Renal pelvis and ureter, transitional cell cancer
- Retinoblastoma
- Rhabdomyosarcoma, childhood
- Salivary gland cancer
- Sarcoma, Ewing family of tumors
- Sarcoma, Kaposi
- Sarcoma, softtissue
- Sarcoma, uterine
- Sézary syndrome
- Skin cancer (nonmelanoma)
- Skin cancer (melanoma)
- Skin carcinoma, Merkel cell
- Small cell lung cancer
- Small intestine cancer
- Soft tissue sarcoma
- Squamous cell carcinoma—see Skin cancer (nonmelanoma)
- Squamous neck cancer with occult primary, metastatic
- Stomach cancer
- Supratentorial primitive neuroectodermal tumor, childhood
- T-Cell lymphoma, cutaneous—see Mycosis Fungoides and Sézary syndrome
- Testicular cancer
- Throat cancer
- Thymoma, childhood
- Thymoma and Thymic carcinoma
- Thyroid cancer
- Thyroid cancer, childhood
- Transitional cell cancer of the renal pelvis and ureter
- Trophoblastic tumor, gestational
- Unknown primary site, carcinoma of, adult
- Unknown primary site, cancer of, childhood
- Ureter and renal pelvis, transitional cell cancer
- Urethral cancer
- Uterine cancer, endometrial
- Uterine sarcoma
- Vaginal cancer
- Visual pathway and hypothalamic glioma, childhood
- Vulvar cancer
- Waldenström macroglobulinemi
- Wilms tumor (kidney cancer), childhood
- Those of ordinary skill in the art will appreciate how cancers are classified. Typically, cancers are classified by the type of cell that the tumor cell resembles and is therefore presumed to be the origin of the tumor. These types include:
- Carcinoma: Cancers derived from epithelial cells. This group includes many of the most common cancers, particularly in the aged, and include nearly all those developing in the breast, prostate, lung, pancreas, and colon.
- Sarcoma: Cancers arising from connective tissue (i.e. bone, cartilage, fat, nerve), each of which develop from cells originating in mesenchymal cells outside the bone marrow.
- Lymphoma and leukemia: These two classes of cancer arise from hematopoietic (blood-forming) cells that leave the marrow and tend to mature in the lymph nodes and blood, respectively.
- Germ cell tumor: Cancers derived from pluripotent cells, most often presenting in the testicle or the ovary (seminoma and dysgerminoma, respectively).
- Blastoma: Cancers derived from immature “precursor” cells or embryonic tissue. These are also most common in children.
- Moreover, it will be appreciated that cancers are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ or tissue of origin as the root. For example, cancers of the liver parenchyma arising from malignant epithelial cells is called hepatocarcinoma, while a malignancy arising from primitive liver precursor cells is called a hepatoblastoma, and a cancer arising from fat cells is called a liposarcoma. For some common cancers, the English organ name is used. For example, the most common type of breast cancer is called ductal carcinoma of the breast. Here, the adjective ductal refers to the appearance of the cancer under the microscope, which suggests that it has originated in the milk ducts.
- Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. For example, a benign tumor of smooth muscle cells is called a leiomyoma (the common name of this frequently occurring benign tumor in the uterus is fibroid). Confusingly, some types of cancer also use the -oma suffix, examples including melanoma and seminoma.
- Some types of cancer are named for the size and shape of the cells under a microscope, such as giant cell carcinoma, spindle cell carcinoma, and small cell carcinoma.
- The present invention generally can treat all forms of the above cancers. For example, the method of the invention advantageously may treat solid tumors arising in any tissue of the body including, but not limited to, the skin, bone, muscle, breast, organ, kidney, liver, lung, gallbladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testes, ovaries, or uterus.
- The present invention generally also may treat all forms of the above cancers and where the cancer is at any stage. The skilled person will appreciate that cancer severity is staged (I to IV) with survival prognosis in stage III and IV often being low for several cancer types.
- The present invention also may be effective against tumors that arise from metastasis of another source or primary tumor. The metastasized sites may be visible tumors, or may also be at the level of single cells, or micrometastases.
- In an embodiment, the present invention is directed to a method for treating a pancreatic tumor or metastasized pancreatic tumor.
- In an exemplary embodiment, the present invention is directed to a method for treating a colon tumor or metastasized colon tumor.
- Reduction of tumor growth means a measurable decrease in growth of the tumor of at least about 0.01-fold (for example 0.01, 0.1, 1, 3, 4, 5, 10, 100, 1000-fold or more) or decrease by at least about 0.01% (for example 0.01, 0.1, 1, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99 or 100%) as compared to the growth measured over time prior to treatment as defined herein.
- Full eradication of the tumor may also be achieved through methods of the invention. Eradication refers elimination of the tumor. The tumor is considered to be eliminated when it is no longer detectable using detection methods known in the art (e.g., imaging).
- Pharmaceutical Compositions
- The invention provides pharmaceutical compositions for use in any of the methods described herein. The pharmaceutical compositions contain a therapeutic agent, an intracellular permeation enhancing agent, and/or an immunotherapeutic agent.
- In embodiments, the pharmaceutical compositions include a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, olive oil, gel (e.g., hydrogel), and the like. Saline is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers particularly for inj ectable solutions.
- Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin, the contents of which are hereby incorporated by reference in its entirety. Such compositions will generally contain a therapeutically effective amount of the therapeutic agent, the intracellular permeation enhancing agent, and/or the immunotherapeutic agent, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
- In embodiments, the therapeutic agent, the intracellular permeation enhancing agent or their combination, and/or the immunotherapeutic agent are administered locally as an immediate release or controlled release composition, for example by controlled dissolution and/or the diffusion of the active substance. Dissolution or diffusion controlled release can be achieved by incorporating the active substance into an appropriate matrix. A controlled release matrix may include one or more of shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
- In related embodiments, the controlled release matrix is a hydrogel. A hydrogel is a three-dimensional, hydrophilic or amphiphilic polymeric network capable of taking up large quantities of water. The networks are composed of homopolymers or copolymers, which are insoluble due to the presence of covalent chemical or physical (e.g., ionic, hydrophobic interactions, entanglements) crosslinks. The crosslinks provide the network structure and physical integrity. Hydrogels exhibit a thermodynamic compatibility with water that allows them to swell in aqueous media. The chains of the network are connected in such a fashion that pores exist and that a substantial fraction of these pores are of dimensions between 1 nm and 1000nm.
- The hydrogels can be prepared by crosslinking hydrophilic biopolymers or synthetic polymers. Examples of the hydrogels formed from physical or chemical crosslinking of hydrophilic biopolymers, include but are not limited to, hyaluronans, chitosans, alginates, collagen, dextran, pectin, carrageenan, polylysine, gelatin, agarose, (meth)acrylate-oligolactide-PEO-oligolactide-(meth)acrylate, poly(ethylene glycol) (PEO), poly(propyleneglycol) (PPO), PEO-PPO-PEO copolymers (Pluronics), poly(phosphazene), poly(methacrylates), poly(N-vinylpyrrolidone), PL(G)A-PEO-PL(G)A copolymers, poly(ethylene imine), and the like. See Hennink and van Nostrum, Adv. Drug Del. Rev. 54:13-36 (2002); Hoffman, Adv. Drug Del. Rev. 43:3-12 (2002); Cadee et al., J Control. Release 78:1-13 (2002); Surini et al., J. Control. Release 90:291-301 (2003); and U.S. Patent No. 7,968,085, each of which is incorporated by reference in its entirety. These materials consist of high-molecular weight backbone chains made of linear or branched polysaccharides or polypeptides.
- The amount of the pharmaceutical composition of the invention which will be effective in the treatment or prevention of a solid tumor may depend on the nature of the tumor and can be determined by standard clinical techniques, including imaging techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation may also depend on the route of administration, and the seriousness of the tumor, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
- Dosages and Administration Regimens
- The therapeutic agents, intracellular permeation enhancing agents, immunotherapeutic agents, or compositions containing these agents are administered in a manner compatible with the dosage formulation, and in such amount as may be therapeutically affective, protective andimmunogenic. The agents and/or compositions may be administered through different routes, including, but not limited to, oral, parenteral, buccal and sublingual, rectal, aerosol, nasal, intramuscular, subcutaneous, intradermal, and topical. The term parenteral as used herein includes, for example, intraocular, subcutaneous, intraperitoneal, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional, and intracranial inj ection, or other infusion techniques.
- In embodiments, administration of the therapeutic agents and/or the intracellular permeation enhancing agent is delivered locally or regionally (e.g., intratumorally).
- In embodiments, the agents and/or compositions formulated according to the present invention are formulated and delivered in a manner to evoke a systemic immune response. Thus, in embodiments, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers. Formulations suitable for administration include aqueous and non-aqueous sterile solutions, which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, immediately prior to use. Extemporaneous solutions and suspensions may be prepared from sterile powders, granules and tablets commonly used by one of ordinary skill in the art.
- The agents and/or compositions may be administered in different forms, including, but not limited to, solutions, emulsions and suspensions, microspheres, particles, microparticles, nanoparticles, liposomes, and the like.
- The agents and/or compositions are administered in a manner compatible with the dosage formulation, and in such amount as may be therapeutically effective, immunogenic and protective. The quantity to be administered depends on the subject to be treated, including, for example, the size of the tumor, the stage of the disease, and the capacity of the individual's immune system to synthesize antibodies and/or to produce a cell-mediated immune response. Precise amounts of active ingredients required to be administered depend on the judgment of the practitioner. However, suitable dosage ranges are readily determinable by one skilled in the art and may be of the order of micrograms to milligrams of the active ingredient(s) per dose. The dosage may also depend on the route of administration and may vary according to the size of the host.
- The agents and/or compositions should be administered to a subject in an amount effective to stimulate a protective immune response in the subject. Specific dosage and treatment regimens for any particular subject may depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease (including tumor size), condition or symptoms, the subject's disposition to the disease, condition or symptoms, method of administration, and the judgment of the treating physician. Actual dosages can be readily determined by one of ordinary skill in the art.
- Exemplary unit dosage formulations are those containing a dose or unit, or an appropriate fraction thereof, of the administered ingredient. It should be understood that in addition to the ingredients mentioned herein, the formulations of the present invention may include other agents commonly used by one of ordinary skill in the art.
- Typically in conventional systemically administered treatments, a therapeutically effective dosage should produce a serum concentration of compound of from about 0.1 ng/ml to about 50-100 μg/ml. The pharmaceutical compositions typically provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. For example, dosages for systemic administration to a human patient can range from 1-10 μg/kg, 20-80 μg/kg, 5-50 μg/kg, 75-150 μg/kg, 100-500 μg/kg, 250-750 μg/kg, 500-1000 μg/kg, 1-10 mg/kg, 5-50 mg/kg, 25-75 mg/kg, 50-100 mg/kg, 100-250 mg/kg, 50-100 mg/kg, 250-500 mg/kg, 500-750 mg/kg, 750-1000 mg/kg, 1000-1500 mg/kg, 1500-2000 mg/kg, 5 mg/kg, 20 mg/kg, 50 mg/kg, 100 mg/kg, 500 mg/kg, 1000 mg/kg, 1500 mg/kg, or 2000 mg/kg. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 5000 mg, for example from about 100 to about 2500 mg of the compound or a combination of essential ingredients per dosage unit form.
- In general, a therapeutically effective amount of the present compounds in dosage form usually ranges from slightly less than about 0.025 mg/kg/day to about 2.5 g/kg/day, preferably about 0.1 mg/kg/day to about 100 mg/kg/day of the patient or considerably more, depending upon the compound used, the condition or infection treated and the route of administration, although exceptions to this dosage range may be contemplated by the present invention. In an exemplary embodiment, intracellular permeation compounds according to the present invention may be administered intratumorally in amounts ranging from about 0.5 mg/ml of dosing solution to about 50 mg/ml. In another exemplary embodiment, intracellular permeation compounds according to the present invention may be administered intratumorally in amounts ranging from about 10 mg/ml to about 30 mg/ml. The dosage of the intracellular permeation compound(s) may depend on the type of cancer being treated, the particular compound used, the therapeutic agent, and other clinical factors and conditions of the patient and the route of administration. It is to be understood that the present invention has application for both human and veterinary use.
- The agents and/or compositions are administered in one or more doses as required to achieve the desired effect. Thus, the agents and/or compositions may be administered in 1, 2, 3, 4, 5, or more doses. Further, the doses may be separated by any period of time, for example hours, days, weeks, months, and years.
- The agents and/or compositions can be formulated as liquids or dry powders, or in the form of microspheres.
- The agents and/or compositions may be stored at temperatures of from about −100° C. to about 25° C. depending on the duration of storage. The agents and/or compositions may also be stored in a lyophilized state at different temperatures including room temperature. The agents and/or compositions may be sterilized through conventional means known to one of ordinary skill in the art. Such means include, but are not limited to, filtration. The composition may also be combined with bacteriostatic agents to inhibit bacterial growth.
- The amount of active ingredient that may be combined with carrier materials to produce a single dosage form may vary depending upon the host treated and the particular mode of administration. In embodiments, a preparation may contain from about 0.1% to about 95% active compound (w/w), from about 20% to about 80% active compound, or from any percentage therebetween.
- In embodiments, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form.
- In embodiments, the pharmaceutical carriers may be in the form of a sterile liquid preparation, for example, as a sterile aqueous or oleaginous suspension. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
- Other commonly used surfactants such as TWEEN® or SPAN® and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- In embodiments, the agents and/or compositions can be delivered in an exosomal delivery system. Exosomes are small membrane vesicles that are released into the extracellular environment during fusion of multivesicular bodies with plasma membrane. Exosomes are secreted by various cell types including hematopoietic cells, normal epithelial cells and even some tumor cells. Exosomes are known to carry MHC class I, various costimulatory molecules and some tetraspanins. Recent studies have shown the potential of using native exosomes as immunologic stimulants.
- Also contemplated by the invention is delivery of the agents and/or compositions using nanoparticles. For example, the agents and/or compositions provided herein can contain nanoparticles having at least one or more agents linked thereto, e.g., linked to the surface of the nanoparticle. A composition typically includes many nanoparticles with each nanoparticle having at least one or more agents linked thereto. Nanoparticles can be colloidal metals. A colloidal metal includes any water-insoluble metal particle or metallic compound dispersed in liquid water. Typically, a colloid metal is a suspension of metal particles in aqueous solution. Any metal that can be made in colloidal form can be used, including gold, silver, copper, nickel, aluminum, zinc, calcium, platinum, palladium, and iron. In some cases, gold nanoparticles are used, e.g., prepared from HAuC14. Nanoparticles can be any shape and can range in size from about 1 nm to about 10 nm in size, e.g., about 2 nm to about 8 nm, about 4 to about 6 nm, or about 5 nm in size. Methods for making colloidal metal nanoparticles, including gold colloidal nanoparticles from HAuCl4, are known to those having ordinary skill in the art. For example, the methods described herein as well as those described elsewhere (e.g., US Pat. Publication Nos. 2001/005581; 2003/0118657; and 2003/0053983, which are hereby incorporated by reference) are useful guidance to make nanoparticles.
- In certain cases, a nanoparticle can have two, three, four, five, six, or more active agents linked to its surface. Typically, many molecules of active agents are linked to the surface of the nanoparticle at many locations. Accordingly, when a nanoparticle is described as having, for example, two active agents linked to it, the nanoparticle has two active agents, each having its own unique molecular structure, linked to its surface. In some cases, one molecule of an active agent can be linked to the nanoparticle via a single attachment site or via multiple attachment sites.
- An active agent can be linked directly or indirectly to a nanoparticle surface. For example, the active agent can be linked directly to the surface of a nanoparticle or indirectly through an intervening linker.
- Any type of molecule can be used as a linker. For example, a linker can be an aliphatic chain including at least two carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms), and can be substituted with one or more functional groups including ketone, ether, ester, amide, alcohol, amine, urea, thiourea, sulfoxide, sulfone, sulfonamide, and disulfide functionalities. In cases where the nanoparticle includes gold, a linker can be any thiol-containing molecule. Reaction of a thiol group with the gold results in a covalent sulfide (-S-) bond. Linker design and synthesis are well known in the art. [000454] In embodiments, the nanoparticle is linked to a targeting agent/moiety. A targeting functionality can allow nanoparticles to accumulate at the target at higher concentrations than in other tissues. In general, a targeting molecule can be one member of a binding pair that exhibits affinity and specificity for a second member of a binding pair. For example, an antibody or antibody fragment therapeutic agent can target a nanoparticle to a particular region or molecule of the body (e.g., the region or molecule for which the antibody is specific) while also performing a therapeutic function. In some cases, a receptor or receptor fragment can target a nanoparticle to a particular region of the body, e.g., the location of its binding pair member. Other therapeutic agents such as small molecules can similarly target a nanoparticle to a receptor, protein, or other binding site having affinity for the therapeutic agent.
- When the compositions of this invention comprise one or more additional therapeutic or prophylactic agents, the therapeutic/enhancing/immunotherapy agent and the additional agent should be present at dosage levels of between about 0.1 to 100%, or between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the agents of this invention. Alternatively, those additional agents may be part of a single dosage form, mixed together with the agents of this invention in a single composition.
- The administration of the agents and/or compositions of the invention elicits an immune response against an immunogen, e.g., a cancer antigen. Typically, the dose can be adjusted within this range based on, e.g., the subject's age, the subject's health and physical condition, the capacity of the subject's immune system to produce an immune response, the subject's body weight, the subject's sex, diet, time of administration, the degree of protection desired, and other clinical factors. Those in the art can also readily address parameters such as biological half-life, bioavailability, route of administration, and toxicity when formulating the agents and/or compositions of the invention.
- The following examples further demonstrate several embodiments of this invention. While the examples illustrate the invention, they are not intended to limit it.
- The structures, materials, compositions, and methods described herein are intended to be representative examples of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. Those skilled in the art will recognize that the invention may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the ambit of the invention.
- Preparation of dosing solution 1: 167mg of NaOH were dissolved into 20 ML of de-ionized water to create a sodium hydroxide solution of 0.21 molar. Eighty (80) mgs of 6-Oxo-6-phenylhexanoic acid (obtained from Rieke Metals, Lincoln Nebr.) were weighed out and dissolved into 2 ML of the 0.21 Normal sodium hydroxide solution. In a separate container 6.2 mg of cis-Diaminodichloroplatinum (obtained from Tocris Bioscience, Elisville Mo.) were dissolved into 2.5 ML of de-ionized water. Each material was vortexed for 1 minute and sonicated for 15 minutes. 1.25 ML of the 6-Oxo-6-phenylhexanoic solution were mixed with the 2.5 ML cis-Diaminodichloroplatinum solution and vortexed for 1 minute. The pH of the resulting clear solution was measured and found to be approximately 5.5. Twenty (20) microliters of 1N sodium hydroxide was added to the combined solution. The pH was measured and found to be approximately 6.8. The volume was adjusted to 5 ML by the addition of approximately 1.2 ML of deionized water.
- Preparation of dosing solution 2: Eighty (80) mgs of 6-Oxo-6-phenylhexanoic acid (obtained from Rieke Metals, Lincoln Nebraska) were weighed out and dissolved into 2 ML of the 0.21 Normal sodium hydroxide solution as described in example 1. In a
separate container 20 mg cis-Diammine(1,1-cyclobutanedicarboxylato) platinum (Sigma Aldrich C2538) were dissolved into 2.5 ML of de-ionized water. Each material was vortexed for 1 minute and sonicated for 15 minutes. 1.25 MLs of the 6-Oxo-6-phenylhexanoic solution were mixed with the 2.5 ML cis-Diammine(1,1-cyclobutanedicarboxylato) platinum solution and vortexed for 1 minute. The pH of the resulting clear combined solution was measured and found to be approximately 6.0. Ten (10) microliters of 1N sodium hydroxide was added to the combined solution. The pH was measured and found to be approximately 6.9. The volume was adjusted to 5 ML by the addition of approximately 1.2 ML of deionized water. - Preparation of dosing solution 3: 137mg of NaOH were dissolved into 20 ML of de-ionized water to create a sodium hydroxide solution of 0.16 molar. Eighty (80) microliters of 2-ethylhexyl 2-hydroxybenzoate (obtained from ChemPacific, Baltimore Maryland) were weighed out and mixed with 2 ML of the 0.16 Normal sodium hydroxide solution. In a separate container 6.2 mg of cis-Diaminodichloroplatinum (obtained from Tocris Bioscience, Elisville Mo.) were dissolved into 2.5 ML of de-ionized water. Each material was vortexed for 1 minute and sonicated for 15 minutes. 1.25 ML of the 2-ethylhexyl 2-hydroxybenzoate solution were mixed with the 2.5 ML cis-Diaminodichloroplatinum solution and vortexed for 1 minute. The pH of the resulting clear solution was measured and found to be approximately 11. Several titrations using 50% HCl solution and 2N sodium hydroxide solution were added to the combined solution. After several titrations the pH was measured and found to be approximately 6.8.
- Preparation of dosing solution 4: Eighty (80) microliters of 2-ethylhexyl 2-hydroxybenzoate (obtained from ChemPacific, Baltimore Maryland) were weighed out and mixed with 2 ML of the 0.16 Normal sodium hydroxide solution as described in example 3. In a
separate container 20 mg cis-Diammine(1,1-cyclobutanedicarboxylato) platinum (Sigma Aldrich C2538) were dissolved into 2.5 ML of de-ionized water. Each material was vortexed for 1 minute and sonicated for 15 minutes. 1.25 MLs of the 2-ethylhexyl 2-hydroxybenzo ate salt solution were mixed with the 2.5 ML cis-Diammine(1,1-cyclobutanedicarboxylato) platinum solution and vortexed for 1 minute. The pH of the resulting clear solution was measured and found to be approximately 11. Several titrations using 50% HC1 solution and 2N sodium hydroxide solution were added to the combined solution. After several titrations the pH was measured and found to be approximately 6.8. - 30 mg of 6-oxo-6 phenylhexanoic acid was added to 1.5ml of 0.1 molar sodium hydroxide, and the pH was adjusted to approximately 7.0. A few drops of India black ink was added to the 7.0 penetration enhancer ink solution. 2×106 BxPC-3-luc2 cells were inoculated into the right flank of 9 female C.B-17 scid mice. Tumor growth was monitored once or twice weekly by caliper measurements until tumor size reached ˜500mm3. In vivo bioluminescent imaging was performed on the day of ink chemical solution delivery as shown in
FIG. 1 . 50 microliters of the enhancer solution were injected into the BxPC subcutaneous tumors of two severely compromised immunodeficient (scid) mice using a programmable syringe pump with a butterfly needle. The needle remained in the tumors for approximately 2 additional minutes. Upon removal of the needle the tumors were immediately excised and examined; the resulting ink dispersion efficacy was observed and is shown inFIG. 2 . - Two scid mice with subcutaneous BxPC tumors were administered intratumorally 100 microliters of the India ink enhancer solution prepared in Example 5 in two minutes using the programmable syringe pump. The needle remained in the tumors for approximately 2 additional minutes. Upon removal of the needle the tumors were immediately excised and examined; the resulting ink dispersion efficacy was observed and is shown in
FIG. 3 . - Example 7
- 2×106 BxPC-3-luc2 cells were inoculated into the right flank of 32 female C.B-17 scid mice. Tumor growth was monitored once or twice weekly by caliper measurements until tumor size reached ˜500mm3. Twenty-four mice with tumors of the appropriate size were selected for dosing. Each selected animal was numbered on their tail and ear tagged with the same number. The final groupings are noted in Table 1.
-
TABLE 1 Animal Group Treatment ID 1 Enhancer in Vehicle 69 1 Enhancer in Vehicle 70 1 Enhancer in Vehicle 78 1 Enhancer in Vehicle 82 1 Enhancer in Vehicle 85 1 Enhancer in Vehicle 87 2 CisplatinIV 71 2 CisplatinIV 73 2 CisplatinIV 76 2 CisplatinIV 77 2 CisplatinIV 84 2 CisplatinIV 92 3 Cisplatin Intratumor 72 3 Cisplatin Intratumor 75 3 Cisplatin Intratumor 80 3 Cisplatin Intratumor 86 3 Cisplatin Intratumor 89 3 Cisplatin Intratumor 94 4 Cisplatin + Enhancer 67 4 Cisplatin + Enhancer 83 4 Cisplatin + Enhancer 91 4 Cisplatin + Enhancer 96 4 Cisplatin + Enhancer 97 4 Cisplatin + Enhancer 98 - The tumor size of each animal was measured by caliper and the animals divided into four groups such that the average tumor volume (using the caliper measure) for each group was similar. The groupings are shown in Table 2.
-
TABLE 2 Animal length Width Volume ID (mm) (mm) (mm3) 69 17.08 10.06 864.28 70 11.54 9.55 526.24 78 11.17 8.98 450.38 82 10.62 10.07 538.46 85 12.48 9.98 621.51 87 12.28 9.73 581.29 Group 1Average 597.03 71 13.70 8.26 467.36 73 11.57 9.57 529.82 76 17.39 9.03 709.00 77 11.58 11.08 710.82 84 11.66 9.94 576.02 92 11.29 9.97 561.12 Group 2Average 592.36 72 15.60 9.14 651.61 75 11.25 8.94 449.57 80 13.32 9.61 615.06 86 15.72 10.36 843.61 89 12.04 9.75 572.28 94 10.16 9.26 435.60 Group 3Average 594.62 67 9.85 9.54 448.23 83 12.30 9.65 572.70 91 11.41 10.74 658.06 96 14.53 10.26 764.77 97 10.04 9.61 463.61 98 14.37 9.69 674.64 Group 4Average 597.00 - The animals were then injected with
luciferase 3 to obtain a tumor bioluminescence measurement (BLI) using a Xenogen photonic instrument (Xenogen became a division of Caliper Life Sciences). The four groups were then assigned to a treatment regimen. Group one was treated intratumorally with 100 microliters of enhancer 6-oxo-6 phenylhexanoic acid prepared as a sodium salt at pH approximately 7.0 and concentration of 13.3 mg/ML. Group two was treated with 100 microliters of cisplatin administered intravenously into the tail artery in a buffered solution at concentration of 1.2 mg/ml. Group three was treated intratumorally with 100 microliters of cisplatin in a buffered solution at a dose of approximately 0.45 mg/ml.Group 4 was administered intratumorally 100 microliters of the sodium salt form of enhancer 6-oxo-6 phenylhexanoic acid prepared with a final concentration of 13.3 mg/ml combined with cisplatin at a final concentration of 0.45 mg/ml. - BLI readings for the animals administered from Example 7 were taken at six hours post dosing, 24 hours post dosing, and 72 hours post dosing. Caliper measurements of the tumors for the animals in all groups were taken pre-dose and 72 hours post dose. Results comparing baseline, 6 hour, 24 hour and 72 hour BLI time-points for the animals are shown in
FIG. 4 . - The animals described in example 7 were administered a second set of treatments following a measurement of their tumor bioluminescence at 72 hours. Group one was treated intratumorally with 100 microliters of enhancer 6-oxo-6 phenylhexanoic acid prepared as a sodium salt at pH approximately 7.0 and concentration of 13.3 mg/ML.
- Group two was treated with 100 microliters cisplatin administered intravenously into the tail artery as a buffered solution at concentration of 1.2 mg/ml. Group three was treated intratumorally with 100 microliters of cisplatin in a buffered solution at a dose of approximately 1.2 mg/ml.
Group 4 was administered intratumorally 100 microliters of the sodium salt form of enhancer 6-oxo-6 phenylhexanoic acid prepared with a final concentration of 13.3 mg/ml combined with cisplatin at a final concentration of 1.2 mg/ml. BLI values of these cisplatin intratumoral doses were evaluated throughday 3 of the study. Relative values of BLI results throughday 3 are shown inFIG. 5 . - The animals described in example 7 were administered a third set of treatments following a measurement of their tumor bioluminescence at 7 and 10 days post baseline. The doses administered for the third treatment to each group (1 to 4) were identical to those administered in in the second treatment described in Example 9. BLI values over the entire study are shown in
FIG. 6 . Relative change in BLI values over the entire study are shown inFIG. 7 .FIG. 8 shows the changes in body weight from baseline today 10. - Formulations were prepared for dosing. An example is that of
group 7 which is as follows: 11.8 mgs of sodium hydroxide pellets were dissolved in 6.0 mls of water. The solution was sonicated for 2 to 3 minutes. 80 mgs of 8-[(2-hydroxybenzoyl)amino]octanoic acid was added to the 6.0 mls of sodium hydroxide solution prepared above, and sonicated for 2 minutes. 2.0 ml of a solution ofTween 80 from a prepared stock solution (0.8mgs ofTween 80/ml) was added to the 6 mls of enhancer salt solution. To the 8.0 ml of enhancer salt solution from above, 12.0 mgs of cisplatin powder obtained from Tocris Bioscience was added and the entire solution was sonicated as needed to assure complete dissolution of all components. The pH was adjusted to between 6.8 and 7.2 using a weak HCL or 1 N sodium hydroxide solution. Once the pH was correct, the solution was filtered using a 0.45 micron sieve. This material was prepared for dosing as noted in example 12. - 1×106 Colon CT26 cells were inoculated into the flank of over 120 female balb/c immune competent mice. Tumor growth was monitored once or twice weekly by caliper measurements until the largest tumor reached ˜500mm3. After sixteen days 120 mice with tumors were selected for inclusion in the study. Each selected animal was numbered and tagged with the corresponding number. The animals were then matched by tumor volume and placed into 12 groups with a mean tumor volume per animal per group ranging from 341 mm3 to 349 mm3. Animals were treated with 1 of 12 different regimens and classified as Group 1-12, respectively, based on the identifying characteristics enumerated in Table 3.
-
TABLE 3 Treatment Regimen 2 Dosed in the same formulation Treatment Regimen 1 with Regimen 1 Group n Enhancer Agent Vehicle mg/animal Route Schedule Agent Vehicle mg/animal Route Schedule 1 # 10 No Treatment — — — — No Treatment — — — — 2 10 Sodium 8 cyclohexyl-8oxo- 0.3 it 2/1/3 Cisplatin 0.05 it 2/1/3 octanoate 3 10 Sodium 8 cyclohexyl-8oxo- 1 it 2/1/3 Cisplatin 0.15 it 2/1/3 octanoate 4 * 10 Sodium 8 cyclohexyl-8oxo- 1 it 2/1/3 Cisplatin 0.05 it 2/1/3 octanoate 5 10 Sodium 8 cyclohexyl-8oxo- 3 it 2/1/3 Cisplatin 0.15 it 2/1/3 octanoate 6 10 Sodium 8-[(2- 0.3 it 2/1/3 Cisplatin 0.05 it 2/1/3 hydroxybenzoyl)amino] octanoate 7 10 Sodium 8-[(2- 1 it 2/1/3 Cisplatin 0.15 it 2/1/3 hydroxybenzoyl)amino] octanoate 8 * 10 Sodium 8-[(2- 1 it 2/1/3 Cisplatin 0.05 it 2/1/3 hydroxybenzoyl)amino] octanoate 9 10 None saline — — — Cisplatin — 0.15 it 2/1/3 10 10 Sodium 6-Oxo-6- 1 it 2/1/3 Cisplatin 0.15 it 2/1/3 phenylhexanoate 11 10 Sodium 6-Oxo-6- 3 it 2/1/3 Cisplatin 0.15 it 2/1/3 phenylhexanoate 12 10 cisplatin saline 2.7 * ip 2/1/3 — — — — — # - Control Group * Dosed per 400 mm3 of tumor volume measured Schedule 2/1/3 means 2 days of dosing, one no dose day followed by 3 days of dosing it means intratumoral, ip means intraperitoneal - The results of this study are shown in
FIG. 9 , which depicts tumor volume over time for each of the 12 Groups analyzed by the study. In addition, as shown inFIG. 10 , several intracellular formulations were able to show a significant extension of animal life versus control groups, and an overall survival benefit versus no treatment and also versus animals given drug alone systemically. Exemplary formulations according to an illustrative embodiment of the invention are shown in Table 4. -
TABLE 4 Enhancer Cisplatin Concentration Concentration Group Enhancer Vehicle mgs/ML mgs/ ML Surfactant 2 Sodium cyclohexyl-8-oxo- octanoate Water 3 0.5 None 3 Sodium cyclohexyl-8-oxo- octanoate Water 10 1.5 None 4 Sodium cyclohexyl-8-oxo- octanoate Water 10 0.5 ~1 % Tween 5 Sodium cyclohexyl-8-oxo- octanoate Water 30 1.5 None 6 Sodium 8-[(2-hydroxybenzoyl) Water 3 0.5 None amino] octanoate 7 Sodium 8-[(2-hydroxybenzoyl) Water 10 1.5 None amino] octanoate 8 Sodium 8-[(2-hydroxybenzoyl) Water 10 0.5 ~1% Tween amino] octanoate 9 None Saline 0 1.5 None 10 Sodium 6-Oxo-6 phenylhexanoate Water 10 1.5 None 11 Sodium 6-Oxo-6 phenylhexanoate Water 30 1.5 None The pH was adjusted to between 6.8 and 7.2 - Ten animals from the study described in example 12, which had received intratumorally administered drug, had their tumors regress to sizes below 18 mm3. These animals were placed in a new study and along with a control group of age matched naive animals. Both groups were then inoculated with 1×106 Colon CT26 cells into their flank. The animals previously inoculated were re-inoculated in the opposite flank. No drug treatment was provided to either group. Tumor growth was inhibited in the animals that have previously demonstrated a regression whereas naive animals showed significant tumor growth.
FIGS. 11A-C show that 90% of the animals that had a complete response were fully immunized against recurrence of the cancer. The top figure (a) is the 10 animals from the control group. The second figure (b) are the animals that had shown a complete response in the study describe in example 12. The bottom figure (c) are the mean values and standard error of the means for the two groups. - Having thus described in detail preferred embodiments of the present invention, it is to be understood that the invention defined by the above paragraphs is not to be limited to particular details set forth in the above description as many apparent variations thereof are possible without departing from the spirit or scope of the present invention. All documents cited or referenced herein and all documents cited or referenced in the herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated by reference, and may be employed in the practice of the invention
Claims (72)
1. A method of treating cancer in a subject in need of treatment, wherein the method comprises administering a therapeutically effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
2. The method of claim 1 , wherein administration of the intracellular permeation agent increases the therapeutic effectiveness of the therapeutic agent.
3. The method of claim 2 , wherein administration of the intracellular permeation agent increases the therapeutic effectiveness of the therapeutic agent by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more as compared to treatment with the therapeutic agent alone.
4. The method of claim 1 , wherein the cancer is one or more tumors.
5. The method of claim 4 , wherein the tumor is selected from the group consisting of a solid tumor, a carcinoma and a sarcoma.
6. The method of claim 5 , wherein the solid tumor, carcinoma, or sarcoma is of the skin, bone, muscle, breast, oral cavity, colon, organ, kidney, liver, lung, gallbladder, pancreas, brain, esophagus, bladder, large intestine, small intestine, spleen, stomach, prostate, testes, ovaries, cervix, rectum, or uterus.
7. The method of claim 4 , wherein the one or more tumors have metastasized.
8. The method of claim 4 , wherein the one or more tumors is a carcinoma of the pancreas.
9. The method of claim 1 , wherein the intracellular permeation enhancing agent is locally or regionally administered to the subject.
10. The method of claim 1 , wherein the therapeutic agent is locally, regionally, or systemically administered to the subject.
11. The method of claim 1 , wherein the therapeutic agent and/or the intracellular permeation enhancing agent is administered intratumorally.
12. The method of claim 4 , wherein the method reduces the growth rate of the one or more tumors, shrinks the one or more tumors, or eradicates the one or more tumors.
13. The method of claim 12 , wherein the tumor mass does not increase.
14. The method of claim 12 , wherein the tumor shrinks by 10%, 25%, 50%, 75%, 85%, 90%, 95%, or 99% or more as compared to its original mass.
15. The method of claim 4 , wherein the method prevents tumor metastasis.
16. The method of claim 1 , wherein the therapeutically effective amount of the therapeutic agent and/or the intracellular permeation enhancing agent is selected based on the volume and type of the tumor.
17. The method of claim 1 , wherein the therapeutic agent is administered on a first day and further administered on one or more subsequent days.
18. The method of claim 1 , wherein the intracellular permeation enhancing agent is administered on a first day and further administered on one or more subsequent days.
19. The method claim 1 , wherein the intracellular permeation enhancing agent and the therapeutic agent are coadministered on a first day and further coadministered on one or more subsequent days.
20. The method of claim 19 , wherein the first day and the one or more subsequent days are separated by between about 1 day and about 3 weeks.
21. The method of claim 19 , wherein the therapeutic agent and the intracellular permeation enhancing agent are coadministered in a ratio of about 1:2, 1:4, 1:10, 1:20, 1:25, 1:50, 1:100, or 1:200 (weight ratio of therapeutic agent: intracellular permeation enhancing agent).
22. The method of claim 19 , wherein the intracellular permeation enhancing agent is administered at a concentration of between about 0.5 mgs per ml of dosing solution and about 50 mgs per ml.
23. The method of claim 19 , wherein the intracellular permeation enhancing agent is administered at a concentration of between about 10 mgs per ml of dosing solution and about 30 mgs per ml.
24. The method of claim 1 , wherein the therapeutic agent and the intracellular permeation enhancing agent are delivered simultaneously in a single formulation or simultaneously in separate formulations.
25. The method of claim 1 , wherein the intracellular permeation enhancing agent is administered before the therapeutic agent.
26. The method of claim 1 , wherein the therapeutic agent is an anticancer agent.
27. The method of claim 26 , wherein the anticancer agent is a chemotherapeutic agent.
28. The method of claim 27 , wherein the chemotherapeutic agent is selected from the group consisting of Abiraterone Acetate, Afatinib, Aldesleukin, Alemtuzumab, Alitretinoin, Altretamine, Amifostine, Aminoglutethimide Anagrelide, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, Azathioprine, Bendamustine, Bevacizumab, Bexarotine, Bicalutamide, Bleomycin, Bortezomib, Busulfan, Capecitabine, Carboplatin, Carmustine, Cetuximab, Chlorambucil, Cisplatin, Cladribine, Crizotinib, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, Denileukin diftitox, Decitabine, Docetaxel, Dexamethasone, Doxifluridine, Doxorubicin, Epirubicin, Epoetin Alpha, Epothilone, Erlotinib, Estramustine, Etinostat, Etoposide, Everolimus, Exemestane, Filgrastim, Floxuridine, Fludarabine, Fluorouracil, Fluoxymesterone, Flutamide, folate linked alkaloids, Gefitinib, Gemcitabine, Gemtuzumab ozogamicin, GM-CT-01, Goserelin, Hexamethylmelamine, Hydroxyureas, Ibritumomab, Idarubicin, Ifosfamide, Imatinib, Interferon alpha, Interferon beta, Irinotecan, Ixabepilone, Lapatinib, Leucovorin, Leuprolide, Lenalidomide, Letrozole, Lomustine, Mechlorethamine, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Nelarabine, Nilotinib, Nilutamide, Octreotide, Ofatumumab, Oprelvekin, Oxaliplatin, Paclitaxel, Panitumumab, Pemetrexed, Pentostatin, polysaccharide galectin inhibitors, Procarbazine, Raloxifene, Retinoic acids, Rituximab, Romiplostim, Sargramostim, Sorafenib, Streptozocin, Sunitinib, Tamoxifen, Temsirolimus, Temozolamide, Teniposide, Thalidomide, Thioguanine, Thiotepa, Tioguanine, Topotecan, Toremifene, Tositumomab, Trametinib, Trastuzumab, Tretinoin, Valrubicin, VEGF inhibitors and traps, Vinblastine, Vincristine, Vindesine, Vinorelbine, Vintafolide (EC145), Vorinostat, a salt thereof, and any combination thereof.
29. The method of claim 1 , wherein the therapeutic agent is a therapeutic antibody or a combination of two or more therapeutic antibodies.
30. The method of claim 29 , wherein the therapeutic antibody or combination of two or more therapeutic antibodies is selected from the group consisting of Abagovomab, Alacizumab pegol, Alemtuzumab, Altumomab pentetate (Hybri-ceaker), Amatuximab, Anatumomab mafenatox, anti-PD-1 antibodies, Apolizumab, Arcitumomab (CEA-Scan), Belimumab, Bevacizumab, Bivatuzumab mertansine, Blinatumomab, Brentuximab vedotin, Cantuzumab mertansine, Cantuzumab ravtansine, Capromab pendetide (Prostascint), Catumaxomab (Removab), Cetuximab (Erbitux), Citatuzumab bogatox, Cixutumumab, Clivatuzumab tetraxetan (hPAM4-Cide), Conatumumab, Dalotuzumab, Denosumab, Drozitumab, Edrecolomab (Panorex), Enavatuzumab, Gemtuzumab, Ibritumomab tiuxetan, Ipilimumab ( MDX-101), Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, and any combination thereof.
31. The method of claim 1 , wherein the therapeutic agent is a nucleic acid molecule.
32. The method of claim 31 , wherein the nucleic acid molecule is an interfering RNA, a gene therapy expression vector, or a gene silencing vector.
33. The method of claim 32 , wherein the interfering RNA is an RNAi or shRNA.
34. The method of claim 1 , wherein the therapeutic agent is a radioisotope, a thymidylate synthase inhibitor, or a platinum compound, a vinca alkaloid agent, or any combination thereof.
35. The method of claim 1 , wherein the intracellular permeation enhancing agent is a chemical compound that enhances passive transport of the therapeutic compound into a cell.
36. The method of claim 1 , wherein the intracellular permeation enhancing agent is selected from the group consisting of functionalized ketoacids, 6-Oxo-6-phenylhexanoic acid, 8-Oxo-8-phenyloctanoic acid, 8-(2,5-Dichlorophenyl)-8-oxooctanoic acid, functionalized ketoesters or aldehydes, modified amino acids, modified amino acids, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, N-[8-(2-hydroxybenzoyl)aminodecanoic acid, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-[4-(4-chloro-2hydroxybenzoyl)amino1 butanoic acid, 2-ethylhexyl 2-hydroxybenzoate, 5-Cyclohexyl-5-oxovaleric acid, 6-Cyclohexyl-6-oxohexanoic acid, 7-Cyclohexyl-7-oxoheptanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, 4-Cyclopentyl-4-oxobutyric acid, 5-Cyclopentyl-5-oxovaleric acid, 6-Cyclopentyl-6-oxohexanoic acid, 7-Cyclopentyl-7-oxoheptanoic acid, 8-Cyclopentyl-8-oxooctanoic acid, 4-Cyclobutyl-4-oxobutyric acid, 5-Cyclobutyl-5-oxovaleric acid, 6-Cyclobutyl-6-oxohexanoic acid, 7-Cyclobutyl-7-oxoheptanoic acid, 8-Cyclobutyl-8-oxooctanoic acid, 4-Cyclopropyl-4-oxobutyric acid, 5-Cyclopropyl-5-oxovaleric acid, 6-Cyclopropyl-6-oxohexanoic acid, 7-Cyclopropyl-7-oxoheptanoic acid, 8-Cyclopropyl-8-oxooctanoic acid, 8-[(3-methylcyclohexyl)oxy]octanoic acid, 7-[(3-methylcyclohexyl)oxy]heptanoic acid, 6-[(3-methylcyclohexyl)oxy]hexanoic acid, 5-[(3-methylcyclohexyl)oxy]pentanoic acid, 4-[(3-methylcyclohexyl)oxy]butanoic acid, 3-[(3-methylcyclohexyl)oxy]propanoic acid, octisalate, Diketopiperazines, saponin, Acylcarnitines, Alkanoylcholines, taurodihydrofusidate, sulphoxides, Oxazolidinones, pyrrolidones, alcohols and alkanols, benzoic acid, glycols, surfactants, terpenes, functionally effective salts of any of the foregoing, derivatives of any of the foregoing, and any combinations thereof.
37. The method of claim 36 , wherein the intracellular permeation enhancing agent is selected from the group consisting of 6-Oxo-6-phenylhexanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, a functionally effective salt of any of the foregoing, a derivative of any of the foregoing, and any combination thereof.
38. The method of claim 37 , wherein the therapeutic agent is cisplatin or other platinum agent, and wherein the intracellular permeation enhancing agent is 6-oxo-6 phenylhexanoic acid, N-[8-(2-hydroxybenzoyl)aminooctanoic acid, or a salt or derivative thereof.
39. The method of claim 38 , wherein the other platinum agent is satraplatin, pcioplatin, nedaplatin, triplatin, carboplatin or oxaplatin.
40. The method of claim 1 , further comprising:
administering a therapeutically effective amount of an immunotherapeutic agent.
41. The method claim 40 , wherein the immunotherapeutic agent is a cancer vaccine, hormone, epitope, cytokine, tumor antigen, CD4 cell stimulator, NKT cell agonist, or adjuvant.
42. The method claim 40 , wherein the immunotherapeutic agent is an interferon, interleukin, tumor necrosis factor, ovalabumin, Neuvenge®, Oncophage, CimaVax-EGF, Mobilan, α-Gal glycolipid, α-Galactosylceramide (α-GalCer), β-mannosylceramide (β-ManCer), adenovirus delivered vaccines, Celldex's CDX1307 and CDX1401; GRNVAC1, viral based vaccines, MVA-BN, PROSTVAC®, Advaxis'; ADXS11-001, ADXS31-001, ADXS31-164, BiovaxID, folate binding protein (E39), Granulocyte macrophage colony stimulating factor (GM-CSF) with and without E75 (NeuVax) or OncoVEX, trastuzumab, Ae-37, IMA901, SC1B1, Stimuvax, peptides that can elicit cytotoxic lymphocyte response, peptide vaccines including telomerase peptide vaccine (GV1001), survivin peptide, MUC1 peptide, ras peptide, TARP 29-37-9V Peptide epitope enhanced peptide, DNA Vector pPRA-PSM with synthetic peptides E-PRA and E-PSM; Ad.p53 DC vaccine, NY-ESO-1 Plasmid DNA (pPJV7611), genetically modified allogeneic (human) tumor cells for the expression of IL-1, IL-7, GM-CSF, CD80 or CD154, HyperAcute(R)-Pancreatic cancer vaccine (HAPa-1 and HAPa-2 components), Melaxin (autologous dendritoma vaccine) and BCG, GVAX (CG8123), CD40 ligand and IL-2 gene modified autologous skin fibroblasts and tumor cells, ALVAC-hB7.1, Vaximm Gmbh's VXM01, Immunovative Therapies' AlloStim-7, ProstAtak™, TG4023 (MVA-FCU1), Antigenic's HSPPC-96, Immunovaccine Technologies' DPX-0907 which consists of specific HLA-A2-restricted peptides, a universal T Helper peptide, a polynucleotide adjuvant, a liposome and Montanide (ISA51 VG), GSK2302032A, Memgen's ISF35, Avax's OVax: Autologous, DNP-Modified Ovarian vaccine, Theratope®, Ad100-gp96Ig-HLA Al, Bioven's recombinant Human rEGF-P64K/Montanide vaccine, TARP 29-37, or Dendreon's DN24-02.
43. The method of claim 40 , wherein the immunotherapeutic agent is an α-Gal glycolipid.
44. The method of claim 42 , wherein the immunotherapeutic agent is a β-ManCer comprising a sphingosine moiety and a fatty acid moiety comprising a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 49 carbon atoms.
45. The method of claim 44 , wherein the fatty acid moiety comprises a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 15 carbon atoms.
46. The method of claim 44 , wherein the fatty acid moiety comprises a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 18 to about 30 carbon atoms.
48. The method of claim 40 , wherein the immunotherapeutic agent enhances the therapeutic effects of the therapeutic agent.
49. The method of claim 48 , wherein the immunotherapeutic agent further reduces the growth of the tumor or further shrinks the tumor.
50. The method of claim 40 , wherein the immunotherapeutic agent is administered after administration of the therapeutic agent and the intracellular permeation enhancing agent.
51. The method of claim 40 , wherein the immunotherapeutic agent is administered simultaneously with the first administration of the therapeutic agent and the intracellular permeation enhancing agent.
52. The method of claim 40 , wherein the immunotherapeutic agent is administered intraperitoneally.
53. The method of claim 40 , wherein the immunotherapeutic agent is administered locally, regionally, or systemically.
54. The method of claim 40 , wherein the immunotherapeutic agent is administered intratumorally.
55. The method of claim 1 , wherein the therapeutic agent and the intracellular permeation enhancing agent are coupled.
56. The method of claim 1 , further comprising:
administering a standard of care therapy to the subject.
57. The method of claim 56 , wherein the standard of care therapy is surgery, radiation, radio frequency, cryogenic, ultranoic ablation, systemic chemotherapy, or a combination thereof.
58. The method of claim 1 , wherein administration of the therapeutic agent and/or the intracellular permeation enhancing agent is conducted with the aid of an imaging system.
59. The method of claim 58 , wherein the dose of the therapeutic agent and/or the intracellular permeation enhancing agent is determine with the aid of the imaging system.
60. The method of claim 40 , wherein administration of the immunotherapeutic agent is conducted with the aid of an imaging system.
61. The method of claim 58 , wherein the imaging system is X-ray computed tomography (CT), fluoroscopy, magnetic resonance imaging (MRI), ultrasound, or positron emission tomography (PET)/computed tomography (CT).
62. The method of claim 4 , further comprising:
imaging the one or more tumors with an imaging system selected from the group consisting of X-ray computed tomography (CT), fluoroscopy, magnetic resonance imaging (MRI), ultrasound, and positron emission tomography (PET)/computed tomography (CT);
determining the volume of the one or more tumors; and
calculating, based on the determined tumor volume, a therapeutically effective tumor-specific dose of the therapeutic agent and the intracellular permeation enhancing agent.
63. The method of claim 62 , wherein each of the one or more tumors is intratumorally co-administered the therapeutically effective tumor-specific dose of the therapeutic agent and the intracellular permeation enhancing agent calculated for that tumor.
64. The method of claim 1 , wherein the subject is a mammal.
65. The method of claim 64 , wherein the mammal is a dog, cat, horse, cow, sheep, goat, pig, mouse, rat, guinea pig, monkey, or human.
66. The method of claim 1 , wherein the subject is human.
67. A method of inhibiting growth of one or more tumors in a subject, wherein the method comprises administering a therapeutically effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
68. A method of treating one or more tumors in a subject comprising locally or regionally coadministering to the subject a therapeutically effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
69. An immunogenic composition comprising a therapeutically effective amount of a therapeutic agent and an intracellular permeation enhancing agent.
70. A method of inducing immunity against a cancer in a subject comprising administering a therapeutically effective amount of a therapeutic agent and an intracellular permeation enhancing agent to the subject.
71. The method of claim 70 , wherein the intracellular permeation enhancing agent and the therapeutic agent are coadministered intratumorally.
72. The method of claim 1 , wherein the therapeutic agent is a combination of two or more selected from the group consisting of a chemotherapeutic agent, an antibody, and a nucleic acid molecule.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/108,099 US20210077627A1 (en) | 2012-09-21 | 2020-12-01 | Method of treating cancer |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261703890P | 2012-09-21 | 2012-09-21 | |
US201261707733P | 2012-09-28 | 2012-09-28 | |
US201361779509P | 2013-03-13 | 2013-03-13 | |
PCT/US2013/059841 WO2014046983A1 (en) | 2012-09-21 | 2013-09-15 | Method of treating cancer |
US14/280,036 US9351997B2 (en) | 2012-09-21 | 2014-05-16 | Method of treating cancer |
US15/052,326 US9636406B2 (en) | 2012-09-21 | 2016-02-24 | Method of treating cancer |
US15/441,907 US10888618B2 (en) | 2012-09-21 | 2017-02-24 | Method of treating cancer |
US17/108,099 US20210077627A1 (en) | 2012-09-21 | 2020-12-01 | Method of treating cancer |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/441,907 Continuation US10888618B2 (en) | 2012-09-21 | 2017-02-24 | Method of treating cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
US20210077627A1 true US20210077627A1 (en) | 2021-03-18 |
Family
ID=50341876
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/280,036 Active 2033-12-06 US9351997B2 (en) | 2012-09-21 | 2014-05-16 | Method of treating cancer |
US15/052,326 Active US9636406B2 (en) | 2012-09-21 | 2016-02-24 | Method of treating cancer |
US15/441,907 Active 2033-12-22 US10888618B2 (en) | 2012-09-21 | 2017-02-24 | Method of treating cancer |
US17/108,099 Abandoned US20210077627A1 (en) | 2012-09-21 | 2020-12-01 | Method of treating cancer |
US18/336,379 Pending US20230338251A1 (en) | 2012-09-21 | 2023-06-16 | Method of treating cancer |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/280,036 Active 2033-12-06 US9351997B2 (en) | 2012-09-21 | 2014-05-16 | Method of treating cancer |
US15/052,326 Active US9636406B2 (en) | 2012-09-21 | 2016-02-24 | Method of treating cancer |
US15/441,907 Active 2033-12-22 US10888618B2 (en) | 2012-09-21 | 2017-02-24 | Method of treating cancer |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US18/336,379 Pending US20230338251A1 (en) | 2012-09-21 | 2023-06-16 | Method of treating cancer |
Country Status (19)
Country | Link |
---|---|
US (5) | US9351997B2 (en) |
EP (1) | EP2897620B1 (en) |
JP (2) | JP6374388B2 (en) |
KR (1) | KR101839864B1 (en) |
CN (1) | CN104884065B (en) |
AU (2) | AU2013318338B2 (en) |
BR (1) | BR112015006176B1 (en) |
CA (1) | CA2884707C (en) |
CL (1) | CL2015000699A1 (en) |
CY (1) | CY1123258T1 (en) |
DK (1) | DK2897620T3 (en) |
ES (1) | ES2813340T3 (en) |
IL (1) | IL237791B (en) |
MX (1) | MX2015003643A (en) |
PL (1) | PL2897620T3 (en) |
PT (1) | PT2897620T (en) |
RU (1) | RU2657749C2 (en) |
SG (2) | SG10202011046RA (en) |
WO (1) | WO2014046983A1 (en) |
Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT2897620T (en) | 2012-09-21 | 2020-09-03 | Intensity Therapeutics Inc | Method of treating cancer |
CA2889530A1 (en) * | 2012-10-25 | 2014-05-01 | Glaxosmithkline Llc | Combination |
EP3003316B1 (en) * | 2013-05-31 | 2020-07-22 | Merck Sharp & Dohme Corp. | Combination therapies for cancer |
JP6495899B2 (en) | 2013-06-21 | 2019-04-03 | ジェムバックス アンド カエル カンパニー,リミティド | Hormone secretion regulator and composition containing the same |
HUE046249T2 (en) | 2013-12-12 | 2020-02-28 | Shanghai hengrui pharmaceutical co ltd | Pd-1 antibody, antigen-binding fragment thereof, and medical application thereof |
EP3085380B1 (en) | 2013-12-17 | 2020-06-17 | Gemvax & Kael Co., Ltd. | Composition for treating prostate cancer |
TW201615186A (en) * | 2014-10-24 | 2016-05-01 | 朗齊生物醫學股份有限公司 | The new cancer therapy indication of the cinacalcet HCl |
US20160166679A1 (en) * | 2014-12-12 | 2016-06-16 | Purdue Research Foundation | Method of treatment using folate conjugates and tyrosine kinase inhibitors |
KR102413243B1 (en) | 2014-12-23 | 2022-06-27 | 주식회사 젬백스앤카엘 | Peptides for treating ophthalmopathy and the Composition Comprising the Same |
CN105983097B (en) * | 2015-01-28 | 2021-06-08 | 华中科技大学同济医学院附属协和医院 | Anti-tumor preparation and preparation method thereof |
EP3263122B1 (en) * | 2015-02-27 | 2020-05-06 | Gemvax & Kael Co., Ltd. | Peptide for preventing hearing loss, and composition comprising same |
EP3267969A1 (en) * | 2015-03-09 | 2018-01-17 | King's College London | Combination therapy with rar alpha agonists for enhancing th1 response |
US10722527B2 (en) | 2015-04-10 | 2020-07-28 | Capsugel Belgium Nv | Abiraterone acetate lipid formulations |
CA3026452C (en) | 2015-06-04 | 2023-03-21 | Crititech, Inc. | Nozzle assembly and methods for use |
ES2760699T3 (en) * | 2015-06-18 | 2020-05-14 | Vaximm Ag | VEGFR-2 Targeted DNA Vaccine for Combination Therapy |
US11015179B2 (en) | 2015-07-02 | 2021-05-25 | Gemvax & Kael Co., Ltd. | Peptide having anti-viral effect and composition containing same |
EP3925599A1 (en) * | 2015-07-24 | 2021-12-22 | Sorrento Therapeutics, Inc. | Methods for better delivery of active agents to tumors |
CN105241872B (en) * | 2015-09-01 | 2018-09-25 | 中国科学院深圳先进技术研究院 | Detect the method and agents useful for same of half lactadherin -1 in blood |
BR112018011131A2 (en) * | 2015-12-07 | 2018-11-21 | Kyoto University | A combined therapy of PD-1 signal inhibitor |
TWI733719B (en) | 2015-12-07 | 2021-07-21 | 美商河谷控股Ip有限責任公司 | Improved compositions and methods for viral delivery of neoepitopes and uses thereof |
EP3419668A4 (en) * | 2016-02-24 | 2019-10-09 | Ramot at Tel-Aviv University Ltd. | Polymeric conjugates and uses thereof |
KR102490665B1 (en) | 2016-04-04 | 2023-01-27 | 크리티테크, 인크. | Methods for Solid Tumor Treatment |
JP7114481B2 (en) | 2016-04-07 | 2022-08-08 | ジェムバックス アンド カエル カンパニー,リミティド | Peptides with the efficacy of increasing telomerase activity and lengthening telomeres, and compositions containing the same |
WO2017185038A1 (en) | 2016-04-22 | 2017-10-26 | Receptor Life Sciences | Fast-acting plant-based medicinal compounds and nutritional supplements |
TWI808055B (en) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Combination therapies of hdac inhibitors and pd-1 inhibitors |
TWI794171B (en) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Combination therapies of hdac inhibitors and pd-l1 inhibitors |
WO2017214974A1 (en) * | 2016-06-17 | 2017-12-21 | Johnpro Biotech Inc. | Method for treating tumor |
JP6982078B2 (en) * | 2016-09-14 | 2021-12-17 | アビバックス | Antitumor drugs and combination formulations containing ABX196 for the treatment of cancer |
EA201892396A1 (en) | 2016-12-02 | 2019-04-30 | Ресептор Лайф Сайенсиз, Инк. | QUICKLY PRODUCTIVE PLANT MEDICINES AND BIOLOGICALLY ACTIVE ADDITIVES |
KR20210118468A (en) | 2017-06-14 | 2021-09-30 | 크리티테크, 인크. | Methods for treating lung disorders |
WO2019042247A1 (en) * | 2017-08-28 | 2019-03-07 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of cyp17 inhibitor and preparation method therefor |
CN107475181B (en) | 2017-09-30 | 2021-03-02 | 中国农业大学 | In-vitro maturation culture solution for immature oocyte and application thereof |
CA3076919A1 (en) | 2017-10-03 | 2019-04-11 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
CA3078549A1 (en) * | 2017-10-05 | 2019-04-11 | Receptor Holdings, Inc. | Rapid onset and extended action plant-based and synthetic cannabinoid formulations |
KR20200066319A (en) * | 2017-10-05 | 2020-06-09 | 리셉터 홀딩스, 인크. | Herbal composition with improved bioavailability |
RU2704020C1 (en) * | 2018-06-22 | 2019-10-23 | Общество с ограниченной ответственностью "ПеритонТрит" | Combination of dehydroxymethyl epoxyquinomycin (dhmeq) and cytostatics for treating ovarian cancer |
BR112021005104A2 (en) | 2018-10-16 | 2021-06-08 | US Nano Food & Drug INC | intratumoral injection formulation |
US20220160888A1 (en) * | 2019-04-01 | 2022-05-26 | Industry-University Cooperation Foundation Hanyang University | Cp2c-targeting peptide-based anticancer agent |
IL297015A (en) | 2020-04-13 | 2022-12-01 | US Nano Food & Drug INC | Basic chemotherapeutic intratumour injection formulation |
CR20230308A (en) * | 2020-12-11 | 2023-09-08 | Civi Biopharma Inc | ORAL DELIVERY OF ANTISENSE CONJUGATES TARGETTING PCSK9 |
WO2022197743A1 (en) * | 2021-03-16 | 2022-09-22 | Multiple Energy Technologies Llc | Bioceramic compositions for cancer recovery |
US11541134B1 (en) | 2021-08-02 | 2023-01-03 | Rayzebio, Inc. | Stabilized compositions of radionuclides and uses thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090123562A1 (en) * | 2004-12-29 | 2009-05-14 | Emisphere Technologies, Inc. | Pharmaceutical Formulations of Gallium Salts |
WO2011112889A2 (en) * | 2010-03-12 | 2011-09-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | β-MANNOSYLCERAMIDE AND STIMULATION OF NKT CELL ANTI-TUMOR IMMUNITY |
Family Cites Families (146)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE35748E (en) * | 1984-05-29 | 1998-03-17 | Matrix Pharmaceutical, Inc. | Treatments employing drug containing matrices for introduction into cellular lesion areas |
US4619913A (en) | 1984-05-29 | 1986-10-28 | Matrix Pharmaceuticals, Inc. | Treatments employing drug-containing matrices for introduction into cellular lesion areas |
US4983396A (en) | 1985-12-06 | 1991-01-08 | Key Pharmaceuticals, Inc. | Percutaneous penetration enhancer of oleic acid and 2-ethyl-1,3-hexanediol |
US4764381A (en) | 1985-12-06 | 1988-08-16 | Key Pharmaceuticals, Inc. | Percutaneous penetration enhancer of oleic acid and 2-ethyl-1, 3-hexanediol |
US5118845A (en) | 1986-09-29 | 1992-06-02 | Whitby Research, Inc. | Penetration enhancer for transdermal delivery of systemic agents |
US4783450A (en) | 1987-04-13 | 1988-11-08 | Warner-Lambert Company | Use of commercial lecithin as skin penetration enhancer |
US5045553A (en) | 1987-06-24 | 1991-09-03 | Fujisawa Pharmaceutical Company, Ltd. | Pharmaceutical composition for percutaneous drug absorption and percutaneous drug absorption promoter |
US4978332A (en) * | 1987-09-28 | 1990-12-18 | Matrix Pharmaceutical, Inc. | Treatments employing vasoconstrictive substances in combination with cytotoxic agents for introduction into cellular lesion areas |
US5162115A (en) * | 1989-05-09 | 1992-11-10 | Pietronigro Dennis D | Antineoplastic solution and method for treating neoplasms |
US5219877A (en) | 1989-09-25 | 1993-06-15 | Bristol-Myers Squibb Company | Lauryl alcohol as skin penetration enhancer for topical imidazole agents |
US6221367B1 (en) | 1992-06-15 | 2001-04-24 | Emisphere Technologies, Inc. | Active agent transport systems |
US5714167A (en) | 1992-06-15 | 1998-02-03 | Emisphere Technologies, Inc. | Active agent transport systems |
US6099856A (en) | 1992-06-15 | 2000-08-08 | Emisphere Technologies, Inc. | Active agent transport systems |
US5578323A (en) | 1992-06-15 | 1996-11-26 | Emisphere Technologies, Inc. | Proteinoid carriers and methods for preparation and use thereof |
US5541155A (en) | 1994-04-22 | 1996-07-30 | Emisphere Technologies, Inc. | Acids and acid salts and their use in delivery systems |
US6331318B1 (en) | 1994-09-30 | 2001-12-18 | Emisphere Technologies Inc. | Carbon-substituted diketopiperazine delivery systems |
US5629020A (en) | 1994-04-22 | 1997-05-13 | Emisphere Technologies, Inc. | Modified amino acids for drug delivery |
US5451410A (en) | 1993-04-22 | 1995-09-19 | Emisphere Technologies, Inc. | Modified amino acids for encapsulating active agents |
US5443841A (en) | 1992-06-15 | 1995-08-22 | Emisphere Technologies, Inc. | Proteinoid microspheres and methods for preparation and use thereof |
US5693338A (en) | 1994-09-29 | 1997-12-02 | Emisphere Technologies, Inc. | Diketopiperazine-based delivery systems |
WO1992020369A1 (en) * | 1991-05-14 | 1992-11-26 | Dana Farber Cancer Institute | Use of hemoglobin in a method for the treatment of tumors with chemotherapeutic agents |
US5693769A (en) | 1991-12-13 | 1997-12-02 | Transcell Technologies, Inc. | Glycosylated steroid derivatives for transport across biological membranes and process for making and using same |
US5627270A (en) | 1991-12-13 | 1997-05-06 | Trustees Of Princeton University | Glycosylated steroid derivatives for transport across biological membranes and process for making and using same |
US6916489B2 (en) | 1992-06-15 | 2005-07-12 | Emisphere Technologies, Inc. | Active agent transport systems |
US5792451A (en) | 1994-03-02 | 1998-08-11 | Emisphere Technologies, Inc. | Oral drug delivery compositions and methods |
US5401516A (en) | 1992-12-21 | 1995-03-28 | Emisphere Technologies, Inc. | Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof |
ATE298561T1 (en) | 1993-04-22 | 2005-07-15 | Emisphere Tech Inc | ORAL DOSAGE FORM |
US6461643B2 (en) | 1993-04-22 | 2002-10-08 | Emisphere Technologies, Inc. | Oral drug delivery compositions and methods |
US5709861A (en) | 1993-04-22 | 1998-01-20 | Emisphere Technologies, Inc. | Compositions for the delivery of antigens |
US5643957A (en) | 1993-04-22 | 1997-07-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5958457A (en) | 1993-04-22 | 1999-09-28 | Emisphere Technologies, Inc. | Compositions for the delivery of antigens |
US20010003001A1 (en) | 1993-04-22 | 2001-06-07 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5908635A (en) | 1994-08-05 | 1999-06-01 | The United States Of America As Represented By The Department Of Health And Human Services | Method for the liposomal delivery of nucleic acids |
US6090958A (en) | 1995-03-31 | 2000-07-18 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5989539A (en) | 1995-03-31 | 1999-11-23 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
BR9604880A (en) | 1995-03-31 | 1998-05-19 | Emisphere Tech Inc | Compound composition dosage unit form methods for administering a biologically active agent for preparing a composition for administering an active agent and for preparing a compound and pharmacological composition |
US6001347A (en) | 1995-03-31 | 1999-12-14 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5965121A (en) | 1995-03-31 | 1999-10-12 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5866536A (en) * | 1995-03-31 | 1999-02-02 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5650386A (en) | 1995-03-31 | 1997-07-22 | Emisphere Technologies, Inc. | Compositions for oral delivery of active agents |
US5601839A (en) | 1995-04-26 | 1997-02-11 | Theratech, Inc. | Triacetin as a penetration enhancer for transdermal delivery of a basic drug |
US5820881A (en) | 1995-04-28 | 1998-10-13 | Emisphere Technologies, Inc. | Microspheres of diamide-dicarboxylic acids |
US5756122A (en) | 1995-06-07 | 1998-05-26 | Georgetown University | Liposomally encapsulated nucleic acids having high entrapment efficiencies, method of manufacturer and use thereof for transfection of targeted cells |
US6051258A (en) | 1995-06-07 | 2000-04-18 | Emisphere Technologies, Inc. | Proteinoid emulsions and methods for preparation and use thereof |
IL115199A (en) | 1995-09-07 | 2005-05-17 | Opperbas Holding Bv | Composition comprising a polynucleic acid molecule in a liposome and method using said composition |
AUPN814496A0 (en) | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
AU2275697A (en) * | 1996-02-21 | 1997-09-10 | Matrix Pharmaceutical, Inc. | Use of cell membrane permeants in the treatment of cellular proliferative disea ses |
SI9720025A (en) | 1996-03-29 | 1999-08-31 | Emishphere Technologies, Inc. | Compounds and compositions for delivering active agents |
AU2911197A (en) | 1996-05-24 | 1998-01-05 | Imperial College Of Science, Technology And Medicine | Polycationic sterol derivatives as transfection agents |
US5939381A (en) | 1997-02-07 | 1999-08-17 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5876710A (en) | 1997-02-07 | 1999-03-02 | Emisphere Technologies Inc. | Compounds and compositions for delivering active agents |
US6313088B1 (en) | 1997-02-07 | 2001-11-06 | Emisphere Technologies, Inc. | 8-[(2-hydroxy-4-methoxy benzoyl) amino]-octanoic acid compositions for delivering active agents |
US5776888A (en) | 1997-02-07 | 1998-07-07 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5990166A (en) | 1997-02-07 | 1999-11-23 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5804688A (en) | 1997-02-07 | 1998-09-08 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5879681A (en) | 1997-02-07 | 1999-03-09 | Emisphere Technolgies Inc. | Compounds and compositions for delivering active agents |
US5773647A (en) | 1997-02-07 | 1998-06-30 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6051561A (en) | 1997-02-07 | 2000-04-18 | Emisphere Technologies Inc. | Compounds and compositions for delivering active agents |
US6060513A (en) | 1997-02-07 | 2000-05-09 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6358504B1 (en) | 1997-02-07 | 2002-03-19 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6126965A (en) | 1997-03-21 | 2000-10-03 | Georgetown University School Of Medicine | Liposomes containing oligonucleotides |
US20030229040A1 (en) | 1997-03-21 | 2003-12-11 | Georgetown University | Cationic liposomal delivery system and therapeutic use thereof |
US5863944A (en) | 1997-04-30 | 1999-01-26 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
JP4656675B2 (en) | 1997-05-14 | 2011-03-23 | ユニバーシティー オブ ブリティッシュ コロンビア | High rate encapsulation of charged therapeutic agents in lipid vesicles |
AU8053898A (en) | 1997-05-28 | 1998-12-30 | Jenner Biotherapies, Inc. | Immunogenic compositions |
ATE321882T1 (en) | 1997-07-01 | 2006-04-15 | Isis Pharmaceuticals Inc | COMPOSITIONS AND METHODS FOR ADMINISTRATION OF OLIGONUCLEOTIDES VIA THE ESOPHAUS |
US20030073640A1 (en) | 1997-07-23 | 2003-04-17 | Ribozyme Pharmaceuticals, Inc. | Novel compositions for the delivery of negatively charged molecules |
WO1999004819A1 (en) | 1997-07-24 | 1999-02-04 | Inex Pharmaceuticals Corporation | Liposomal compositions for the delivery of nucleic acid catalysts |
US6225118B1 (en) | 1997-10-01 | 2001-05-01 | Biocure Limited | Multicellular in vitro assay of angiogenesis |
US7229841B2 (en) | 2001-04-30 | 2007-06-12 | Cytimmune Sciences, Inc. | Colloidal metal compositions and methods |
US6506559B1 (en) | 1997-12-23 | 2003-01-14 | Carnegie Institute Of Washington | Genetic inhibition by double-stranded RNA |
JPH11246439A (en) | 1998-03-02 | 1999-09-14 | Hisamitsu Pharmaceut Co Inc | Transmucosal absorption accelerator |
KR20010074777A (en) | 1998-07-27 | 2001-08-09 | 추후제출 | Pulmonary delivery of active agents |
US7648695B2 (en) | 1998-08-06 | 2010-01-19 | Provectus Pharmatech, Inc. | Medicaments for chemotherapeutic treatment of disease |
HUP0103188A2 (en) | 1998-08-07 | 2001-12-28 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6991798B1 (en) | 1998-08-07 | 2006-01-31 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
WO2000031123A2 (en) | 1998-11-19 | 2000-06-02 | Elan Corporation, Plc | Retro-inversion peptides that target gastro-intestinal tract transport receptors and use thereof |
EP1146860A4 (en) | 1999-01-08 | 2002-07-03 | Emisphere Tech Inc | Polymeric delivery agents and delivery agent compounds |
US7084279B1 (en) | 1999-02-11 | 2006-08-01 | Emisphere Technologies Inc. | Oxadiazole compounds and compositions for delivering active agents |
AU3703100A (en) | 1999-02-22 | 2000-09-14 | Georgetown University | Antibody fragment-targeted immunoliposomes for systemic gene delivery |
EP1163209A4 (en) | 1999-02-26 | 2004-12-29 | Emisphere Tech Inc | Compounds and compositions for delivering active agents |
US6537585B1 (en) * | 1999-03-26 | 2003-03-25 | Guilford Pharmaceuticals, Inc. | Methods and compositions for treating solid tumors |
EP1175390B1 (en) | 1999-04-05 | 2005-02-02 | Emisphere Technologies, Inc. | Disodium salts, monohydrates, and ethanol solvates |
US7112337B2 (en) | 1999-04-23 | 2006-09-26 | Alza Corporation | Liposome composition for delivery of nucleic acid |
US20030181367A1 (en) | 1999-09-27 | 2003-09-25 | O'mahony Daniel | Conjugates of membrane translocating agents and pharmaceutically active agents |
US6780846B1 (en) | 1999-09-27 | 2004-08-24 | Elan Corporation, Plc | Membrane translocating peptide drug delivery system |
US6200599B1 (en) | 1999-10-07 | 2001-03-13 | The Regents Of The University Of California | Ortho ester lipids |
US7279597B1 (en) | 1999-11-05 | 2007-10-09 | Emisphere Technologies, Inc. | Phenyl amine carboxylic acid compounds and compositions for delivering active agents |
US6511676B1 (en) | 1999-11-05 | 2003-01-28 | Teni Boulikas | Therapy for human cancers using cisplatin and other drugs or genes encapsulated into liposomes |
US7129274B1 (en) | 1999-11-05 | 2006-10-31 | Emisphere Technologies Inc. | Phenoxy carboxylic acid compounds and compositions for delivering active agents |
US20050037086A1 (en) | 1999-11-19 | 2005-02-17 | Zycos Inc., A Delaware Corporation | Continuous-flow method for preparing microparticles |
JP4850379B2 (en) | 1999-12-16 | 2012-01-11 | エミスフェアー・テクノロジーズ・インク | Compounds and compositions for transporting active agents |
US7151191B2 (en) | 2000-01-13 | 2006-12-19 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US20020012998A1 (en) | 2000-03-29 | 2002-01-31 | Igor Gonda | Cationic liposomes |
US20030072794A1 (en) | 2000-06-09 | 2003-04-17 | Teni Boulikas | Encapsulation of plasmid DNA (lipogenes™) and therapeutic agents with nuclear localization signal/fusogenic peptide conjugates into targeted liposome complexes |
JP2004521857A (en) | 2000-06-29 | 2004-07-22 | エミスフェアー・テクノロジーズ・インク | Compounds and compositions for delivery of active agents |
EP1326825A2 (en) | 2000-08-18 | 2003-07-16 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
EP1317412A1 (en) | 2000-08-18 | 2003-06-11 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
WO2002019969A2 (en) | 2000-09-06 | 2002-03-14 | Emisphere Technologies Inc. | (5-(2-hydroxy-4-chlorobenzoyl) aminovaleric acid and salts thereof and compositions containing the same for delivering active agents |
JP5089845B2 (en) | 2000-09-06 | 2012-12-05 | エミスフェアー・テクノロジーズ・インク | Cyanophenoxycarboxylic acid compounds and compositions for delivering active agents |
US6673574B2 (en) | 2000-11-30 | 2004-01-06 | Unigene Laboratories Inc. | Oral delivery of peptides using enzyme-cleavable membrane translocators |
CZ308053B6 (en) | 2000-12-01 | 2019-11-27 | Max Planck Gesellschaft | Isolated double-stranded RNA molecule, process for producing it and its use |
AU2002245580B2 (en) | 2001-03-01 | 2006-11-09 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
WO2002076427A2 (en) | 2001-03-26 | 2002-10-03 | Thomas Jefferson University | Ph sensitive liposomal drug delivery |
CN1294991C (en) | 2001-03-26 | 2007-01-17 | 阿尔扎公司 | Liposome composition for improved intracellular delivery of therapeutic agent |
US20030026831A1 (en) | 2001-04-20 | 2003-02-06 | Aparna Lakkaraju | Anionic liposomes for delivery of bioactive agents |
JP2004535388A (en) | 2001-04-30 | 2004-11-25 | ターゲティッド ジェネティクス コーポレイション | Lipid-containing drug delivery conjugates and methods for their production |
JP4489356B2 (en) | 2001-05-11 | 2010-06-23 | メリオン リサーチ スリー リミテッド | Penetration enhancer |
CA2451741C (en) | 2001-07-02 | 2014-02-18 | Elan Corporation, Plc | Peyers's patch and/or m-celle targeting ligands |
JP4381805B2 (en) | 2001-07-02 | 2009-12-09 | メリオン リサーチ スリー リミテッド | Delivery of bioactive materials |
BR0103887C1 (en) * | 2001-07-17 | 2005-11-08 | Univ Minas Gerais | Immunogenic compositions containing biodegradable microspheres encapsulating antigens, gene vectors and adjuvants |
WO2003015698A2 (en) | 2001-08-13 | 2003-02-27 | University Of Pittsburgh | Application of lipid vehicles and use for drug delivery |
DE10152145A1 (en) | 2001-10-19 | 2003-05-22 | Novosom Ag | Stabilization of liposomes and emulsions |
WO2003045306A2 (en) | 2001-11-13 | 2003-06-05 | Emisphere Technologies, Inc. | Phenoxy amine compounds and compositions for delivering active agents |
WO2003047633A2 (en) | 2001-12-04 | 2003-06-12 | Nanospectra Biosciences, Inc. | Treatment of angiogenesis disorders using targeted nanoparticles |
WO2003057190A1 (en) | 2001-12-31 | 2003-07-17 | Elan Pharmaceuticals, Inc. | Efficient nucleic acid encapsulation into medium sized liposomes |
EP2272501B1 (en) | 2002-01-09 | 2013-03-20 | Emisphere Technologies, Inc. | Polymorphs of sodium 4-((4-chloro-2-hydroxybenzoyl) amino) butanoate |
AU2003205049B2 (en) | 2002-01-09 | 2009-05-28 | Transave, Inc. | Efficient nucleic acid encapsulation into medium sized liposomes |
DE10207177A1 (en) | 2002-02-19 | 2003-09-04 | Novosom Ag | Optionally cationic lipids |
US7037520B2 (en) | 2002-03-22 | 2006-05-02 | Baylor College Of Medicine | Reversible masking of liposomal complexes for targeted delivery |
WO2003083443A2 (en) | 2002-03-29 | 2003-10-09 | University Of Florida | Lipid mediated screening of drug candidates for identification of active compounds |
AU2003237686A1 (en) | 2002-05-24 | 2003-12-12 | Max-Planck Gesellschaft Zur Forderung Der Wissenschaften E.V. | Rna interference mediating small rna molecules |
US8088734B2 (en) | 2003-01-21 | 2012-01-03 | Unigene Laboratories Inc. | Oral delivery of peptides |
US20070071677A1 (en) * | 2003-03-10 | 2007-03-29 | Park Yoon J | Non-toxic membrane-translocating peptides |
EP1622540A4 (en) * | 2003-03-11 | 2009-12-30 | Qlt Usa Inc | Formulations for cell- schedule dependent anticancer agents |
CA2559955C (en) | 2004-03-15 | 2016-02-16 | City Of Hope | Methods and compositions for the specific inhibition of gene expression by double-stranded rna |
AU2005247306A1 (en) | 2004-04-16 | 2005-12-08 | Emisphere Technologies, Inc. | 8-(2-hydroxyphenoxy)octyldiethanolamine and salts thereof for delivery of active agents |
AU2005240213B8 (en) * | 2004-05-06 | 2011-10-20 | Emisphere Technologies, Inc. | Crystalline polymorphic forms of monosodium n-[8-(2-hydroxybenzoyl)amino]caprylate |
AU2005249410A1 (en) * | 2004-05-14 | 2005-12-15 | Emisphere Technologies, Inc. | Aryl ketone compounds and compositions for delivering active agents |
US7968085B2 (en) | 2004-07-05 | 2011-06-28 | Ascendis Pharma A/S | Hydrogel formulations |
US7297786B2 (en) | 2004-07-09 | 2007-11-20 | University Of Iowa Research Foundation | RNA interference in respiratory epitheial cells |
US7820628B2 (en) | 2005-02-22 | 2010-10-26 | University Of Massachusetts Medical School | Tumor lesion regression and conversion in situ into autologous tumor vaccines by compositions that result in anti-Gal antibody binding |
US20070049557A1 (en) | 2005-08-24 | 2007-03-01 | Hashim Ahmed | Solid pharmaceutical dosage forms comprising bisphosphonates and modified amino acid carriers |
KR20080049128A (en) | 2005-09-19 | 2008-06-03 | 에미스페어 테크놀로지스, 인코포레이티드 | Crystalline forms of the di-sodium salt of n-(5-chlorosalicyloyl)-8-aminocaprylic acid |
AU2006325030B2 (en) * | 2005-12-16 | 2012-07-26 | Cellectis | Cell penetrating peptide conjugates for delivering nucleic acids into cells |
WO2007085026A2 (en) | 2006-01-20 | 2007-07-26 | The Board Of Regents Of The University Of Texas System | Compositions and methods for the direct therapy of tumors |
CN101668512A (en) * | 2007-01-31 | 2010-03-10 | 新泽西鲁特格斯州立大学 | Controlled release of actives in skin |
US8168757B2 (en) * | 2008-03-12 | 2012-05-01 | Merck Sharp & Dohme Corp. | PD-1 binding proteins |
US20090275654A1 (en) | 2008-04-30 | 2009-11-05 | Genta Incorporated | Pharmaceutical Gallium Compositions and Methods |
WO2009155070A2 (en) * | 2008-05-30 | 2009-12-23 | Novelix Pharmaceuticals, Inc. | Compositions and methods for treatment of inflammation and hyperkeratotic lesions |
CN102333541B (en) * | 2009-02-27 | 2014-09-03 | 东丽株式会社 | Immunogenic composition |
WO2011084061A1 (en) * | 2010-01-08 | 2011-07-14 | Universitair Medisch Centrum St. Radboud | Cpp (cell penetrating peptide) and its uses |
CN101928234B (en) | 2010-01-15 | 2012-12-12 | 北京欧凯纳斯科技有限公司 | 6/7-(hetero)aryl-N-hydroxyl hexanamide/heptamide compounds and method for preparing same |
US20130156859A1 (en) | 2010-08-26 | 2013-06-20 | Toray Industries, Inc | Immunogenic composition |
AU2013295549B2 (en) | 2012-07-27 | 2018-04-19 | Izumi Technology, Llc | Efflux inhibitor compositions and methods of treatment using the same |
PT2897620T (en) | 2012-09-21 | 2020-09-03 | Intensity Therapeutics Inc | Method of treating cancer |
-
2013
- 2013-09-15 PT PT138386396T patent/PT2897620T/en unknown
- 2013-09-15 CN CN201380059949.2A patent/CN104884065B/en active Active
- 2013-09-15 AU AU2013318338A patent/AU2013318338B2/en active Active
- 2013-09-15 SG SG10202011046RA patent/SG10202011046RA/en unknown
- 2013-09-15 WO PCT/US2013/059841 patent/WO2014046983A1/en active Application Filing
- 2013-09-15 MX MX2015003643A patent/MX2015003643A/en active IP Right Grant
- 2013-09-15 DK DK13838639.6T patent/DK2897620T3/en active
- 2013-09-15 JP JP2015533122A patent/JP6374388B2/en active Active
- 2013-09-15 CA CA2884707A patent/CA2884707C/en active Active
- 2013-09-15 RU RU2015114767A patent/RU2657749C2/en active
- 2013-09-15 KR KR1020157010173A patent/KR101839864B1/en active IP Right Grant
- 2013-09-15 EP EP13838639.6A patent/EP2897620B1/en active Active
- 2013-09-15 PL PL13838639T patent/PL2897620T3/en unknown
- 2013-09-15 SG SG11201501850VA patent/SG11201501850VA/en unknown
- 2013-09-15 ES ES13838639T patent/ES2813340T3/en active Active
- 2013-09-15 BR BR112015006176-1A patent/BR112015006176B1/en active IP Right Grant
-
2014
- 2014-05-16 US US14/280,036 patent/US9351997B2/en active Active
-
2015
- 2015-03-16 IL IL237791A patent/IL237791B/en active IP Right Grant
- 2015-03-19 CL CL2015000699A patent/CL2015000699A1/en unknown
-
2016
- 2016-02-24 US US15/052,326 patent/US9636406B2/en active Active
-
2017
- 2017-02-24 US US15/441,907 patent/US10888618B2/en active Active
- 2017-05-04 AU AU2017202970A patent/AU2017202970B2/en active Active
-
2018
- 2018-03-06 JP JP2018039402A patent/JP2018123137A/en active Pending
-
2020
- 2020-08-12 CY CY20201100752T patent/CY1123258T1/en unknown
- 2020-12-01 US US17/108,099 patent/US20210077627A1/en not_active Abandoned
-
2023
- 2023-06-16 US US18/336,379 patent/US20230338251A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090123562A1 (en) * | 2004-12-29 | 2009-05-14 | Emisphere Technologies, Inc. | Pharmaceutical Formulations of Gallium Salts |
WO2011112889A2 (en) * | 2010-03-12 | 2011-09-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | β-MANNOSYLCERAMIDE AND STIMULATION OF NKT CELL ANTI-TUMOR IMMUNITY |
Non-Patent Citations (1)
Title |
---|
X. Li et al., "Superior antitumor efficiency of cisplatin-loaded nanoparticles by intratumoral delivery with decreased tumor metabolism rate," European Journal of Pharmaceutics and Biopharmaceutics 70 (2008) 726-734. * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210077627A1 (en) | Method of treating cancer | |
ES2784554T3 (en) | Drug Carrier and Drug Carrier Kit to Inhibit Fibrosis | |
JP6426706B2 (en) | GLA monotherapy for use in cancer treatment | |
JP6953591B2 (en) | An aqueous emulsion of fluorocarbon for use with fractionated radiation therapy and chemotherapy, and a sensitizing composition containing it. | |
Fang et al. | Macrophage-targeted hydroxychloroquine nanotherapeutics for rheumatoid arthritis therapy | |
EA032345B1 (en) | Method of treating cancer using coenzyme q10 | |
US20220211663A1 (en) | Nano co-delivery of quercetin and alantolactone promotes anti-tumor response through synergistic immunogenic cell death for microsatellite-stable colorectal cancer | |
JP7520321B2 (en) | Lipid particles containing A-type CpG oligodeoxynucleotides | |
CN115176006A (en) | RNA nanoparticles for liver cancer treatment | |
TWI359030B (en) | Treatment of cellular proliferative disorders | |
JP6992984B2 (en) | Intratumor venous formation promoter |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: INTENSITY THERAPEUTICS, INC., CONNECTICUT Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BENDER, LEWIS H.;REEL/FRAME:054574/0961 Effective date: 20160226 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: APPLICATION DISPATCHED FROM PREEXAM, NOT YET DOCKETED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |