CN115245500A - 一种低温速冻法制备的吞噬细胞膜包覆的药物递送系统 - Google Patents
一种低温速冻法制备的吞噬细胞膜包覆的药物递送系统 Download PDFInfo
- Publication number
- CN115245500A CN115245500A CN202210663668.9A CN202210663668A CN115245500A CN 115245500 A CN115245500 A CN 115245500A CN 202210663668 A CN202210663668 A CN 202210663668A CN 115245500 A CN115245500 A CN 115245500A
- Authority
- CN
- China
- Prior art keywords
- cell
- cell membrane
- drug
- carrier
- delivery system
- 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.)
- Pending
Links
- 239000012528 membrane Substances 0.000 title claims abstract description 54
- 238000012377 drug delivery Methods 0.000 title claims abstract description 44
- 238000007710 freezing Methods 0.000 title claims abstract description 34
- 210000001539 phagocyte Anatomy 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 23
- 210000004027 cell Anatomy 0.000 claims abstract description 97
- 210000000170 cell membrane Anatomy 0.000 claims abstract description 46
- 230000008014 freezing Effects 0.000 claims abstract description 22
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 20
- 239000011248 coating agent Substances 0.000 claims abstract description 12
- 238000000576 coating method Methods 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims description 58
- 229940079593 drug Drugs 0.000 claims description 42
- 210000002540 macrophage Anatomy 0.000 claims description 42
- 108090000623 proteins and genes Proteins 0.000 claims description 29
- 102000004169 proteins and genes Human genes 0.000 claims description 28
- 239000002539 nanocarrier Substances 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 230000000242 pagocytic effect Effects 0.000 claims description 8
- 239000007853 buffer solution Substances 0.000 claims description 7
- 210000001616 monocyte Anatomy 0.000 claims description 7
- 210000000440 neutrophil Anatomy 0.000 claims description 7
- 206010057249 Phagocytosis Diseases 0.000 claims description 6
- 230000005859 cell recognition Effects 0.000 claims description 6
- 230000008782 phagocytosis Effects 0.000 claims description 6
- 210000002390 cell membrane structure Anatomy 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 2
- 239000011159 matrix material Substances 0.000 abstract description 14
- 230000008901 benefit Effects 0.000 abstract description 6
- 206010028980 Neoplasm Diseases 0.000 description 72
- 201000011510 cancer Diseases 0.000 description 31
- 230000003211 malignant effect Effects 0.000 description 30
- -1 anagli Chemical compound 0.000 description 21
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.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 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 18
- 239000011257 shell material Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 230000006907 apoptotic process Effects 0.000 description 10
- 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 10
- 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 description 9
- 108010000817 Leuprolide Proteins 0.000 description 9
- 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 description 9
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 9
- 229910002091 carbon monoxide Inorganic materials 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 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 description 9
- 102000003390 tumor necrosis factor Human genes 0.000 description 9
- 229930012538 Paclitaxel Natural products 0.000 description 8
- 229960005395 cetuximab Drugs 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000002502 liposome Substances 0.000 description 8
- 229960001592 paclitaxel Drugs 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- 208000009956 adenocarcinoma Diseases 0.000 description 7
- 229960000397 bevacizumab Drugs 0.000 description 7
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000008685 targeting Effects 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- 229960000575 trastuzumab Drugs 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 210000001185 bone marrow Anatomy 0.000 description 6
- 235000011089 carbon dioxide Nutrition 0.000 description 6
- 229960005243 carmustine Drugs 0.000 description 6
- 229910052681 coesite Inorganic materials 0.000 description 6
- 239000011258 core-shell material Substances 0.000 description 6
- 229910052906 cristobalite Inorganic materials 0.000 description 6
- 238000012258 culturing Methods 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 229960004338 leuprorelin Drugs 0.000 description 6
- 201000001441 melanoma Diseases 0.000 description 6
- 239000002105 nanoparticle Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 229960001972 panitumumab Drugs 0.000 description 6
- 230000001575 pathological effect Effects 0.000 description 6
- 229960004641 rituximab Drugs 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 229910052682 stishovite Inorganic materials 0.000 description 6
- 229910052905 tridymite Inorganic materials 0.000 description 6
- 210000003462 vein Anatomy 0.000 description 6
- 201000009030 Carcinoma Diseases 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 5
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin-C1 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 description 5
- 229940041181 antineoplastic drug Drugs 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229960004630 chlorambucil Drugs 0.000 description 5
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 229960003301 nivolumab Drugs 0.000 description 5
- 229960002450 ofatumumab Drugs 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.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 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 5
- 102000003952 Caspase 3 Human genes 0.000 description 4
- 108090000397 Caspase 3 Proteins 0.000 description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- 102100037391 Gasdermin-E Human genes 0.000 description 4
- 101001026269 Homo sapiens Gasdermin-E Proteins 0.000 description 4
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 description 4
- 101000884271 Homo sapiens Signal transducer CD24 Proteins 0.000 description 4
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 description 4
- 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 description 4
- 101150036449 SIRPA gene Proteins 0.000 description 4
- 206010039491 Sarcoma Diseases 0.000 description 4
- 102100038081 Signal transducer CD24 Human genes 0.000 description 4
- 229960000548 alemtuzumab Drugs 0.000 description 4
- 229960000455 brentuximab vedotin Drugs 0.000 description 4
- 239000006285 cell suspension Substances 0.000 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 description 4
- 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 description 4
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 230000002147 killing effect Effects 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 208000037819 metastatic cancer Diseases 0.000 description 4
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 4
- 229960004857 mitomycin Drugs 0.000 description 4
- 229960001756 oxaliplatin Drugs 0.000 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 description 4
- 229960003359 palonosetron hydrochloride Drugs 0.000 description 4
- OLDRWYVIKMSFFB-SSPJITILSA-N palonosetron hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 OLDRWYVIKMSFFB-SSPJITILSA-N 0.000 description 4
- 229960002621 pembrolizumab Drugs 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.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 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 229960004964 temozolomide Drugs 0.000 description 4
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.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=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 4
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 3
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.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 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 3
- 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 description 3
- ZHSKUOZOLHMKEA-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid;hydron;chloride Chemical compound Cl.ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 ZHSKUOZOLHMKEA-UHFFFAOYSA-N 0.000 description 3
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 3
- MKBLHFILKIKSQM-UHFFFAOYSA-N 9-methyl-3-[(2-methyl-1h-imidazol-3-ium-3-yl)methyl]-2,3-dihydro-1h-carbazol-4-one;chloride Chemical compound Cl.CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 MKBLHFILKIKSQM-UHFFFAOYSA-N 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 206010003571 Astrocytoma Diseases 0.000 description 3
- 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 description 3
- 102100025680 Complement decay-accelerating factor Human genes 0.000 description 3
- 108010092160 Dactinomycin Proteins 0.000 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 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 108010069236 Goserelin Proteins 0.000 description 3
- 101000856022 Homo sapiens Complement decay-accelerating factor Proteins 0.000 description 3
- 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 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 108010078049 Interferon alpha-2 Proteins 0.000 description 3
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 3
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 3
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 3
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 108010008038 Synthetic Vaccines Proteins 0.000 description 3
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 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 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000000735 allogeneic effect Effects 0.000 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 description 3
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 3
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 description 3
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].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 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 3
- 108010021331 carfilzomib Proteins 0.000 description 3
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 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 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 3
- UFNVPOGXISZXJD-JBQZKEIOSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-JBQZKEIOSA-N 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 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 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 230000002519 immonomodulatory effect Effects 0.000 description 3
- 230000005847 immunogenicity Effects 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 229960003507 interferon alfa-2b Drugs 0.000 description 3
- 229940087857 lupron Drugs 0.000 description 3
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 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 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 description 3
- 229960003347 obinutuzumab Drugs 0.000 description 3
- 201000008968 osteosarcoma Diseases 0.000 description 3
- 229960002566 papillomavirus vaccine Drugs 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- BKXVVCILCIUCLG-UHFFFAOYSA-N raloxifene hydrochloride Chemical compound [H+].[Cl-].C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 BKXVVCILCIUCLG-UHFFFAOYSA-N 0.000 description 3
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 3
- VZZJRYRQSPEMTK-CALCHBBNSA-N sonidegib Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(N=C1)=CC=C1NC(=O)C1=CC=CC(C=2C=CC(OC(F)(F)F)=CC=2)=C1C VZZJRYRQSPEMTK-CALCHBBNSA-N 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 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 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 229960004982 vinblastine sulfate Drugs 0.000 description 3
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 3
- RWRDJVNMSZYMDV-SIUYXFDKSA-L (223)RaCl2 Chemical compound Cl[223Ra]Cl RWRDJVNMSZYMDV-SIUYXFDKSA-L 0.000 description 2
- 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 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 208000009458 Carcinoma in Situ Diseases 0.000 description 2
- 208000005243 Chondrosarcoma Diseases 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 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 description 2
- 201000008808 Fibrosarcoma Diseases 0.000 description 2
- 206010018691 Granuloma Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 102100032818 Integrin alpha-4 Human genes 0.000 description 2
- 108010041012 Integrin alpha4 Proteins 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 2
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 2
- 231100000416 LDH assay Toxicity 0.000 description 2
- 206010027145 Melanocytic naevus Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 201000010133 Oligodendroglioma Diseases 0.000 description 2
- 206010061332 Paraganglion neoplasm Diseases 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 239000006180 TBST buffer Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229960001686 afatinib Drugs 0.000 description 2
- USNRYVNRPYXCSP-JUGPPOIOSA-N afatinib dimaleate Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 USNRYVNRPYXCSP-JUGPPOIOSA-N 0.000 description 2
- 108700025316 aldesleukin Proteins 0.000 description 2
- 229960002749 aminolevulinic acid Drugs 0.000 description 2
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 2
- 229960001372 aprepitant Drugs 0.000 description 2
- LZYIDMKXGSDQMT-UHFFFAOYSA-N arsenic dioxide Chemical compound [O][As]=O LZYIDMKXGSDQMT-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 2
- 229960001215 bendamustine hydrochloride Drugs 0.000 description 2
- 229960002938 bexarotene Drugs 0.000 description 2
- 229960000997 bicalutamide Drugs 0.000 description 2
- 229940031416 bivalent vaccine Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- 229960003736 bosutinib Drugs 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- 229960001573 cabazitaxel Drugs 0.000 description 2
- 235000008207 calcium folinate Nutrition 0.000 description 2
- 239000011687 calcium folinate Substances 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 210000000234 capsid Anatomy 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 2
- 229960002438 carfilzomib Drugs 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229960000928 clofarabine Drugs 0.000 description 2
- 238000003501 co-culture Methods 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 239000000599 controlled substance Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 229960002448 dasatinib Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- BIFMNMPSIYHKDN-FJXQXJEOSA-N dexrazoxane hydrochloride Chemical compound [H+].[Cl-].C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BIFMNMPSIYHKDN-FJXQXJEOSA-N 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229960004497 dinutuximab Drugs 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 229960004671 enzalutamide Drugs 0.000 description 2
- 230000002327 eosinophilic effect Effects 0.000 description 2
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 229960000439 eribulin mesylate Drugs 0.000 description 2
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960005304 fludarabine phosphate Drugs 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 229960005144 gemcitabine hydrochloride Drugs 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
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229960003690 goserelin acetate Drugs 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 229960001507 ibrutinib Drugs 0.000 description 2
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 2
- 229960001176 idarubicin hydrochloride Drugs 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.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 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000010954 inorganic particle Substances 0.000 description 2
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.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 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 2
- 238000002843 lactate dehydrogenase assay Methods 0.000 description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229960002868 mechlorethamine hydrochloride Drugs 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 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 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 229960004635 mesna Drugs 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 2
- 229960000801 nelarabine Drugs 0.000 description 2
- 229940080607 nexavar Drugs 0.000 description 2
- 229960001346 nilotinib Drugs 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- FDLYAMZZIXQODN-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC=2C3=CC=CC=C3C(=O)NN=2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FDLYAMZZIXQODN-UHFFFAOYSA-N 0.000 description 2
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 description 2
- 229960000770 ondansetron hydrochloride Drugs 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 2
- 208000007312 paraganglioma Diseases 0.000 description 2
- 229960002087 pertuzumab Drugs 0.000 description 2
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229960000688 pomalidomide Drugs 0.000 description 2
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- OGSBUKJUDHAQEA-WMCAAGNKSA-N pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 229960002119 raloxifene hydrochloride Drugs 0.000 description 2
- 229960002633 ramucirumab Drugs 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 229960004836 regorafenib Drugs 0.000 description 2
- 229960003452 romidepsin Drugs 0.000 description 2
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 2
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 2
- 108010091666 romidepsin Proteins 0.000 description 2
- JFMWPOCYMYGEDM-XFULWGLBSA-N ruxolitinib phosphate Chemical compound OP(O)(O)=O.C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 JFMWPOCYMYGEDM-XFULWGLBSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 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 2
- 229960000714 sipuleucel-t Drugs 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[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 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 229960005325 sonidegib Drugs 0.000 description 2
- 229960000487 sorafenib tosylate Drugs 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- 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 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- FQZYTYWMLGAPFJ-OQKDUQJOSA-N tamoxifen citrate Chemical compound [H+].[H+].[H+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 FQZYTYWMLGAPFJ-OQKDUQJOSA-N 0.000 description 2
- 229940031351 tetravalent vaccine Drugs 0.000 description 2
- 229960003433 thalidomide Drugs 0.000 description 2
- 229960002190 topotecan hydrochloride Drugs 0.000 description 2
- 229960005026 toremifene Drugs 0.000 description 2
- 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 description 2
- 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 description 2
- 229960001612 trastuzumab emtansine Drugs 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 229960002110 vincristine sulfate Drugs 0.000 description 2
- 229960002166 vinorelbine tartrate Drugs 0.000 description 2
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[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-IWWDSPBFSA-N 0.000 description 2
- 229960004449 vismodegib Drugs 0.000 description 2
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 2
- 229960000237 vorinostat Drugs 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- VVFNKRFSOQCQJP-DDDPLHQBSA-N (8s,9s,10r,13s,14s,17s)-17-acetyl-1,10,13-trimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound C1C[C@@H]2[C@@]3(C)C(C)CC(=O)C=C3CC[C@H]2[C@@H]2CC[C@H](C(C)=O)[C@]21C VVFNKRFSOQCQJP-DDDPLHQBSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- 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 description 1
- UHDGCWIWMRVCDJ-STUHELBRSA-N 4-amino-1-[(3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1C1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-STUHELBRSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 1
- 208000004804 Adenomatous Polyps Diseases 0.000 description 1
- ULXXDDBFHOBEHA-ONEGZZNKSA-N Afatinib Chemical compound N1=CN=C2C=C(OC3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-ONEGZZNKSA-N 0.000 description 1
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 206010007275 Carcinoid tumour Diseases 0.000 description 1
- 201000000274 Carcinosarcoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010008583 Chloroma Diseases 0.000 description 1
- 241000579895 Chlorostilbon Species 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- VGMFHMLQOYWYHN-UHFFFAOYSA-N Compactin Natural products OCC1OC(OC2C(O)C(O)C(CO)OC2Oc3cc(O)c4C(=O)C(=COc4c3)c5ccc(O)c(O)c5)C(O)C(O)C1O VGMFHMLQOYWYHN-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 241000588700 Dickeya chrysanthemi Species 0.000 description 1
- 208000007033 Dysgerminoma Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 208000005431 Endometrioid Carcinoma Diseases 0.000 description 1
- 206010014958 Eosinophilic leukaemia Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 241000588698 Erwinia Species 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 201000006107 Familial adenomatous polyposis Diseases 0.000 description 1
- 108010029961 Filgrastim Proteins 0.000 description 1
- 241000628997 Flos Species 0.000 description 1
- 208000004463 Follicular Adenocarcinoma Diseases 0.000 description 1
- 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 1
- 208000002966 Giant Cell Tumor of Bone Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 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 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 208000005234 Granulosa Cell Tumor Diseases 0.000 description 1
- 208000002125 Hemangioendothelioma Diseases 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 208000002291 Histiocytic Sarcoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000863873 Homo sapiens Tyrosine-protein phosphatase non-receptor type substrate 1 Proteins 0.000 description 1
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 1
- 102000012355 Integrin beta1 Human genes 0.000 description 1
- 108010022222 Integrin beta1 Proteins 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 241000222342 Irpex Species 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 208000000265 Lobular Carcinoma Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- 201000009574 Mesenchymal Chondrosarcoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010057269 Mucoepidermoid carcinoma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101000836952 Mus musculus Sialic acid-binding Ig-like lectin 10 Proteins 0.000 description 1
- PLILLUUXAVKBPY-SBIAVEDLSA-N NCCO.NCCO.CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 Chemical compound NCCO.NCCO.CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 PLILLUUXAVKBPY-SBIAVEDLSA-N 0.000 description 1
- 208000007871 Odontogenic Tumors Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102000008212 P-Selectin Human genes 0.000 description 1
- 108010035766 P-Selectin Proteins 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000009077 Pigmented Nevus Diseases 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 1
- 208000003252 Signet Ring Cell Carcinoma Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 241001494489 Thielavia Species 0.000 description 1
- 201000009365 Thymic carcinoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 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
- 102100029948 Tyrosine-protein phosphatase non-receptor type substrate 1 Human genes 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- ZSTCHQOKNUXHLZ-PIRIXANTSA-L [(1r,2r)-2-azanidylcyclohexyl]azanide;oxalate;pentyl n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]carbamate;platinum(4+) Chemical compound [Pt+4].[O-]C(=O)C([O-])=O.[NH-][C@@H]1CCCC[C@H]1[NH-].C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 ZSTCHQOKNUXHLZ-PIRIXANTSA-L 0.000 description 1
- AUYLVPGDOVEOML-UHFFFAOYSA-N [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(piperidin-1-ylmethoxy)phenyl]methanone Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 AUYLVPGDOVEOML-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229960004103 abiraterone acetate Drugs 0.000 description 1
- 229940028652 abraxane Drugs 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- RUGAHXUZHWYHNG-NLGNTGLNSA-N acetic acid;(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5, Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 RUGAHXUZHWYHNG-NLGNTGLNSA-N 0.000 description 1
- 208000006336 acinar cell carcinoma Diseases 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 1
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 1
- 201000000452 adenoid squamous cell carcinoma Diseases 0.000 description 1
- 201000008395 adenosquamous carcinoma Diseases 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 229940064305 adrucil Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 229940029184 akynzeo Drugs 0.000 description 1
- 229960005310 aldesleukin Drugs 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
- 206010065867 alveolar rhabdomyosarcoma Diseases 0.000 description 1
- 230000002707 ameloblastic effect Effects 0.000 description 1
- 208000010029 ameloblastoma Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940087620 aromasin Drugs 0.000 description 1
- 229940014583 arranon Drugs 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 230000002886 autophagic effect Effects 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 201000007551 basophilic adenocarcinoma Diseases 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- FUKOGSUFTZDYOI-BMANNDLBSA-O beacopp protocol Chemical compound ClCCN(CCCl)P1(=O)NCCCO1.CNNCC1=CC=C(C(=O)NC(C)C)C=C1.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.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.COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3C(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.C([C@H](C[C@]1(C(=O)OC)C=2C(=C3C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)=CC=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21.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(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=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C FUKOGSUFTZDYOI-BMANNDLBSA-O 0.000 description 1
- 229940077840 beleodaq Drugs 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
- 229940108502 bicnu Drugs 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 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 description 1
- 229940101815 blincyto Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 208000007047 blue nevus Diseases 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 201000011143 bone giant cell tumor Diseases 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 210000004979 bone marrow derived macrophage Anatomy 0.000 description 1
- 229940083476 bosulif Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000003714 breast lobular carcinoma Diseases 0.000 description 1
- HFCFMRYTXDINDK-WNQIDUERSA-N cabozantinib malate Chemical compound OC(=O)[C@@H](O)CC(O)=O.C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 HFCFMRYTXDINDK-WNQIDUERSA-N 0.000 description 1
- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 1
- BQRGNLJZBFXNCZ-UHFFFAOYSA-N calcein am Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=C(OC(C)=O)C=C1OC1=C2C=C(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(=O)C)C(OC(C)=O)=C1 BQRGNLJZBFXNCZ-UHFFFAOYSA-N 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- PGMBSCDPACPRSG-SCSDYSBLSA-N capiri 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.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 PGMBSCDPACPRSG-SCSDYSBLSA-N 0.000 description 1
- IQXIUTMSTALSFW-VJFOLWCZSA-N carboplatin paclitaxel Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1.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 IQXIUTMSTALSFW-VJFOLWCZSA-N 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229960001602 ceritinib Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 201000005217 chondroblastoma Diseases 0.000 description 1
- 208000021668 chronic eosinophilic leukemia Diseases 0.000 description 1
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 229940103380 clolar Drugs 0.000 description 1
- 229940034568 cometriq Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229940088547 cosmegen Drugs 0.000 description 1
- 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 description 1
- 238000005520 cutting process Methods 0.000 description 1
- IMBXRZKCLVBLBH-OGYJWPHRSA-N cvp protocol Chemical compound ClCCN(CCCl)P1(=O)NCCCO1.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.C([C@H](C[C@]1(C(=O)OC)C=2C(=C3C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)=CC=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 IMBXRZKCLVBLBH-OGYJWPHRSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 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 description 1
- 230000034994 death Effects 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960000605 dexrazoxane Drugs 0.000 description 1
- 229960004102 dexrazoxane hydrochloride Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- NYDXNILOWQXUOF-UHFFFAOYSA-L disodium;2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)NC(CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-UHFFFAOYSA-L 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229940115080 doxil Drugs 0.000 description 1
- 229940063519 doxorubicin hydrochloride liposome Drugs 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 229940099302 efudex Drugs 0.000 description 1
- 229940053603 elitek Drugs 0.000 description 1
- 229940087477 ellence Drugs 0.000 description 1
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 description 1
- 229940108890 emend Drugs 0.000 description 1
- 229910052876 emerald Inorganic materials 0.000 description 1
- 239000010976 emerald Substances 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 208000028730 endometrioid adenocarcinoma Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960005073 erlotinib hydrochloride Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 210000001808 exosome Anatomy 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 201000008825 fibrosarcoma of bone Diseases 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- 229940064300 fluoroplex Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- HSZCIIHXQDBPOI-UHFFFAOYSA-N fluorourea Chemical compound NC(=O)NF HSZCIIHXQDBPOI-UHFFFAOYSA-N 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- PJZDLZXMGBOJRF-CXOZILEQSA-L folfirinox Chemical compound [Pt+4].[O-]C(=O)C([O-])=O.[NH-][C@H]1CCCC[C@@H]1[NH-].FC1=CNC(=O)NC1=O.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.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 PJZDLZXMGBOJRF-CXOZILEQSA-L 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 229940039573 folotyn Drugs 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 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 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000007863 gel particle Substances 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 229940087158 gilotrif Drugs 0.000 description 1
- 229940084910 gliadel Drugs 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 239000006481 glucose medium Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 201000007574 granular cell carcinoma Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 229940118951 halaven Drugs 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 229940061301 ibrance Drugs 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 229940099279 idamycin Drugs 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 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 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229940005319 inlyta Drugs 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229950000038 interferon alfa Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 206010073095 invasive ductal breast carcinoma Diseases 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 206010073096 invasive lobular breast carcinoma Diseases 0.000 description 1
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 1
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940045773 jakafi Drugs 0.000 description 1
- 229940025735 jevtana Drugs 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 229940000764 kyprolis Drugs 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- 229960001739 lanreotide acetate Drugs 0.000 description 1
- 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 description 1
- 229960001320 lapatinib ditosylate Drugs 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 210000001930 leg bone Anatomy 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 229960001429 lenvatinib mesylate Drugs 0.000 description 1
- HWLFIUUAYLEFCT-UHFFFAOYSA-N lenvatinib mesylate Chemical compound CS(O)(=O)=O.C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 HWLFIUUAYLEFCT-UHFFFAOYSA-N 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 229940063725 leukeran Drugs 0.000 description 1
- 229940118199 levulan Drugs 0.000 description 1
- 229940103064 lipodox Drugs 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 208000025036 lymphosarcoma Diseases 0.000 description 1
- 229940100352 lynparza Drugs 0.000 description 1
- 201000006812 malignant histiocytosis Diseases 0.000 description 1
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 1
- 208000028676 malignant spindle cell neoplasm Diseases 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 229940034322 marqibo Drugs 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 201000008749 mast-cell sarcoma Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- XIUUSFJTJXFNGH-UHFFFAOYSA-N mebicar Chemical compound CN1C(=O)N(C)C2C1N(C)C(=O)N2C XIUUSFJTJXFNGH-UHFFFAOYSA-N 0.000 description 1
- 229960004639 mebicar Drugs 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 229940090004 megace Drugs 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- 229940083118 mekinist Drugs 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 201000008806 mesenchymal cell neoplasm Diseases 0.000 description 1
- 229940101533 mesnex Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000002923 metal particle Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 201000010225 mixed cell type cancer Diseases 0.000 description 1
- 208000029638 mixed neoplasm Diseases 0.000 description 1
- 201000006894 monocytic leukemia Diseases 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 229940074923 mozobil Drugs 0.000 description 1
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 1
- 208000010492 mucinous cystadenocarcinoma Diseases 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- 201000005987 myeloid sarcoma Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- AZBFJBJXUQUQLF-UHFFFAOYSA-N n-(1,5-dimethylpyrrolidin-3-yl)pyrrolidine-1-carboxamide Chemical compound C1N(C)C(C)CC1NC(=O)N1CCCC1 AZBFJBJXUQUQLF-UHFFFAOYSA-N 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 208000029974 neurofibrosarcoma Diseases 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- 229940024847 odomzo Drugs 0.000 description 1
- 229960002378 oftasceine Drugs 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 description 1
- 229940100027 ontak Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 229960005184 panobinostat Drugs 0.000 description 1
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 201000010210 papillary cystadenocarcinoma Diseases 0.000 description 1
- 208000024641 papillary serous cystadenocarcinoma Diseases 0.000 description 1
- 201000001494 papillary transitional carcinoma Diseases 0.000 description 1
- 208000031101 papillary transitional cell carcinoma Diseases 0.000 description 1
- 229960003349 pemetrexed disodium Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 208000031223 plasma cell leukemia Diseases 0.000 description 1
- 229960002169 plerixafor Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 229960000214 pralatrexate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229960004618 prednisone Drugs 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
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- RJKFOVLPORLFTN-UHFFFAOYSA-N progesterone acetate Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 RJKFOVLPORLFTN-UHFFFAOYSA-N 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 229940092597 prolia Drugs 0.000 description 1
- 229940021945 promacta Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000013368 pseudoglandular squamous cell carcinoma Diseases 0.000 description 1
- 229940117820 purinethol Drugs 0.000 description 1
- 229940069591 purixan Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 108010084837 rasburicase Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229940061969 rheumatrex Drugs 0.000 description 1
- HEBKCHPVOIAQTA-ZXFHETKHSA-N ribitol Chemical compound OC[C@H](O)[C@H](O)[C@H](O)CO HEBKCHPVOIAQTA-ZXFHETKHSA-N 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 108010017584 romiplostim Proteins 0.000 description 1
- 229960002539 ruxolitinib phosphate Drugs 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 208000018964 sebaceous gland cancer Diseases 0.000 description 1
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960003323 siltuximab Drugs 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 229940068117 sprycel Drugs 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229940090374 stivarga Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229960002812 sunitinib malate Drugs 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 229940110546 sylatron Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 229940022873 synribo Drugs 0.000 description 1
- 229960003454 tamoxifen citrate Drugs 0.000 description 1
- 229940099419 targretin Drugs 0.000 description 1
- 229940069905 tasigna Drugs 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229940061353 temodar Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940034915 thalomid Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- 208000015191 thyroid gland papillary and follicular carcinoma Diseases 0.000 description 1
- 208000013076 thyroid tumor Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940035307 toposar Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 208000029335 trabecular adenocarcinoma Diseases 0.000 description 1
- 229960004066 trametinib Drugs 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 229940066958 treanda Drugs 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- 229940022919 unituxin Drugs 0.000 description 1
- ATCJTYORYKLVIA-SRXJVYAUSA-N vamp regimen Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1.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.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.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C(C45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 ATCJTYORYKLVIA-SRXJVYAUSA-N 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229940065658 vidaza Drugs 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- 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 description 1
- 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 description 1
- AQTQHPDCURKLKT-PNYVAJAMSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.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=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-PNYVAJAMSA-N 0.000 description 1
- 229940034332 vincristine sulfate liposome Drugs 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
- 239000012224 working solution Substances 0.000 description 1
- 229940049068 xalkori Drugs 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229940014556 xgeva Drugs 0.000 description 1
- 229940066799 xofigo Drugs 0.000 description 1
- 229940085728 xtandi Drugs 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- 229940036061 zaltrap Drugs 0.000 description 1
- 229940034727 zelboraf Drugs 0.000 description 1
- 229940072018 zofran Drugs 0.000 description 1
- 229940033942 zoladex Drugs 0.000 description 1
- 229940061261 zolinza Drugs 0.000 description 1
- 229940052129 zykadia Drugs 0.000 description 1
Images
Classifications
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5176—Compounds of unknown constitution, e.g. material from plants or animals
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Botany (AREA)
- Zoology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本申请涉及一种低温速冻法制备的吞噬细胞膜包覆的药物递送系统,其具有包含药物递送基质的内核以及包覆所述内核的细胞膜外壳。本申请的递送系统不仅能极大地减少细胞炎性因子释放,而且能同时保持特异性、有效性、可控性、和安全性等综合优势,应用前景十分广阔。
Description
技术领域
本申请涉及一种低温速冻法制备的吞噬细胞膜包覆的药物递送系统,属于生物技术领域。
背景技术
近年来,纳米药物载体介导的靶向递送,在疾病治疗中起到了越来越重要的作用,其优势之一是能提高靶向位置的药物浓度,但纳米药物的体内治疗效果往往受到体内细胞或系统(如网状内皮系统屏障) 的限制或清除。为了消除或减轻这种影响,基于自身细胞的药物递送载体,如红细胞、血小板、干细胞、单核细胞/巨噬细胞、淋巴细胞、树突细胞、外泌体和嗜中性粒细胞等,己成为药物递送领域的新兴药物载体。尽管这些药物载体可逃逸机体系统的清除,但直接将药物装载于细胞中,药物也将杀伤载体细胞。
目前,科研人员已尝试采用将载体细胞和纳米载体相结合的策略,即先将药物封装(或负载)在纳米载体中作为“内核”,再用细胞膜 (外壳)包覆于该纳米载体上,形成“核壳”结构的递送系统。这种系统能同时逃逸机体系统的清除以及有效避免药物对载体细胞的杀伤。然而,这种系统至少还存在两个问题:一方面,其不可避免的导致载体细胞中产生较多的炎性因子,这些炎性因子对载体细胞产生刺激使其具有长时间的免疫原性,从而影响治疗效果;另一方面,产生的炎性因子对包覆于载体细胞内的纳米载体的稳定性也有影响,甚至导致药物在载体细胞内不受控制地释放。
发明内容
为了解决上述两个问题,本申请提供一种制备药物递送系统的方法,包括如下步骤:(1)获得细胞膜包覆的负载有药物的载体;(2) 将包覆后的载体进行低温冷冻。可选地,包括步骤(3):洗涤。
在一种实施方式中,细胞膜为有吞噬功能的自体或异体的天然细胞膜,如单核细胞,巨噬细胞或中性粒细胞的细胞膜或工程化的吞噬细胞膜。
在一种实施方式中,包覆为任何将细胞膜包被于载体外部表面的方式,如为细胞通过吞噬作用使载体进入细胞内而被细胞膜包裹、或人工膜包覆等。
本申请还提供上述方法制备得到的药物递送系统。
本申请还提供一种药物递送系统,包括内核和外壳,所述内核为负载有药物的载体,所述外壳为细胞膜,所述外壳包覆于内核的外表面,且该递送系统经过低温冷冻;可选地,低温冷冻之后经过洗涤处理。
在一种实施方式中,细胞膜为有吞噬功能的自体或异体的天然细胞膜,如单核细胞,巨噬细胞或中性粒细胞的细胞膜或工程化的吞噬细胞膜。
本申请还提供上述的系统在制备治疗疾病药物中的用途。
在一种实施方式中,洗涤为任何将炎性因子从细胞膜中洗脱出来的方法,例如加入缓冲溶液(如PBS)进行离心洗涤。
在一种实施方式中,细胞膜上具有细胞识别因子或包含至少一种异源的细胞外活性蛋白。
在一种实施方式中,上述负载有药物的载体为纳米载体,和/或能可控地释放负载的药物。
在一种实施方式中,所述低温冷冻使得细胞膜表面出现小孔,其改变了载体的细胞膜结构(但不改变细胞膜的基本或主体结构),使炎性因子能够从细胞中被移除而药物仍被保留在细胞中。
本申请的优点:
1.本申请的药物递送系统具有良好的稳定性和药物释放的可控性(见图2,图6)。
2.本申请的药物递送系统显著地降低了载体细胞的炎性因子,从而降低了免疫原性(见图3)。
3.本申请的药物递送系统最大限度的保留了细胞膜上的成分及其功能(见图4),因而仍能特异性地靶向目标细胞,并在体内进行良好地循环(见图5,图8)。
4.本申请的药物递送系统不影响药物的有效性,也没有带来安全性问题(见图6,图9)。
附图说明
构成本申请的一部分的附图用来提供对本申请的进一步理解,使得本申请的其它特征、目的和优点变得更明显。
图1AuNRs@SiO2的特性。
图2Cryo-MC@AuNRs@SiO2-DOX的稳定性。
图3低温冷冻对细胞炎性因子释放的影响。
图4低温冷冻对细胞表面抗体的影响。
图5低温冷冻对细胞识别功能的影响。
图6Cryo-MC@AuNRs@SiO2-DOX的可控杀伤性。
图7Cryo-MC@AuNRs@SiO2-DOX致细胞焦亡的机理。
图8Cryo-MC@AuNRs@SiO2-DOX具肿瘤特异靶向性和良好的体内循环性。
图9Cryo-MC@AuNRs@SiO2-DOX能有效抑制肿瘤且毒性小。
具体实施方式
下面参考附图来说明本申请的实施例。在本申请的一个附图或一种实施方式中描述的元素和特征可以与一个或更多个其他附图或实施方式中示出的元素和特征相结合。应当注意,为了清楚的目的,附图和说明中省略了与本申请无关的、本领域普通技术人员已知的表示和描述。下面结合附图对本申请做进一步描述。
本申请提供一种制备药物递送系统的方法,包括:(1)采用细胞膜包覆负载有药物的载体;(2)将包覆后的载体进行低温冷冻。
在一种实施方式中,细胞膜为有吞噬功能的自体或异体的天然细胞膜,如单核细胞,巨噬细胞或中性粒细胞的细胞膜或工程化的吞噬细胞膜。
在一种实施方式中,包覆为细胞通过吞噬作用使载体进入细胞内而被细胞膜包裹。
在一种实施方式中,负载有药物的载体为纳米载体。
本申请还提供一种药物递送系统,包括内核和外壳,所述内核为负载有药物的载体,所述外壳为细胞膜,所述外壳包覆于内核的外表面。
在一种实施方式中,细胞膜为有吞噬功能的自体或异体的天然细胞膜,如单核细胞,巨噬细胞或中性粒细胞的细胞膜或工程化的吞噬细胞膜。
在一种实施方式中,载有药物的载体为纳米载体。
本申请还提供上述的系统在制备治疗疾病药物中的用途。
在一种实施方式中,细胞膜上具有细胞识别因子或包含至少一种异源的细胞外活性蛋白。
在一种实施方式中,上述负载有药物的载体能可控地释放负载的药物。
定义
术语“递送系统”是指递送载体,或者细胞膜包覆的负载有药物的载体。
术语“低温冷冻”也称低温速冻,包括但不限于液氮冷冻,干冰冷冻、或其他瞬时降低温度至-80℃以下的急速冷冻;低温冷冻使载体的细胞膜结构发生改变且不会破坏细胞表面的识别因子,因此,可以通过洗涤将炎性因子从细胞中温和移除,而体积或表面积更大的药物则仍被保留在细胞中。发明人推测,通过低温速冻后,载体细胞膜形成冰晶而出现极其微小的孔,因而炎性因子能在后续的常规洗涤过程中被自然除去,有效的避免了机体的炎症反应。
术语“洗涤”是指任何将炎性因子从细胞膜内洗脱出来的方法,是药物递送过程中的常规步骤,例如使用包括但不限于PBS,对材料进行反复离心重悬以去除材料中相应成分如炎性因子等。
术语“包覆”任何将细胞膜包被于载体外部表面的方式,如通过利用吞噬细胞的吞噬作用使载体进入细胞内而被细胞膜包裹。
术语“载体”是指当与化合物或组合物组合时,根据其预期用途或目的而有助于或促进该化合物或组合物的制备、储存、施用、递送、有效性、选择性或任何其他特征的化合物、组合物、物质或结构。例如,可以选择载体以使活性成分的任何降解降至最低程度,并使受试者的任何不良副作用降至最低程度。
术语“纳米载体”指具有小于约5000nm的直径,诸如小于约4000nm、小于约3000nm、小于约2000nm、从约lOnm至约2000nm、从约20nm至约2000nm、从约50nm至约2000nm、从约100nm至约2000nm、从约200nm至约2000nm、从约250nm至约2000nm、从约300nm至约 2000nm、从约350nm至约2000nm、从约400nm至约2000nm、从约lOnm 至约1000nm,从约20nm至约1000nm、从约50nm至约1000nm、从约 100nm至约1000nm、从约200nm至约1000nm、从约250nm至约1000nm、从约300nm至约1000nm、从约350nm至约1000nm、从约400nm至约 1000nm、小于5000nm、小于4000nm、小于3000nm,小于2000nm、从lOnm至2000nm、从20nm至2000nm、从50nm至2000nm、从100nm至 2000nm、从200nm至2000nm、从250nm至2000nm、从300nm至2000nm、从350nm至2000nm、从400nm至2000nm、从lOnm至1000nm、从20nm 至1000nm、从50nm至1000nm、从100nm至1000nm、从200nm至 1000nm、从250nm至1000nm、从300nm至1000nm、从350nm至1000nm、从400nm至1000nm等的颗粒。
颗粒的形状并不特别重要:球形颗粒是典型的。在使用非球形纳米颗粒的情况下,“直径”意指具有非球形纳米颗粒的相同体积的假想球体的直径。为了本申请的目的,当超过50%(例如,超过60%、超过65%、超过70%、超过75%、超过80%、超过85%、超过90%等)具有特定直径或在特定的直径范围内的直径时,纳米颗粒的“大部分”被认为具有特定的直径或特定的直径范围。例如,纳米颗粒直径范围在 1至1000nm范围内,或具有在2至200nm的范围内、优选地在2至 150nm的范围内、甚至更优选地2至100nm范围内的尺寸。
另外,纳米载体可以具有从-1mV至一40mV的平均zeta电位(表面电荷),包括约-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或-40mV。
术语“药物”或治疗剂,是指可用于实现受试者的生理变化的化合物、混合物或组合物,包括但不限于小分子、多肽和核酸等。例如,紫杉醇、喜树碱、多西他赛、阿霉素、顺铂、5-氟尿嘧啶等抗肿瘤药物。
在一些实施方式中,化合物可被配制为组合物中唯一的药物活性成分,或者可以与其他活性成分组合。例如,化合物可与己知的NSAID、抗炎化合物、类固醇和/或抗生素一起配制或组合。
在一些实施方案中,药物是亲水性或疏水性抗肿瘤药物。例如,该药物可选自乙酸阿比特龙酷,Abitrexate(甲氨蝶吟),Abraxane(白蛋白稳定化紫杉醇纳米颗粒制剂)、ABVD,ABVE,ABVE-PC,AC,AC- T,Adcetris,ADE,Ado-TrastuzumabEmtansine,Adriamycin(盐酸阿霉素),Adrucil(氟尿嚓咤)、马来酸阿法替尼、飞尼妥(依维莫司),Akynzeo(奈妥毗坦和盐酸帕洛诺司琼)、艾达乐(咪哇莫特)、阿地白介素、阿仑单抗、力比泰(培美曲塞二钠),Aloxi(盐酸帕洛诺司琼),Ambochlorin(苯丁酸氮芥),Amboclorin(苯丁酸氮芥)、氨基乙酞丙酸、阿那曲哩、阿瑞匹坦、阿可达帅白米嶙酸二钠)、瑞宁得(阿那曲哩),Aromasin(依西美坦),Arranon(奈拉滨)、三氧化二砷、 Arzerra(Ofatumumab)、菊欧文氏菌(Erwiniachrysanthemi)天冬酞胺酶、安维汀(贝伐单抗)、阿昔替尼、阿扎胞普、BEACOPP,Becenum(卡莫司汀),Beleodaq(贝利司他)、贝利司他、盐酸苯达莫司汀、BEP、贝伐单抗、贝沙罗汀、百克沙(托西莫单抗和碘工131托西莫单抗)、比卡鲁胺,BiCNU(卡莫司汀)、博来霉素、博纳吐单抗、Blincyto(博纳吐单抗)、硼替佐米、Bosulif(博舒替尼)、博舒替尼、BrentuximabVedotin、白消安、白舒非(白消安)、卡巴他赛、卡博替尼-S-苹果酸盐、CAF,Campath(阿仑单抗),Camptosar(盐酸伊立替康)、卡培他滨,CAPOX、卡铂、卡铂-紫杉醇、卡非佐米、Carmubris(卡莫司汀)、卡莫司汀、卡莫司汀植入膜剂、康士得(比卡鲁胺)、CeeNU(洛莫司汀)、色瑞替尼、柔红霉素(盐酸柔红霉素)、希瑞适(重组HPV二价疫苗)、西妥昔单抗、苯丁酸氮芥、苯丁酸氮芥一泼尼松、CHOP、顺铂、 Clafen(环磷酞胺)、克罗拉滨,Clofarex(克罗拉滨),Clolar(克罗拉滨),CMF,Cometriq(卡博替尼一S一苹果酸盐),COPP,COPP- ABV,Cosmegen(放线菌素D)、克哩替尼、CVP、环磷酞胺,Cyfos(异环磷酞胺),Cyramza(雷莫芦单抗)、阿糖胞普、阿糖胞普脂质体、 Cytosar-U(阿糖胞普)、癌得星(环磷酞胺)、达拉菲尼、达卡巴嗦、达坷(地西他滨)、放线菌素D、达沙替尼、盐酸柔红霉素、地西他滨、地加瑞克、地尼白介素-2、狄诺塞麦、DepoCyt(阿糖胞普脂质体),DepoFoam(阿糖胞普脂质体)、盐酸右雷佐生、Dinutuximab、多西他赛、Doxil盐酸阿霉素脂质体)、盐酸阿霉素、盐酸阿霉素脂质体、Dox-SL(盐酸阿霉素脂质体),DT工C-Dome(达卡巴嗦),Efudex氟尿嚓咤),Elitek(拉布立酶),Ellence(盐酸表阿霉素)、乐沙定(奥沙利铂)、艾曲波帕乙醇胺,Emend(阿瑞匹坦)、恩杂鲁胺、盐酸表阿霉素、EPOCH、尔必得舒(西妥昔单抗)、甲磺酸艾日布林、维莫德吉(Vismodegib)、盐酸厄洛替尼、Erwinaze(菊欧文氏菌天冬酞胺酶)、凡毕复(磷酸依托泊普)、依托泊普、磷酸依托泊普,Evacet(盐酸阿霉素脂质体)、依维莫司、易维特(盐酸雷洛昔芬)、依西美坦、Fareston(托瑞米芬),Farydak(帕比司他),Faslodex(氟维司群),FEC、弗隆(来曲哩)、非格司亭、氟达拉滨(磷酸氟达拉滨)、磷酸氟达拉滨,Fluoroplex(氟尿嚓咤)、氟尿嚓咤,Folex(甲氨蝶吟),FolexPFS(甲氨蝶吟),FOLFIRI、FOLFIRI-贝伐单抗、FOLFIRI-西妥昔单抗、FOLFIRINOX、奥沙利铂、Folotyn(普拉曲沙),FU-LV,氟维司群、加德西(重组HPV四价疫苗)、加德西9(重组HPV九价疫苗),Gazyva(Obinutuzumab)、吉非替尼、盐酸吉西他滨、吉西他滨一顺铂、吉西他滨一奥沙利铂、吉妥单抗、健择(盐酸吉西他滨),Gilotrif(马来酸阿法替尼)、格列卫呷磺酸伊马替尼),Gliadel(卡莫司汀植入膜剂),Gliadel wafer(卡莫司汀植入膜剂)、梭肤酶、醋酸戈舍瑞林、Halaven(甲磺酸艾日布林)、赫赛汀(曲妥单抗)、重组HPV二价疫苗、重组HPV九价疫苗、重组HPV四价疫苗、Hycamtin(盐酸拓扑替康)、Hyper-CVAD、Ibrance 帅白博西尼)、替伊莫单抗、依鲁替尼、ICE、Iclusig(盐酸普纳替尼)、Idamycin(盐酸伊达比星)、盐酸伊达比星、艾代拉里斯、工fex(异环磷酞胺)、异环磷酞胺、Ifosfamidum(异环磷酞胺)、甲磺酸伊马替尼、 Imbruvica(依鲁替尼)、咪哇莫特、Inlyta(阿西替尼)、重组干扰素 Alfa-2b、Intron A(重组干扰素Alfa-2b)、碘工131托西莫单抗和托西莫单抗、易普利姆玛、易瑞沙(吉非替尼)、盐酸依立替康、 Istodax(罗米地辛)、伊沙匹隆、Ixempra(伊沙匹隆),Jakafi(磷酸鲁索利替尼),Jevtana(卡巴他赛),Kadcyla(Ado-Trastuzumab Emtansine),Keoxifene(盐酸雷洛昔芬),Kepivance帅白利夫明)、健痊得(Pembrolizumab),Kyprolis(卡非佐米)、醋酸兰瑞肤、二甲苯磺酸拉帕替尼、来那度胺、甲磺酸乐伐替尼、Lenvima(甲磺酸乐伐替尼)、来曲哩、亚叶酸钙、Leukeran(苯丁酸氮芥)、醋酸亮丙瑞林、 Levulan(氨基乙酞丙酸),Linfolizin(苯丁酸氮芥),LipoDox(盐酸阿霉素脂质体)、阿糖胞普脂质体、洛莫司汀、Lupron(醋酸亮丙瑞林),Lupron Depot(醋酸亮丙瑞林),Lupron Depot-Ped(醋酸亮丙瑞林),Lupron Depot-3Month(醋酸亮丙瑞林),LupronDepot-4Month(醋酸亮丙瑞林),Lynparza(奥拉帕尼),Marqibo(硫酸长春新碱脂质体)、 Matulane(盐酸甲基节胁)、盐酸氮芥、Megace(醋酸甲地孕酮)、醋酸甲地孕酮,Mekinist(曲美替尼)、琉嘿吟、美司钠、Mesnex(美司钠),Methazolastone(替莫哩胺)、甲氨蝶吟、甲氨蝶吟LPF(甲氨蝶吟),Mexate(甲氨蝶吟),Mexate-AQ(甲氨蝶吟)、丝裂霉素C、盐酸米托蕙醒、Mitozytrex(丝裂霉素C),MOPP,Mozobil(普乐沙福),Mustargen(盐酸氮芥),Mutamycin(丝裂霉素C)、马利兰泊消安),Mylosar(阿扎胞普),Mylotarg(吉妥单抗)、纳米颗粒紫杉醇(白蛋白稳定化紫杉醇纳米颗粒制剂),Navelbine(酒石酸长春瑞滨)、奈拉滨,Neosar(环磷酞胺)、奈妥毗坦和盐酸帕洛诺司琼、Neupogen(非格司亭),Nexavar(甲苯磺酸索拉非尼)、尼罗替尼、Nivolumab、三苯氧胺(柠檬酸他莫昔芬),Nplate(罗米司亭),Obinutuzumab,Odomzo(Sonidegib),OEPA,Ofatumumab,OFF、奥拉帕尼、高三尖杉酷碱、Oncaspar(培门冬酶)、盐酸昂丹司琼、Ontak 她尼白介素一2),Opdivo(Nivolumab),OPPA、奥沙利铂、紫杉醇、白蛋白稳定化紫杉醇纳米颗粒制剂、PAD、帕博西尼、帕利夫明、盐酸帕洛诺司琼、盐酸帕洛诺司琼和奈妥毗坦、帕米嶙酸二钠、帕尼单抗、帕比司他、Paraplat(卡铂),Paraplatin(卡铂)、盐酸培哩帕尼、培门冬酶、聚乙二醇干扰素Alfa-2b,PEG-Intron聚乙二醇干扰素Alfa- 2b),Pembrolizumab、培美曲塞二钠、Perjeta帅白妥珠单抗)、帕妥珠单抗、顺氯氨铂(顺铂)、顺氯氨铂-AQ(顺铂)、 Plerixafor,Pomalidomide,Pomalyst(Pomalidomide)、盐酸普纳替尼、 Pralatrexate、泼尼松、盐酸甲基节胁,Proleukin(阿地白介素),Prolia(狄诺塞麦),Promacta(艾曲波帕乙醇胺)、 Provenge(Sipuleucel-T),Purinethol(琉嘿吟)、Purixan(琉嘿吟)、镭223氯、盐酸雷洛昔芬、雷莫芦单抗、拉布立酶、R-CHOP,R-CVP、重组人乳头瘤病毒((HPV)二价疫苗、重组人乳头瘤病毒((HPV)九价疫苗、重组人乳头瘤病毒((HPV)四价疫苗、重组干扰素Alfa-2b、瑞戈非尼、R-EPOCH,Revlimid(来那度胺),Rheumatrex(甲氨蝶吟)、美罗华(利妥昔单抗)、利妥昔单抗、Romidepsin,Romiplostim、红比霉素 (盐酸柔红霉素)、磷酸鲁索利替尼、SclerosolIntrapleuralAerosol(Talc),Siltuximab,Sipuleucel-T,Somatuline Depot(醋酸兰瑞肤),Sonidegib、甲苯磺酸索拉非尼、Sprycel(达沙替尼),STANFORD V、无菌Talc粉末(Talc),Steritalc(Talc),Stivarga(瑞戈非尼)、苹果酸舒尼替尼、Sutent(苹果酸舒尼替尼),Sylatron(聚乙二醇干扰素Alfa- 2b),Sylvant(Siltuximab),Synovir(沙利度胺),Synribo(高三尖杉酷碱),TAC,Tafinlar(达拉菲尼)、Talc、柠檬酸他莫昔芬、Tarabine PFS(阿糖胞普),Tarceva(盐酸厄洛替尼),Targretin(贝沙罗汀),Tasigna(尼罗替尼),Taxol(紫杉醇),Taxotere(多西他赛),Temodar(替莫哩胺)、替莫哩胺、西罗莫司脂化物、沙利度胺,Thalomid(沙利度胺)、曝替呱,Toposar(依托泊普)、盐酸拓扑替康、托瑞米芬、Torisel(西罗莫司脂化物)、托西莫单抗和碘131托西莫单抗、Toted(盐酸右雷佐生),TPF、曲美替尼、曲妥单抗、 Treanda(盐酸苯达莫司汀),Trisenox(三氧化二砷),Tykerb、 Unituxin(Dinutuximab),Vandetanib,VAMP,Vectibix(帕尼单抗),VeIP,Velban(硫酸长春碱),Velcade(硼替佐米),Velsar(硫酸长春碱)、维罗非尼、VePesid(依托泊普),Viadur(醋酸亮丙瑞林),Vidaza(阿扎胞普)、硫酸长春碱、Vincasar PFS(硫酸长春新碱)、硫酸长春新碱、硫酸长春新碱脂质体、酒石酸长春瑞滨,VIP,Vismodegib,Voraxaze(梭肤酶)、伏立诺他、Votrient(盐酸帕哩帕尼)、Wellcovorin(亚叶酸钙),Xalkori(克哩替尼),Xeloda(卡培他滨),XELIRI、XELOX,Xgeva(狄诺塞麦),Xofigo(镭223 氯),Xtandi(恩杂鲁胺),Yervoy(易普利姆玛),Zaltrap(Ziv-阿柏西普),Zelboraf(维罗非尼),Zevalin(Ibritumomab Tiuxetan),Zinecard(盐酸右雷佐生),Ziv-阿柏西普、Zofran(盐酸昂丹司琼),Zoladex(醋酸戈舍瑞林)、哩来嶙酸、Zolinza(伏立诺他),Zometa(哩来嶙酸),Zydelig(艾代拉里斯),Zykadia(色瑞替尼) 以及Zytiga(乙酸阿比特龙酷)。
术语“小分子”是指分子量小于2,000道尔顿,更优选地小于 1,500道尔顿、最优选地小于1,000道尔顿的分子,诸如有机或有机金属化合物。小分子可以是亲水性、疏水性或两亲性化合物。
术语“治疗”是指对患者进行的意图治愈、改善、稳定或预防疾病、病理状况或障碍的医疗管理。该术语包括积极治疗,即治疗特别指向疾病、病理状况或障碍的改善,并且还包括病因治疗,即治疗指向去除相关疾病、病理状况或障碍的病因。此外,该术语还包括姑息治疗,即为减轻症状而不是治愈疾病、病理状况或障碍而设计的治疗;预防性治疗,即旨在尽量最小化或者部分或完全抑制相关疾病、病理状况或障碍发展的治疗;和支持治疗,即用于补充指向相关疾病、病理状况或障碍的改善的另一种特定疗法的治疗。
“炎性因子”(或炎症因子),也称炎性细胞因子或炎症细胞因子,参与炎症反应的各种细胞因子,例如IL-6,IL-8,IL-10,IL-12,IL- 1β,TNFα等。
术语“细胞识别因子”是指能识别目标细胞的因子,例如CD47, CD24,SIRPα/SHPS1,CD55或CD5等自我识别免疫调节蛋白。
术语“异源性细胞外活性蛋白”可以是在与目标细胞接触时将具有治疗效果的任何天然或合成的蛋白。例如,该细胞外活性蛋白可以是肿瘤坏死因子((TNF)相关的细胞凋亡诱导配体(TRA工L),其可以结合肿瘤细胞上的DR4和DR5死亡受体并诱导细胞凋亡。又如,该细胞外活性蛋白可以是治疗性抗体,诸如西妥昔单抗(Cetuximab)、曲妥单抗(Trastuzumab)、贝伐单抗(Bevacizumab)、帕尼单抗 (Panitumumab)、易普利单抗(Ipi 1imumab)、利妥昔单抗 (Rituximab)、阿仑单抗((Alemtuzumab)、奥法木单抗((Ofatumumab)、吉妥珠单抗奥佐米星(Gemtuzumab ozogamicin)、贝伦妥单抗一维多汀(Brentuximab vedotin),Pembrolizumab(Keytruda),nivolumab (Opdivo)或它们的组合。
本申请的药物递送系统可以静脉内、皮内、动脉内、腹腔内、病灶内、颅内、关节内、前列腺内、胸腔内、气管内、玻璃体内、阴道内、直肠内、瘤内、肌内、腹腔内、皮下、结膜下、囊内、粘膜、心包内、脐带内、眼内、鞘内、局部、通过注射、通过输注、通过连续输注、通过直接局部灌注浸浴靶细胞、经由导管或经由灌洗来施用。例如,该药物递送系统可通过注射或输注来施用。
在一些实施方案中,通过将该药物递送系统注射到肿瘤位点附近而进行非肠道给药。如本文所用,“肿瘤位点附近”意指将药物递送系统局部靶向并递送至肿瘤位点,并且意在包括直接注射到肿瘤中以及注射到距肿瘤约lcm(例如,在lcm内、在约5mm内、在5mm内、在约2mm内、在2mm内等)的范围内。药物递送系统可以例如经由单次注射或经由多次注射来施用,例如在通过将药物递送系统注射到肿瘤中和肿瘤边缘周围的方式来施用。在一些实施方案中,如在静脉内施用的情况下,例如通过将药物递送系统注射到受试者的循环系统中,向受试者全身性施用。在一些实施方案中,将药物递送系统肠内施用,例如以灌注胃肠道中的肿瘤。
为了拥有更好的治疗益处,药物递送系统或其携带的药物可以与选自放射治疗剂、激素治疗剂、免疫治疗剂、化学治疗剂、冷冻治疗剂和基因治疗剂的至少一种另外的试剂组合施用。
本文在实施例中具体公开了一种巨噬细胞膜包覆的核-壳纳米载体,该纳米载体可以具有细胞靶向特异性地将细胞外活性药物和细胞内功能性药物递送至癌细胞。通过利用巨噬细胞与癌细胞之间的高亲和力,巨噬细胞膜包覆的核-壳纳米载体有效地聚集在癌细胞的表面上,从而可以促进细胞外活性药物的相互作用。同时通过外源性刺激如近红外光、放射射线、超声等,可控的使得细胞内功能性药物释放并在癌细胞中进一步累积。此外,巨噬细胞膜包覆的核-壳纳米载体可以体内消除原发肿瘤细胞并显著抑制肿瘤转移。
本申请实施例中巨噬细胞膜包覆的核-壳纳米载体的优点:第一,利用自体吞噬细胞自身优良的吞噬性能可高效的进行药物装载;第二,利用低温速冻技术冷冻处理装载药物后的吞噬细胞可最大限度的保留膜上成分保留其功能、降低免疫原性、同时可快速大量制备;第三,利用自体或自体工程化吞噬细胞可有效的降低免疫排异、提高药物的体内循环稳定性、并提高其肿瘤靶向效果;第四,可适用范围广,可通过该系统装载各种肿瘤治疗的小分子、蛋白、纳米材料等药物,均可有效提高其在肿瘤部位的积累。
下文实施例具体描述了一种巨噬细胞膜包覆的纳米载体,其具有包含药物递送基质的内核以及包覆内核的外壳巨噬细胞膜。内核可以是能够将治疗剂递送至细胞的任何药物递送基质。例如,治疗剂可以是亲水性或疏水性小分子化合物。在一些情况下,治疗剂是从细胞内的内核释放的细胞内活性小分子药物。例如,药物可以是疏水性或亲水性抗肿瘤药物。
巨噬细胞膜可以是包含能够与癌细胞相互作用的巨噬细胞的天然或工程化改造膜。在一些情况下,巨噬细胞是通过骨髓分离诸如来自待治疗的受试者的自体骨髓而产生的。在其他情况下,外壳是工程化改造膜诸如通过基因或药物刺激的巨噬细胞的细胞膜,其被设计成含有能够与癌细胞相互作用的相关识别蛋白。
无论是天然的还是合成的,外壳巨噬细胞膜都可以被设计成包含至少一种异源的细胞外活性蛋白。这种细胞外活性蛋白可以是在与癌细胞接触时将具有治疗效果的任何天然或合成的蛋白。例如,该细胞外活性蛋白可以是肿瘤坏死因子((TNF)相关的细胞凋亡诱导配体 (TRA工L),其可以结合肿瘤细胞上的DR4和DR5死亡受体并诱导细胞凋亡。又如,该细胞外活性蛋白可以是治疗性抗体,诸如西妥昔单抗(Cetuximab)、曲妥单抗(Trastuzumab)、贝伐单抗(Bevacizumab)、帕尼单抗(Panitumumab)、易普利单抗(Ipi1imumab)、利妥昔单抗 (Rituximab)、阿仑单抗((Alemtuzumab)、奥法木单抗((Ofatumumab)、吉妥珠单抗奥佐米星(Gemtuzumab ozogamicin)、贝伦妥单抗一维多汀(Brentuximab vedotin),Pembrolizumab(Keytruda),nivolumab (Opdivo)或它们的组合。
本申请还具体公开了一种用于治疗受试者的癌症的方法,该方法涉及向受试者施用本文所公开的巨噬细胞膜包覆的纳米载体。在一些情况下,巨噬细胞膜是自体的,即由从受试者获得的骨髓产生。在一些情况下,癌症是一种原发性癌细胞。在一些情况下,癌症是一种转移性癌细胞。
本申请更具体地提供了一种通过低温速冻法制备的吞噬细胞膜包覆的纳米载体,包含:a)内核,所述内核包含药物递送基质,其中所述药物递送基质包括抗肿瘤药物;以及b)外壳吞噬细胞膜,所述外壳吞噬细胞包覆所述内核,其中所述吞噬细胞还包含肿瘤坏死因子 (TNF)相关细胞凋亡诱导配体(TRAIL)。
内核可以是能够将治疗剂包封并递送至细胞的任何药物递送基质。例如,药物递送基质可以是金属颗粒,聚合物凝胶颗粒、脂质颗粒或无机颗粒。在一些情况下,药物递送基质是可生物降解的。在一些情况下,药物递送基质对pH,近红外光,放射射线,超声波敏感。
药物递送基质可以用于包封从靶细胞内的内核释放的细胞内活性药物。该药物可以是在细胞内具有治疗活性的任何类型的分子,诸如蛋白质、核酸(miRNA,RNAi,dsDNA等)或小分子化合物。药物递送基质可以基于待包封的期望的细胞内活性药物来选择。因此,细胞内活性药物可以是亲水的或疏水的。
可通过巨噬细胞细胞自身的吞噬作用将吞噬细胞膜或工程化膜组分与内核组合来使纳米载体与巨噬细胞膜组合。
外壳巨噬细胞膜可以是包含能够与癌细胞相互作用的相关蛋白的天然或工程化膜。在一些情况下,巨噬细胞膜是通过原代巨噬细胞诸如来自待治疗的受试者的自体骨髓进行分化培养而产生的。在其他情况下,外壳是工程化膜,其被设计成含有能够与癌细胞相互作用的相关蛋白。例如,外壳巨噬细胞膜可以包含P-选择素蛋白。外壳巨噬细胞膜可以包含整合素αⅡbβ3。壳巨噬细胞膜可以包含选自CD47, CD24,SIRPα/SHPS1,CD55和CD59的自我识别的免疫调节蛋白。
无论是天然的还是合成的,外壳巨噬细胞膜都可以被设计成包含至少一种异源的细胞外活性蛋白。这种细胞外活性蛋白可以是在与癌细胞接触时具有治疗效果的任何天然或合成的蛋白。例如,该细胞外活性蛋白可以是肿瘤坏死因子((TNF)相关的细胞凋亡诱导配体 (TRAIL),其可以结合肿瘤细胞上的DR4和DR5死亡受体并诱导细胞凋亡。又如,细胞外活性蛋白可以是治疗性抗体,诸如西妥昔单抗、曲妥单抗或它们的组合。
在一些实施方案中,抗肿瘤药物包含疏水性小分子或亲水性小分子。
在一些实施方案中,外壳吞噬细胞膜包含选自有吞噬功能的天然细胞膜,如单核细胞,巨噬细胞,中性粒细胞等或选自工程化的吞噬细胞膜。在一些实施方案中,外壳吞噬细胞膜包含整合素-α4,β1。在一些实施方案中,外壳吞噬细胞膜包含选自CD47,CD24,SIRPα/SHPS1,CD55和CD59的自我识别免疫调节蛋白。优选的,外壳吞噬细胞膜还包含异源性细胞外活性蛋白。在一些方案中,细胞外活性蛋白包括治疗性抗体,如西妥昔单抗、曲妥单抗或它们的组合。
在一些实施方案中,药物递送基质包括聚合物凝胶、无机颗粒、脂质颗粒、和/或树枝状体颗粒。
在一些实施方式中,纳米载体具有10nm至1000nm的平均直径。
在一些实施方案中,低温速冻法包括液氮冷冻,干冰冷冻等瞬时降低温度至-80℃以下的急速冷冻技术。
在一些实施方案中,纳米载体具有-1mV至-40mV的平均zeta电位。在一些实施方案中,纳米载体可以是对pH,过氧化氢,谷胱甘肽敏感。在一些实施方案中,纳米载体可以是对近红外光,放射射线,超声敏感。
本申请具体还提供了吞噬细胞膜包覆的纳米载体在制备用于治疗受试者的癌症的药物中的用途。
在一些实施方式中,吞噬细胞膜是自体的。在一些实施方式中,癌症是原位癌细胞或转移性癌细胞。
本申请所公开的巨噬细胞膜包覆的纳米载体具有包含药物递送基质的内核以及包覆该内核的外壳巨噬细胞膜。
本申请还公开了一种用于治疗受试者的癌症的方法,所述方法涉及向所述受试者施用本文所公开的巨噬细胞膜包覆的纳米载体。在一些情况下,巨噬细胞膜是自体的,即由从受试者获得的巨噬细胞产生。
“癌症”可能是实体瘤、转移性癌症或非转移性癌症。在某些实施方案中,癌症可起源于膀肤、血液、骨骼、骨髓、脑、乳房、结肠、食道、十二指肠、小肠、大肠、结肠、直肠、肛门、牙酿、头、肾、肝、肺、鼻咽、颈部、卵巢、前列腺、皮肤、胃、翠丸、舌头或子宫。在某些实施方案中,癌症是卵巢癌。在特定方面,癌症可能是抗化疗癌症。在一些情况下,癌症是一种原位癌细胞。
“癌症”可能特别是以下组织学类型,但不限于以下这些:赘生物,恶性;恶性上皮细胞肿瘤;恶性上皮细胞肿瘤,未分化;巨细胞和梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌;移行细胞癌;乳头状移行细胞癌;腺癌;胃泌素瘤,恶性;胆管癌;肝细胞癌;混合型肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤性息肉中的腺癌;腺癌,家族性结肠息肉病;实体肿瘤;类癌肿瘤,恶性;细支气管一肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸性腺癌;嗜碱细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡性腺癌;乳头状和滤泡性腺癌;非包围性硬化性癌;肾上腺皮质癌;子宫内膜样癌;皮肤附属器癌;顶浆分泌腺癌;皮脂腺癌;盯聆腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;佩吉特氏病,乳腺;腺泡细胞癌;腺鳞癌;伴随鳞状化生的腺癌;胸腺瘤,恶性;卵巢间质肿瘤,恶性;泡膜细胞瘤,恶性;粒层细胞瘤,恶性;男性细胞瘤,恶性;塞尔托利氏细胞癌;间质细胞瘤,恶性;脂细胞瘤,恶性;副神经节瘤,恶性;乳腺外副神经节瘤,恶性;嗜铬细胞瘤;肾小球肉瘤 (glomangiosarcoma);恶性黑素瘤;无黑素性黑素瘤;浅表扩散性黑素瘤;巨大色素痣恶性黑素瘤;上皮样细胞黑素瘤;蓝痣,恶性;肉瘤;纤维肉瘤;纤维性组织细胞瘤,恶性;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;腺泡状横纹肌肉瘤;间质肉瘤;混合瘤,恶性;子宫中胚叶混合瘤;肾母细胞瘤;肝母细胞瘤;癌肉瘤;间叶瘤,恶性;布伦内罗氏瘤,恶性;叶状肿瘤,恶性;滑膜肉瘤;间皮瘤,恶性;无性细胞瘤;胚胎性癌;畸胎瘤,恶性;卵巢甲状腺瘤,恶性;绒毛膜癌;中肾瘤,恶性;血管肉瘤;血管内皮瘤,恶性;卡波西肉瘤;血管外皮细胞瘤,恶性;淋巴管肉瘤;骨肉瘤;皮质旁骨肉瘤;软骨肉瘤;成软骨细胞瘤,恶性;间叶性软骨肉瘤;骨巨细胞瘤;尤因氏肉瘤;牙源性肿瘤,恶性;成釉细胞性牙骨肉瘤;成釉细胞瘤,恶性;成釉细胞纤维肉瘤;松果体瘤,恶性;脊索瘤;胶质瘤,恶性;室管膜瘤;星形细胞瘤;原浆型星形细胞瘤;纤维性星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突神经胶质瘤;成少突神经胶质细胞瘤;原始性神经外胚层肿瘤;小脑肉瘤;节细胞性神经母细胞瘤;神经母细胞瘤;视网膜母细胞瘤;嗅神经源性肿瘤;脑膜瘤,恶性;神经纤维肉瘤;神经鞘瘤,恶性;颗粒细胞瘤,恶性;恶性淋巴瘤;霍奇金氏病;霍奇金氏副肉芽肿;恶性淋巴瘤,小淋巴细胞性;恶性淋巴瘤,大细胞,弥漫性;恶性淋巴瘤,滤泡性;草样肉芽肿;其他指定的非霍奇金氏淋巴瘤;恶性组织细胞增多症;多发性骨髓瘤;肥大细胞肉瘤;免疫增生性小肠疾病;白血病;淋巴细胞性白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;骨髓性白血病;嗜碱性粒细胞白血病;嗜酸性粒细胞白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;髓样肉瘤;和毛细胞白血病。
实施例
实施例1制备AuNRs@SiO2-DOX
首先根据(Zhang et al.,2012)方法制备AuNRs@SiO2(见图1),AuNRs@SiO2即为二氧化硅包覆金纳米棒材料。由图1可见,已成功制备了均匀的介孔AuNRs@SiO2核壳材料,并且其最大吸光度为808nm左右,后续实验采用808nm光进行激发可得到较好的光热效果。为了制备具有光控特性的载药体系,使用AuNRs@SiO2装载DOX。具体方法为:将制备好的材料和DOX水溶液按1:1混合,室温震荡24小时, 7000rpm/10min洗涤离心得到装载DOX的AuNRs@SiO2(AuNRs@SiO2- DOX)。
实施例2制备Cryo-MC@AuNRs@SiO2-DOX
制备骨髓来源的巨噬细胞。8周龄balb/c鼠断颈处死,用75%酒精消毒,在超净台中取下腿骨,用PBS冲出骨髓,300rpm5min离心,弃上清。5ml培养基(10%FBS,1%双抗的DMEM高糖培养基)重悬,加入M-CSF(50ng/ml),铺板。在培养箱中放置7天得到成熟的原代巨噬细胞。
制备巨噬细胞膜包覆的AuNRs@SiO2-DOX(Cryo-MC@AuNRs@SiO2- DOX)。将制备好的AuNRs@SiO2-DOX加入成熟的原代巨噬细胞中共培养 12h,用PBS洗去多余的材料,将贴壁细胞用枪吹打下来,1000rpm,3min 离心洗涤得到MC@AuNRs@SiO2-DOX,将细胞沉淀(MC@AuNRs@SiO2-DOX) 重悬于DMEM高糖培养基中,迅速放入液氮中急速冷冻(如18h),即得到Cryo-MC@AuNRs@SiO2-DOX。
实施例3 Cryo-MC@AuNRs@SiO2-DOX的体外稳定性及其Dox的释放
为了分析Cryo-MC@AuNRs@SiO2-DOX的体外稳定性,将Cryo- MC@AuNRs@SiO2-DOX加入1mlPBS(Hyclone公司)中,或加入内嵌在 14mLpH为7.2的PBS缓冲溶液(含有0.1%Tween-80)中的透析管 (lOKMWCO)(Slide-A-Lyzer,赛默飞世尔科技公司(ThermoScientific))中,并于37℃下在振荡器(New Brunswick Scientific 公司)中以100rpm轻轻振荡。在预定的时间间隔处,取出全部缓冲溶液,随后用14mL具有相同pH的新鲜缓冲溶液替代。通过酶标仪,以 480nm的激发波长,在596nm处测量释放的Dox的荧光强度。
具体地,为了分析体外Dox释放,将0.5mL Cryo-MC@AuNRs@SiO2- DOX加入内嵌在14mL pH为7.2的PBS缓冲溶液(含有0.1%Tween-80)中的透析管(lOKMWCO)(Slide-A-Lyzer,赛默飞世尔科技公司(Thermo Scientific))中,用808nm近红外光光照在预定的时间间隔处,取出2 微升溶液,随后用具有相同pH的新鲜缓冲溶液替代。取等量的Cryo- MC@AuNRs@SiO2-DOX,对比808nm近红外光光照前后的DOX释放情况。通过酶标仪,以480nm的激发波长,在596nm处测量释放的DOX的荧光强度。
从图2中可知,Cryo-MC@AuNRs@SiO2-DOX具有优良的稳定性,在没有808nm近红外光刺激的情况下12h DOX的释放量仅为4%。然而通过 808nm近红外光刺激,12h DOX的释放量可达到95%以上,说明制备的材料具有优良的光控释放特性,可进一步提高其治疗的特异性。
实施例4低温冷冻在减少细胞炎症因子的同时保留了细胞表面识别因子
将Cryo-MC@AuNRs@SiO2-DOX组与MC@AuNRs@SiO2-DOX组细胞炎性因子的释放量进行对比。每组细胞分别取2h和24h上清,应用 ELISA双抗体夹心法进行IL-1β,IL-6,IL-10,IL-12和TNF-α的检测(n=3)。从图3中可知,将材料直接装载在活细胞中会对细胞造成强刺激使其释放大量炎性因子。其中,BMDM是指原代的小鼠巨噬细胞通过提取小鼠骨髓细胞,经体外刺激分化得到;Cryo-BMDM,指利用本发明的方法经低温速冻BMDM后制备得到。如果将这样的药物递送系统直接用于活体将造成机体全身性炎症反应,对身体健康造成影响,而通过低温速冻后,载体细胞膜形成冰晶而出现极其微小的孔,因而炎性因子能在后续的常规洗涤过程中被自然除去,有效的避免了机体的炎症反应。
通过对相同细胞数的正常的Raw264.7和液氮冷冻的Raw264.7 (Cry-Raw264.7)膜表面对于细胞识别和避免吞噬细胞吞噬的抗体进行WB测试发现,液氮冷冻对于细胞表面抗体损伤较小,说明通过液氮冷冻可较大范围的保留表面抗体从而保留其相关功能(见图4)。
实施例5体外肿瘤细胞靶向和光控药物递送
细胞培养。从中国科学院干细胞库获得EMT6细胞并在含10% FBS,100U/mL青霉素和100ug/mL链霉素的Dulbecco's改良的1640培养基中培养。
体外肿瘤细胞靶向和光控药物递送。用钙黄绿素-AM(Sigma, 50ug/ml)与肿瘤细胞EMT6在细胞培养箱(Thermo Scientific)中,在 37℃5%CO2条件下孵育30min,之后用2ml PBS轻轻冲洗5遍。将Cryo- MC@AuNRs@SiO2-DOX与EMT6@钙黄绿素-AM在细胞培养箱(Thermo Scientific)中,在37℃5%CO2条件下孵育6h,用2ml PBS轻轻冲洗5 遍。在共聚焦显微镜(奥林巴斯Olympus)下观察Cryo-MC@AuNRs@SiO2- DOX与EMT6@钙黄绿素-AM的结合。
肿瘤细胞EMT6用钙黄绿素(绿色)标记,Cryo-MC@AuNRs@SiO2- DOX用DiI(红色)标记。从图5中可以看出处理后的材料大量的粘附于靶细胞,说明通过低温速冻的方法能很好的保留原本细胞对癌细胞的识别能力。
实施例6体外细胞毒性
在96孔板中接种EMT6细胞悬液100ul(细胞计数5000),将培养板放在培养箱中,在37℃5%CO2条件下预培养6h。在EMT6细胞贴壁后,加入5倍细胞数量的Cryo-MC@AuNRs@SiO2-DOX,在37℃5%CO2条件下孵育6h,用2ml PBS轻轻冲洗5遍。使用激光器(北京宏蓝光电)在808nm 近红外光光照5min(5W),在37℃5%CO2条件下培养16h。向每孔加入10ul的CCK-8溶液(Cell Counting Kit-8,日本同仁),在37℃5%CO2条件下孵育3h。通过酶标仪,在450nm处测定吸光度。具体操作如下:
1、细胞凋亡测定
诱导细胞凋亡。在6孔板中接种EMT6细胞悬液2ml(细胞计数 1*106),将培养板放在培养箱中,在37℃5%CO2条件下预培养6h。在 EMT6细胞贴壁后,加入5倍细胞数量的Cryo-MC@AuNRs@SiO2-DOX,在 37℃5%CO2条件下孵育6h,用2ml PBS轻轻冲洗5遍。使用激光器(北京宏蓝光电)在808nm近红外光光照5min(5W),在37℃5%CO2条件下培养16h。
2、细胞焦亡测定
在96孔板中接种EMT6细胞悬液100ul(细胞计数5000),将培养板放在培养箱中,在37℃5%CO2条件下预培养6h。在EMT6细胞贴壁后,加入5倍细胞数量的Cryo-MC@AuNRs@SiO2-DOX,在37℃5%CO2条件下孵育6h,用2ml PBS轻轻冲洗5遍。使用激光器(北京宏蓝光电)在808nm 近红外光光照5min(5W),在37℃5%CO2条件下培养16h。向每孔加入 100ul的Working Solution(Cytotoxicity LDH Assay Kit-WST,日本同仁),采用包裹铝箔等方法避光,在室温反应30min。在每孔中加入50ul Stop Solution(Cytotoxicity LDH AssayKit-WST,日本同仁)后,立刻用酶标仪测定490nm的吸光度。
细胞活性(CCK-8)和细胞膜破裂死亡(LDH)的测定。未处理的 EMT6细胞和EMT6+Cryo-MC@AuNRs@SiO2-DOX作为对照(n=3)。从图6中可以看出,Cryo-MC@AuNRs@SiO2-DOX本身对细胞并没有什么毒性,只有在808nm近红外光刺激的情况下才可造成细胞大死亡,并且其可导致EMT6细胞实现膜破裂的死亡。这说明Cryo-MC@AuNRs@SiO2-DOX具有很好的癌细胞杀伤效果,并且是可控的。
3、免疫印迹试验分析杀伤机理
细胞培养。在6孔板中接种EMT6细胞悬液2ml(细胞计数1*106),将培养板放在培养箱中,在37℃5%CO2条件下预培养6h。在EMT6细胞贴壁后,加入5倍细胞数量的Cryo-MC@AuNRs@SiO2-DOX,在37℃5%CO2 条件下孵育6h,用2mlPBS轻轻冲洗5遍。使用激光器(北京宏蓝光电) 在808nm近红外光光照5min(5W),在37℃5%CO2条件下培养16h。
细胞蛋白提取。用适量的PBS清洗一次,收集液体,1000rpm离心5min,弃上清,加入1mLPBS清洗细胞一次,1000rpm离心 5min,收集沉淀的细胞。用适量含有蛋白酶抑制剂cocktail的细胞裂解液将细胞裂解,加入合适体积的5XSDS上样缓冲液,100℃加热 10min。
采用western blot方法检测GSDME和Caspase-3的切割。取合适体积的样品加入SDS-PAGE胶进样孔,蛋白胶的浓度为4%-2 0%梯度胶(雅酶),跑胶电泳电压150V30min,结束后,组成“三明治”结构转膜至PVDF膜,转膜电流为400mA 30min,结束后室温封闭30min(雅酶,无蛋白快读封闭液)。将要检测的蛋白一抗, GSDME,caspase-3,CD47,SIRPα/SHPS1,Integrinα4,Integrin β1,CD24,Siglec-G和β-actin用一抗稀释液(碧云天)进行稀释 1:1000,室温孵育90min。TBST缓冲液漂洗5次,每次5min。将一抗对应的二抗用二抗稀释液(碧云天)进行稀释,室温孵育60min。TBST缓冲液漂洗5次,每次5min。取显影液1:1(Thermo Scientific)混合均匀,每张膜0.5mL。放入自动显影曝光机(Cytiva)进行显影。
GSDME的切割和caspase-3的活化检测。分别用Cryo- MC@AuNRs@SiO2-DOX+NIR808nm和化疗药物DOX处理细胞12h后,将细胞裂解,通过Western blot检测。从图7中可看出Cryo- MC@AuNRs@SiO2-DOX对EMT6细胞的可控杀伤是其释放的DOX激活了 EMT6中的Caspase-3从而切割GSDME而导致的细胞焦亡。
实施例7体内靶向能力
制备Cryo-MC@AuNRs@SiO2-DOX@DiI。先用膜染料DiI(1mM)与巨噬细胞在37℃5%CO2条件下共同孵育90min,用2ml PBS轻轻冲洗5次。再将制备好的AuNRs@SiO2-DOX加入成熟的原代巨噬细胞中共培养12h,制备巨噬细胞膜包覆的AuNRs@SiO2-DOX(Cryo-MC@AuNRs@SiO2- DOX@DiI)。
构建肿瘤模型。在7周龄BALB/c雌性小鼠的右肩上,皮下接种 1*106个EMT6细胞。
体内靶向。待肿瘤体积到150mm3后,尾静脉注射100ul体积的2*106个Cryo-MC@AuNRs@SiO2-DOX@DiI,分别在6h,12h,24h,48h,72h, 96h后,剖开小鼠,取出心脏、肝脏、脾脏、肺脏、肾脏、和肿瘤组织,用小动物成像仪,检测DiI的荧光强度。
尾静脉注射Cryo-MC@AuNRs@SiO2-DOX@DiI后,分别在6h,12h, 24h,48h,72h和96h后,取出小鼠的心、肝、脾、肺、肾和肿瘤检测DiI的荧光强度(n=3)。图8的平均荧光强度中,从左到右的柱状条依次代表红色(肿瘤),绿色(肝),橘色(肺),蓝色(肾),紫色 (心),黑色(脾)。从图8中可看出Cryo-MC@AuNRs@SiO2-DOX其在 96h后在肿瘤部位仍然有大量的留存且其在其他器官中的沉积非常少,说明其具有很好的体内循环性以及肿瘤特异靶向性。
实施例8体内抗肿瘤效力测定
构建肿瘤模型。在7周龄BALB/c雌性小鼠的右肩上,皮下接种 1*106个EMT6细胞。
分组:①Cryo-MC@AuNRs@SiO2-DOX+NIR_808nm组(n=6),②Cryo- MC@AuNRs@SiO2+NIR_808nm组(n=6),③DOX肿瘤组织原位注射组 (n=6),④DOX尾静脉注射组(n=6),⑤PBS组(n=6)。
治疗。如上所述,当肿瘤体积达到50mm3后,开始治疗实验:A. 对①②两组,通过尾静脉分别注射100μLCryo-MC@AuNRs@SiO2-DOX 和Cryo-MC@AuNRs@SiO2的PBS溶液,细胞量为1*107;对③组,肿瘤组织原位注射25μL DOX药物的PBS溶液,注射量为5mg/kg;对④组,尾静脉注射100μL DOX药物的PBS溶液,注射量为5mg/kg;对⑤组,尾静脉注射100μL的PBS溶液。B.24小时后,对①②两组使用激光器(北京宏蓝光电)在808nm近红外光光照肿瘤位置15min(0.3W) C.再过24小时后,重复B中操作。然后再过24小时后,开始第二个治疗周期。D.在治疗开始后的第3天开始采集肿瘤生长信息和小动物体重变化,采用游标卡尺对肿瘤大小进行测量,通过下述公式计算肿瘤体积V=0.5*a*b*b(a长,b宽),当肿瘤体积达到1000mm3时,处死小鼠。E.根据上述肿瘤生长数据,做出生长曲线。
统计。呈现的所有结果均为平均值的标准偏差。采用Student's t检验进行统计分析。当p值<0.05时,实验组与对照组之间的差异被认为具有统计学意义。
在对不同分组的小鼠治疗后,每隔2天测量小鼠的肿瘤体积和体重(n=6)。从图9中可看出,通过对接种了EMT6的小鼠注射Cryo- MC@AuNRs@SiO2-DOX并用808nm近红外光进行治疗可有效的抑制肿瘤的增长(与其他组具有统计学差异),且通过对小鼠体重的监测可知其对小鼠机体并没有什么损伤(与其他组无统计学差异)。
参考文献
Zhang,Z.,Wang,L.,Wang,J.,Jiang,X.,Li,X.,Hu,Z.,...Chen,C.(2012).Mesoporous Silica-Coated Gold Nanorods as a Light-Mediated MultifunctionalTheranostic Platform for Cancer Treatment.Advanced Materials,24(11),1418-1423.doi:10.1002/adma.201104714 。
Claims (10)
1.一种制备药物递送系统的方法,其特征在于,包括如下步骤:
(1)获得细胞膜包覆的负载有药物的载体;
(2)将包覆后的载体进行低温冷冻。
2.如权利要求1或2所述的方法,所述包覆为细胞通过吞噬作用使载体进入细胞内而被细胞膜包裹。
3.一种由权利要求1-3之一所述方法制备得到的药物递送系统。
4.一种药物递送系统,包括内核和外壳,所述内核为负载有药物的载体,所述外壳为细胞膜,所述外壳包覆于内核的外表面,且该递送系统经过低温冷冻;可选地,低温冷冻之后经过洗涤处理。
5.如权利要求5所述的系统,所述洗涤为加入缓冲溶液例如PBS进行离心洗涤。
6.权利要求5-7之一所述的系统在制备治疗疾病药物中的用途。
7.如前述任一权利要求中所述的细胞膜,其特征在于,所述细胞膜为有吞噬功能的自体或异体的天然细胞膜,如单核细胞,巨噬细胞或中性粒细胞的细胞膜或工程化的吞噬细胞膜。
8.如前述任一权利要求中所述的细胞膜,其特征在于,细胞膜上具有细胞识别因子或包含至少一种异源的细胞外活性蛋白。
9.如前述任一权利要求中所述的负载有药物的载体,其特征在于,所述载体为纳米载体,和/或所述载体为可控地释放负载的药物的载体。
10.如前述任一权利要求中所述的低温冷冻,其特征在于,所述低温冷冻在不改变载体的基本细胞膜结构的情况下,使得细胞膜表面出现小孔使炎性因子能够从细胞中被移除而药物仍被保留在细胞中。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210663668.9A CN115245500A (zh) | 2022-06-10 | 2022-06-10 | 一种低温速冻法制备的吞噬细胞膜包覆的药物递送系统 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210663668.9A CN115245500A (zh) | 2022-06-10 | 2022-06-10 | 一种低温速冻法制备的吞噬细胞膜包覆的药物递送系统 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115245500A true CN115245500A (zh) | 2022-10-28 |
Family
ID=83697794
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210663668.9A Pending CN115245500A (zh) | 2022-06-10 | 2022-06-10 | 一种低温速冻法制备的吞噬细胞膜包覆的药物递送系统 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115245500A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117899110A (zh) * | 2024-01-24 | 2024-04-19 | 吉林大学中日联谊医院 | 一种具有治疗关节炎作用的组合物及其制备方法和应用 |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108853052A (zh) * | 2018-08-07 | 2018-11-23 | 广东省第二人民医院 | 一种用于靶向控释药物的相变介孔硅仿生制剂及其制备方法和应用 |
CN110812497A (zh) * | 2019-11-05 | 2020-02-21 | 中国科学院苏州生物医学工程技术研究所 | 用于CTCs特异性捕获的仿生型Janus磁-介孔二氧化硅纳米粒子及制备方法和应用 |
CN112245658A (zh) * | 2020-10-09 | 2021-01-22 | 北京大学 | 一种可注射晶胶微球细胞扩增载体及其制备方法 |
CN112807288A (zh) * | 2021-01-12 | 2021-05-18 | 中南大学湘雅医院 | 一种特异靶向感染部位的中性粒细胞膜仿生纳米材料的制备方法 |
CN113289030A (zh) * | 2021-03-04 | 2021-08-24 | 石河子大学 | 一种光热协同化疗的靶向长循环纳米药物载体的制备方法 |
CN113855802A (zh) * | 2021-10-29 | 2021-12-31 | 山东大学 | 一种仿生纳米诱饵及其制备方法和在脓毒症治疗中应用 |
CN114259477A (zh) * | 2022-01-28 | 2022-04-01 | 中国人民解放军海军军医大学第一附属医院 | 一种促渗透、缓解肿瘤缺氧并能靶向肿瘤细胞的纳米递送体系及其制备方法和应用 |
CN114544930A (zh) * | 2022-02-25 | 2022-05-27 | 中国人民解放军空军军医大学 | 一种基于电穿孔的细胞膜包覆磁珠垂钓中药活性成分的方法及其应用 |
-
2022
- 2022-06-10 CN CN202210663668.9A patent/CN115245500A/zh active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108853052A (zh) * | 2018-08-07 | 2018-11-23 | 广东省第二人民医院 | 一种用于靶向控释药物的相变介孔硅仿生制剂及其制备方法和应用 |
CN110812497A (zh) * | 2019-11-05 | 2020-02-21 | 中国科学院苏州生物医学工程技术研究所 | 用于CTCs特异性捕获的仿生型Janus磁-介孔二氧化硅纳米粒子及制备方法和应用 |
CN112245658A (zh) * | 2020-10-09 | 2021-01-22 | 北京大学 | 一种可注射晶胶微球细胞扩增载体及其制备方法 |
CN112807288A (zh) * | 2021-01-12 | 2021-05-18 | 中南大学湘雅医院 | 一种特异靶向感染部位的中性粒细胞膜仿生纳米材料的制备方法 |
CN113289030A (zh) * | 2021-03-04 | 2021-08-24 | 石河子大学 | 一种光热协同化疗的靶向长循环纳米药物载体的制备方法 |
CN113855802A (zh) * | 2021-10-29 | 2021-12-31 | 山东大学 | 一种仿生纳米诱饵及其制备方法和在脓毒症治疗中应用 |
CN114259477A (zh) * | 2022-01-28 | 2022-04-01 | 中国人民解放军海军军医大学第一附属医院 | 一种促渗透、缓解肿瘤缺氧并能靶向肿瘤细胞的纳米递送体系及其制备方法和应用 |
CN114544930A (zh) * | 2022-02-25 | 2022-05-27 | 中国人民解放军空军军医大学 | 一种基于电穿孔的细胞膜包覆磁珠垂钓中药活性成分的方法及其应用 |
Non-Patent Citations (5)
Title |
---|
AN DU NGUYEN ET AL.: "Macrophage-Mediated Delivery of Multifunctional Nanotherapeutics for Synergistic Chemo-Photothermal Therapy of Solid Tumors", APPLIED MATERIALS &INTERFACES, vol. 12, no. 9, pages 10130 - 10141 * |
MINGJUN XUAN ET AL.: "Macrophage Cell Membrane Camouflaged Au Nanoshells for in Vivo Prolonged Circulation Life and Enhanced Cancer Photothermal Therapy", vol. 8, no. 15, pages 9610 * |
VAN DU NGUYEN ET AL.: "Macrophage-Mediated Delivery of Multifunctional Nanotherapeutics for Synergistic Chemo−Photothermal Therapy of Solid Tumors", vol. 12, no. 9, pages 10130 * |
ZHENJIANG ZHANG, ET AL.: "Mesoporous Silica-Coated Gold Nanorods as a Light-Mediated Multifunctional Theranostic Platform for Cancer Treatment", vol. 24, no. 11, pages 1418 - 1423 * |
李树玲: "头颈部肿瘤诊断、治疗及预后", vol. 1, 天津科学技术出版, pages: 46 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117899110A (zh) * | 2024-01-24 | 2024-04-19 | 吉林大学中日联谊医院 | 一种具有治疗关节炎作用的组合物及其制备方法和应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Xu et al. | Cell membrane-camouflaged nanoparticles as drug carriers for cancer therapy | |
Le et al. | Potato virus X, a filamentous plant viral nanoparticle for doxorubicin delivery in cancer therapy | |
CN108136023B (zh) | 血小板膜包覆的药物递送系统 | |
Huang et al. | Gold nanoparticles induce tumor vessel normalization and impair metastasis by inhibiting endothelial Smad2/3 signaling | |
Li et al. | Doxorubicin-loaded polysaccharide nanoparticles suppress the growth of murine colorectal carcinoma and inhibit the metastasis of murine mammary carcinoma in rodent models | |
JP7497087B2 (ja) | 治療剤送達のための血小板組成物及び方法 | |
Wang et al. | Toxicity and therapy of cisplatin-loaded EGF modified mPEG-PLGA-PLL nanoparticles for SKOV3 cancer in mice | |
WO2018041261A1 (zh) | 一种肿瘤治疗药物 | |
Das et al. | Nanomaterials in anticancer applications and their mechanism of action-A review | |
Bourbour et al. | Evaluation of anti-cancer and anti-metastatic effects of folate-PEGylated niosomes for co-delivery of letrozole and ascorbic acid on breast cancer cells | |
Franiak-Pietryga et al. | Dendrimers as drug nanocarriers: the future of gene therapy and targeted therapies in cancer | |
JP7470988B2 (ja) | 生物応答性ヒドロゲルマトリックス及び使用方法 | |
Zeng et al. | Cell membrane-coated nanomaterials for cancer therapy | |
Sawant et al. | Cancer research and therapy: Where are we today | |
Zhou et al. | Bio-mimicking nanoparticles for targeted therapy of malignant melanoma | |
Zhang et al. | Co-delivery of doxorubicin and pheophorbide A by pluronic F127 micelles for chemo-photodynamic combination therapy of melanoma | |
Yang et al. | iRGD-mediated and enzyme-induced precise targeting and retention of gold nanoparticles for the enhanced imaging and treatment of breast cancer | |
CN115245500A (zh) | 一种低温速冻法制备的吞噬细胞膜包覆的药物递送系统 | |
Li et al. | Nanodiamond-based multifunctional platform for oral chemo-photothermal combinational therapy of orthotopic colon cancer | |
Yu et al. | Combined Chemo–Immuno–Photothermal Therapy for Effective Cancer Treatment via an All-in-One and One-for-All Nanoplatform | |
Luo et al. | Non-covalent assembly of albumin nanoparticles by hydroxyl radical: A possible mechanism of the nab technology and a one-step green method to produce protein nanocarriers | |
Peng et al. | Recent progress in nanocarrier-based drug delivery systems for antitumour metastasis | |
Fu et al. | Therapeutic effects of paclitaxel loaded polyethylene glycol-polylactic acid-glycolic acid copolymer nanoparticles on pancreatic cancer in rats | |
Wang et al. | Synergistic reinforcement of immunogenic cell death and transformation of tumor-associated macrophages via an M1-type macrophage membrane-camouflaged ferrous-supply-regeneration nanoplatform | |
Mohammad Jafari et al. | Does pharmacodynamics of drugs change after presenting them as nanoparticles like their pharmacokinetics? |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |