CN109890420B - 用于递送治疗剂的血小板组合物和方法 - Google Patents
用于递送治疗剂的血小板组合物和方法 Download PDFInfo
- Publication number
- CN109890420B CN109890420B CN201780066511.5A CN201780066511A CN109890420B CN 109890420 B CN109890420 B CN 109890420B CN 201780066511 A CN201780066511 A CN 201780066511A CN 109890420 B CN109890420 B CN 109890420B
- Authority
- CN
- China
- Prior art keywords
- apdl1
- platelet
- antibody
- cancer
- cells
- 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.)
- Active
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 107
- 239000003814 drug Substances 0.000 title claims abstract description 99
- 229940124597 therapeutic agent Drugs 0.000 title claims abstract description 80
- 238000000034 method Methods 0.000 title abstract description 67
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 166
- 201000011510 cancer Diseases 0.000 claims abstract description 57
- 239000002955 immunomodulating agent Substances 0.000 claims abstract description 44
- 206010027476 Metastases Diseases 0.000 claims abstract description 22
- 230000009401 metastasis Effects 0.000 claims abstract description 20
- 125000005647 linker group Chemical group 0.000 claims description 62
- 239000000126 substance Substances 0.000 claims description 60
- 230000004913 activation Effects 0.000 claims description 19
- 201000001441 melanoma Diseases 0.000 claims description 10
- 239000011859 microparticle Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 210000001772 blood platelet Anatomy 0.000 description 223
- 241000699670 Mus sp. Species 0.000 description 84
- 229920000642 polymer Polymers 0.000 description 66
- 210000004027 cell Anatomy 0.000 description 52
- -1 isomers Substances 0.000 description 48
- 239000002904 solvent Substances 0.000 description 35
- 238000011282 treatment Methods 0.000 description 35
- 229920001223 polyethylene glycol Polymers 0.000 description 26
- 239000000243 solution Substances 0.000 description 25
- 235000002639 sodium chloride Nutrition 0.000 description 23
- 238000002560 therapeutic procedure Methods 0.000 description 22
- 239000002202 Polyethylene glycol Substances 0.000 description 21
- 208000027418 Wounds and injury Diseases 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 206010052428 Wound Diseases 0.000 description 19
- 238000001727 in vivo Methods 0.000 description 19
- 239000002105 nanoparticle Substances 0.000 description 19
- 150000003839 salts Chemical class 0.000 description 19
- 238000001356 surgical procedure Methods 0.000 description 19
- 208000007660 Residual Neoplasm Diseases 0.000 description 18
- 210000001744 T-lymphocyte Anatomy 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 18
- 239000002245 particle Substances 0.000 description 18
- 239000000546 pharmaceutical excipient Substances 0.000 description 18
- 239000012071 phase Substances 0.000 description 18
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- 101100268548 Caenorhabditis elegans apl-1 gene Proteins 0.000 description 16
- 239000013543 active substance Substances 0.000 description 16
- 239000003755 preservative agent Substances 0.000 description 16
- 239000000412 dendrimer Substances 0.000 description 15
- 229920000736 dendritic polymer Polymers 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 230000010118 platelet activation Effects 0.000 description 15
- 229920002125 Sokalan® Polymers 0.000 description 14
- 238000005538 encapsulation Methods 0.000 description 14
- 239000004005 microsphere Substances 0.000 description 14
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 13
- 102000004127 Cytokines Human genes 0.000 description 13
- 108090000695 Cytokines Proteins 0.000 description 13
- 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 13
- 229920002472 Starch Polymers 0.000 description 13
- 230000008901 benefit Effects 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 239000000839 emulsion Substances 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 13
- 235000019698 starch Nutrition 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 238000005415 bioluminescence Methods 0.000 description 12
- 230000029918 bioluminescence Effects 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 210000004072 lung Anatomy 0.000 description 12
- 230000001225 therapeutic effect Effects 0.000 description 12
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 235000010443 alginic acid Nutrition 0.000 description 11
- 229920000615 alginic acid Polymers 0.000 description 11
- 239000008107 starch Substances 0.000 description 11
- 229940032147 starch Drugs 0.000 description 11
- 230000004083 survival effect Effects 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 10
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 10
- 241000701806 Human papillomavirus Species 0.000 description 10
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 10
- 229960000711 alprostadil Drugs 0.000 description 10
- 239000001913 cellulose Substances 0.000 description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 238000010166 immunofluorescence Methods 0.000 description 10
- 230000002980 postoperative effect Effects 0.000 description 10
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 10
- 239000000454 talc Substances 0.000 description 10
- 235000012222 talc Nutrition 0.000 description 10
- 229910052623 talc Inorganic materials 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 9
- 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 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000002965 ELISA Methods 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
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 239000001768 carboxy methyl cellulose Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 230000021615 conjugation Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000003995 emulsifying agent Substances 0.000 description 9
- 238000003384 imaging method Methods 0.000 description 9
- 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 9
- 230000008569 process Effects 0.000 description 9
- 208000019553 vascular disease Diseases 0.000 description 9
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 8
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 8
- 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 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 235000010980 cellulose Nutrition 0.000 description 8
- 229920002678 cellulose Polymers 0.000 description 8
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 239000000194 fatty acid Substances 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 230000000306 recurrent effect Effects 0.000 description 8
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 7
- 108010010803 Gelatin Proteins 0.000 description 7
- 208000032843 Hemorrhage Diseases 0.000 description 7
- 108010000817 Leuprolide Proteins 0.000 description 7
- 229930006000 Sucrose Natural products 0.000 description 7
- 239000000783 alginic acid Substances 0.000 description 7
- 229960001126 alginic acid Drugs 0.000 description 7
- 150000004781 alginic acids Chemical class 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 230000000740 bleeding effect Effects 0.000 description 7
- 210000000170 cell membrane Anatomy 0.000 description 7
- 238000005119 centrifugation Methods 0.000 description 7
- 229960000684 cytarabine Drugs 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000008273 gelatin Substances 0.000 description 7
- 229940014259 gelatin Drugs 0.000 description 7
- 229920000159 gelatin Polymers 0.000 description 7
- 235000019322 gelatine Nutrition 0.000 description 7
- 235000011852 gelatine desserts Nutrition 0.000 description 7
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 7
- 210000002865 immune cell Anatomy 0.000 description 7
- 229960004338 leuprorelin Drugs 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 229960000485 methotrexate Drugs 0.000 description 7
- 238000002271 resection Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 239000005720 sucrose Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 6
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 6
- 229930012538 Paclitaxel Natural products 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 6
- 238000002619 cancer immunotherapy Methods 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 150000004677 hydrates Chemical class 0.000 description 6
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 6
- 238000011065 in-situ storage Methods 0.000 description 6
- 238000010253 intravenous injection Methods 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229920000609 methyl cellulose Polymers 0.000 description 6
- 235000010981 methylcellulose Nutrition 0.000 description 6
- 239000001923 methylcellulose Substances 0.000 description 6
- 239000000178 monomer Substances 0.000 description 6
- 229960003301 nivolumab Drugs 0.000 description 6
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 229960001592 paclitaxel Drugs 0.000 description 6
- 229920002451 polyvinyl alcohol Polymers 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 235000015424 sodium Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000008247 solid mixture Substances 0.000 description 6
- 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 6
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 6
- 239000001993 wax Substances 0.000 description 6
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 5
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 5
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 5
- 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 5
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 5
- 241000416162 Astragalus gummifer Species 0.000 description 5
- 241000283707 Capra Species 0.000 description 5
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 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 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 5
- 239000004372 Polyvinyl alcohol Substances 0.000 description 5
- 206010038111 Recurrent cancer Diseases 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 108090000190 Thrombin Proteins 0.000 description 5
- 229920001615 Tragacanth Polymers 0.000 description 5
- 235000010419 agar Nutrition 0.000 description 5
- 229960000548 alemtuzumab Drugs 0.000 description 5
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 5
- 210000000612 antigen-presenting cell Anatomy 0.000 description 5
- 235000012216 bentonite Nutrition 0.000 description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 5
- 229940031416 bivalent vaccine Drugs 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 5
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 5
- 229960005243 carmustine Drugs 0.000 description 5
- 235000010418 carrageenan Nutrition 0.000 description 5
- 229920001525 carrageenan Polymers 0.000 description 5
- 239000000679 carrageenan Substances 0.000 description 5
- 229940113118 carrageenan Drugs 0.000 description 5
- 239000004359 castor oil Substances 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 229940107161 cholesterol Drugs 0.000 description 5
- 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 5
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 5
- 230000015271 coagulation Effects 0.000 description 5
- 238000005345 coagulation Methods 0.000 description 5
- 229960003901 dacarbazine Drugs 0.000 description 5
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 5
- 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 5
- 239000000945 filler Substances 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- 238000002073 fluorescence micrograph Methods 0.000 description 5
- 229920000669 heparin Polymers 0.000 description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 5
- 229960005386 ipilimumab Drugs 0.000 description 5
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 206010061289 metastatic neoplasm Diseases 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229960003359 palonosetron hydrochloride Drugs 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000008389 polyethoxylated castor oil Substances 0.000 description 5
- 229940068984 polyvinyl alcohol Drugs 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 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 5
- 208000024891 symptom Diseases 0.000 description 5
- 229960004072 thrombin Drugs 0.000 description 5
- 238000004627 transmission electron microscopy 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
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 4
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 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 4
- 108010088751 Albumins Proteins 0.000 description 4
- 102000009027 Albumins Human genes 0.000 description 4
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 4
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 4
- 206010005003 Bladder cancer Diseases 0.000 description 4
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- 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 4
- 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 4
- 101000622137 Homo sapiens P-selectin Proteins 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 238000012695 Interfacial polymerization Methods 0.000 description 4
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 4
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 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
- 102100023472 P-selectin Human genes 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 4
- 229920002732 Polyanhydride Polymers 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 208000002847 Surgical Wound Diseases 0.000 description 4
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 4
- 238000010162 Tukey test Methods 0.000 description 4
- 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 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 229940023476 agar Drugs 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 4
- 229960004005 amlodipine besylate Drugs 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 229960005370 atorvastatin Drugs 0.000 description 4
- 239000000440 bentonite Substances 0.000 description 4
- 229910000278 bentonite Inorganic materials 0.000 description 4
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 4
- 229960000686 benzalkonium chloride Drugs 0.000 description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 description 4
- 229960003563 calcium carbonate Drugs 0.000 description 4
- 235000010216 calcium carbonate Nutrition 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 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 4
- 108010021331 carfilzomib Proteins 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
- 229960002798 cetrimide Drugs 0.000 description 4
- 229960005395 cetuximab Drugs 0.000 description 4
- 229960000541 cetyl alcohol Drugs 0.000 description 4
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 4
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 4
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 229960000928 clofarabine Drugs 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 229960004397 cyclophosphamide Drugs 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 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 4
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 4
- 229960005304 fludarabine phosphate Drugs 0.000 description 4
- 229960002949 fluorouracil Drugs 0.000 description 4
- 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 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
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- IFSDAJWBUCMOAH-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 IFSDAJWBUCMOAH-HNNXBMFYSA-N 0.000 description 4
- 229960001101 ifosfamide Drugs 0.000 description 4
- 230000005746 immune checkpoint blockade Effects 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 230000008595 infiltration Effects 0.000 description 4
- 238000001764 infiltration Methods 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 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 4
- 229960003881 letrozole Drugs 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 229960004857 mitomycin Drugs 0.000 description 4
- 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 4
- 229940055577 oleyl alcohol Drugs 0.000 description 4
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 238000001543 one-way ANOVA Methods 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
- 238000005191 phase separation Methods 0.000 description 4
- 210000004623 platelet-rich plasma Anatomy 0.000 description 4
- 229920001993 poloxamer 188 Polymers 0.000 description 4
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 4
- 239000004584 polyacrylic acid Substances 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- 230000000770 proinflammatory effect Effects 0.000 description 4
- 230000002685 pulmonary effect Effects 0.000 description 4
- 229960002119 raloxifene hydrochloride Drugs 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 229960004641 rituximab Drugs 0.000 description 4
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- 229920002545 silicone oil Polymers 0.000 description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 235000011078 sorbitan tristearate Nutrition 0.000 description 4
- 206010041823 squamous cell carcinoma Diseases 0.000 description 4
- 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 4
- 235000000346 sugar Nutrition 0.000 description 4
- 235000010487 tragacanth Nutrition 0.000 description 4
- 239000000196 tragacanth Substances 0.000 description 4
- 229940116362 tragacanth Drugs 0.000 description 4
- 229960000575 trastuzumab Drugs 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 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 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
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 4
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 3
- 102400000432 CD40 ligand, soluble form Human genes 0.000 description 3
- 101800000267 CD40 ligand, soluble form Proteins 0.000 description 3
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 3
- 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 3
- 102000019034 Chemokines Human genes 0.000 description 3
- 108010012236 Chemokines Proteins 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- FPVVYTCTZKCSOJ-UHFFFAOYSA-N Ethylene glycol distearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOC(=O)CCCCCCCCCCCCCCCCC FPVVYTCTZKCSOJ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 108010069236 Goserelin Proteins 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 3
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
- 240000007472 Leucaena leucocephala Species 0.000 description 3
- 108010007859 Lisinopril Proteins 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 206010027458 Metastases to lung Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- 229920001214 Polysorbate 60 Polymers 0.000 description 3
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 3
- 238000003917 TEM image Methods 0.000 description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 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
- 229960004103 abiraterone acetate Drugs 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 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 3
- 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 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000003862 amino acid derivatives Chemical class 0.000 description 3
- 229940034982 antineoplastic agent Drugs 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 3
- 229960001215 bendamustine hydrochloride Drugs 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 229960000997 bicalutamide Drugs 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000000903 blocking 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
- 229960002092 busulfan Drugs 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- 229940095259 butylated hydroxytoluene Drugs 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
- 239000001506 calcium phosphate Substances 0.000 description 3
- 229960004117 capecitabine Drugs 0.000 description 3
- 229960002438 carfilzomib Drugs 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 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 3
- 239000002738 chelating agent Substances 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 229960003958 clopidogrel bisulfate Drugs 0.000 description 3
- 235000012343 cottonseed oil Nutrition 0.000 description 3
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 3
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 3
- 229960002448 dasatinib Drugs 0.000 description 3
- 229960000605 dexrazoxane Drugs 0.000 description 3
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 229960000878 docusate sodium Drugs 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000006196 drop Substances 0.000 description 3
- 229950009791 durvalumab Drugs 0.000 description 3
- 229960000439 eribulin mesylate Drugs 0.000 description 3
- 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 3
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 3
- 229940093471 ethyl oleate Drugs 0.000 description 3
- 229960005420 etoposide Drugs 0.000 description 3
- 238000000799 fluorescence microscopy Methods 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 229960000868 fluvastatin sodium Drugs 0.000 description 3
- 229960002584 gefitinib Drugs 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 229960005144 gemcitabine hydrochloride Drugs 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000001087 glyceryl triacetate Substances 0.000 description 3
- 235000013773 glyceryl triacetate Nutrition 0.000 description 3
- 229960003690 goserelin acetate Drugs 0.000 description 3
- 230000023597 hemostasis Effects 0.000 description 3
- 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 3
- 239000012943 hotmelt Substances 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 3
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 3
- 229960001176 idarubicin hydrochloride Drugs 0.000 description 3
- 229960002411 imatinib Drugs 0.000 description 3
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 3
- 229960002014 ixabepilone Drugs 0.000 description 3
- 108010021336 lanreotide Proteins 0.000 description 3
- 229960001739 lanreotide acetate Drugs 0.000 description 3
- 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 3
- 229960001429 lenvatinib mesylate Drugs 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 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 3
- 239000012528 membrane Substances 0.000 description 3
- 229960001428 mercaptopurine Drugs 0.000 description 3
- 229960004635 mesna Drugs 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 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 3
- 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 3
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 3
- 239000002077 nanosphere Substances 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 229960000572 olaparib Drugs 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 description 3
- 229960001756 oxaliplatin Drugs 0.000 description 3
- 229960001972 panitumumab Drugs 0.000 description 3
- 229960005184 panobinostat Drugs 0.000 description 3
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- MQHIQUBXFFAOMK-UHFFFAOYSA-N pazopanib hydrochloride Chemical compound Cl.C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 MQHIQUBXFFAOMK-UHFFFAOYSA-N 0.000 description 3
- 229960002621 pembrolizumab Drugs 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 229920000193 polymethacrylate Polymers 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 150000004804 polysaccharides Chemical class 0.000 description 3
- VWBQYTRBTXKKOG-IYNICTALSA-M pravastatin sodium Chemical compound [Na+].C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC([O-])=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 VWBQYTRBTXKKOG-IYNICTALSA-M 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 229960004063 propylene glycol Drugs 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 229960002633 ramucirumab Drugs 0.000 description 3
- 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 3
- 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 3
- 108010091666 romidepsin Proteins 0.000 description 3
- 235000011803 sesame oil Nutrition 0.000 description 3
- 239000008159 sesame oil Substances 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 3
- 238000000935 solvent evaporation Methods 0.000 description 3
- 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 3
- 229960000487 sorafenib tosylate Drugs 0.000 description 3
- 235000011076 sorbitan monostearate Nutrition 0.000 description 3
- 239000001587 sorbitan monostearate Substances 0.000 description 3
- 229940035048 sorbitan monostearate Drugs 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 229940012831 stearyl alcohol Drugs 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 229960002812 sunitinib malate Drugs 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 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 3
- 229960004964 temozolomide Drugs 0.000 description 3
- 229960003433 thalidomide Drugs 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
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 3
- 229960002622 triacetin Drugs 0.000 description 3
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- 229960003862 vemurafenib Drugs 0.000 description 3
- 229960004982 vinblastine sulfate Drugs 0.000 description 3
- 229960002166 vinorelbine tartrate Drugs 0.000 description 3
- 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 3
- 239000000080 wetting agent Substances 0.000 description 3
- 229920001285 xanthan gum Polymers 0.000 description 3
- 235000010493 xanthan gum Nutrition 0.000 description 3
- 239000000230 xanthan gum Substances 0.000 description 3
- 229940082509 xanthan gum Drugs 0.000 description 3
- 229960004276 zoledronic acid Drugs 0.000 description 3
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 description 2
- 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 2
- QIQSYARFOIKJJR-LUTWCBITSA-N (4z,7z,10z,13z,16z,19z)-docosa-4,7,10,13,16,19-hexaenoic acid;(4z,7z,10z,13z,16z)-docosa-4,7,10,13,16-pentaenoic acid;(7z,10z,13z,16z,19z)-docosa-7,10,13,16,19-pentaenoic acid;(6z,9z,12z,15z,18z)-henicosa-6,9,12,15,18-pentaenoic acid;(5z,8z,11z,14z,17z)-i Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O.CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O.CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O.CC\C=C/C\C=C/C\C=C/C\C=C/CCCCCCC(O)=O.CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O.CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCC(O)=O.CCCCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O.CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(O)=O.CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O QIQSYARFOIKJJR-LUTWCBITSA-N 0.000 description 2
- 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 2
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-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
- WGIMXKDCVCTHGW-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCCO WGIMXKDCVCTHGW-UHFFFAOYSA-N 0.000 description 2
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 2
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- PTKSEFOSCHHMPD-SNVBAGLBSA-N 2-amino-n-[(2s)-2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide Chemical compound COC1=CC=C(OC)C([C@H](O)CNC(=O)CN)=C1 PTKSEFOSCHHMPD-SNVBAGLBSA-N 0.000 description 2
- UBLAMKHIFZBBSS-UHFFFAOYSA-N 3-Methylbutyl pentanoate Chemical compound CCCCC(=O)OCCC(C)C UBLAMKHIFZBBSS-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 244000215068 Acacia senegal Species 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N Arsenious Acid Chemical compound O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 2
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 2
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 235000004936 Bromus mango Nutrition 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 108010029697 CD40 Ligand Proteins 0.000 description 2
- 102100032937 CD40 ligand Human genes 0.000 description 2
- 101100463133 Caenorhabditis elegans pdl-1 gene Proteins 0.000 description 2
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 2
- 108010076119 Caseins Proteins 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 2
- 241000206575 Chondrus crispus Species 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- 108010061435 Enalapril Proteins 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 229920000064 Ethyl eicosapentaenoic acid Polymers 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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 2
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 2
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 2
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 2
- 206010067917 Inflammatory myofibroblastic tumour Diseases 0.000 description 2
- 102100022338 Integrin alpha-M Human genes 0.000 description 2
- 102100022297 Integrin alpha-X Human genes 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.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 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- 206010024612 Lipoma Diseases 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 235000018330 Macadamia integrifolia Nutrition 0.000 description 2
- 235000003800 Macadamia tetraphylla Nutrition 0.000 description 2
- 240000000912 Macadamia tetraphylla Species 0.000 description 2
- 235000014826 Mangifera indica Nutrition 0.000 description 2
- 240000007228 Mangifera indica Species 0.000 description 2
- 240000003183 Manihot esculenta Species 0.000 description 2
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 2
- 208000000172 Medulloblastoma Diseases 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 206010027406 Mesothelioma Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 239000012271 PD-L1 inhibitor Substances 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 2
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 2
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 2
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 2
- 235000009184 Spondias indica Nutrition 0.000 description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- VXFJYXUZANRPDJ-WTNASJBWSA-N Trandopril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 VXFJYXUZANRPDJ-WTNASJBWSA-N 0.000 description 2
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 description 2
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 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 2
- 230000003213 activating effect Effects 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 230000002411 adverse 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
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000006023 anti-tumor response Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 0.000 description 2
- 230000005975 antitumor immune response Effects 0.000 description 2
- 238000013459 approach Methods 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
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960001770 atorvastatin calcium Drugs 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 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 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 229940115925 bidil Drugs 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 description 2
- 108010055460 bivalirudin Proteins 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- 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 2
- 229960001467 bortezomib Drugs 0.000 description 2
- 229960000455 brentuximab vedotin Drugs 0.000 description 2
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
- 229960001573 cabazitaxel Drugs 0.000 description 2
- 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 2
- 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 2
- 239000004227 calcium gluconate Substances 0.000 description 2
- 235000013927 calcium gluconate Nutrition 0.000 description 2
- 229960004494 calcium gluconate Drugs 0.000 description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 2
- 229960004349 candesartan cilexetil Drugs 0.000 description 2
- COWWROCHWNGJHQ-OPKBHZIBSA-J cangrelor tetrasodium Chemical compound [Na+].[Na+].[Na+].[Na+].C1=NC=2C(NCCSC)=NC(SCCC(F)(F)F)=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)C(Cl)(Cl)P([O-])([O-])=O)[C@@H](O)[C@H]1O COWWROCHWNGJHQ-OPKBHZIBSA-J 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 229920003090 carboxymethyl hydroxyethyl cellulose Polymers 0.000 description 2
- 208000002458 carcinoid tumor Diseases 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 238000005266 casting Methods 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 229960001602 ceritinib Drugs 0.000 description 2
- 229960005110 cerivastatin Drugs 0.000 description 2
- GPUADMRJQVPIAS-QCVDVZFFSA-M cerivastatin sodium Chemical compound [Na+].COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 GPUADMRJQVPIAS-QCVDVZFFSA-M 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 2
- 238000005354 coacervation Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 229960005188 collagen Drugs 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 239000002385 cottonseed oil Substances 0.000 description 2
- 229960005061 crizotinib Drugs 0.000 description 2
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 2
- 229960002465 dabrafenib Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 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 2
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 229960002272 degarelix Drugs 0.000 description 2
- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 108010017271 denileukin diftitox Proteins 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- SMVRDGHCVNAOIN-UHFFFAOYSA-L disodium;1-dodecoxydodecane;sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O.CCCCCCCCCCCCOCCCCCCCCCCCC SMVRDGHCVNAOIN-UHFFFAOYSA-L 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- ZQTNQVWKHCQYLQ-UHFFFAOYSA-N dronedarone Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(NS(C)(=O)=O)C=C12 ZQTNQVWKHCQYLQ-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 229960002224 eculizumab Drugs 0.000 description 2
- 210000003162 effector t lymphocyte Anatomy 0.000 description 2
- 235000013345 egg yolk Nutrition 0.000 description 2
- 210000002969 egg yolk Anatomy 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 229960004671 enzalutamide Drugs 0.000 description 2
- 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 2
- 229940088598 enzyme Drugs 0.000 description 2
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 2
- 229960005073 erlotinib hydrochloride Drugs 0.000 description 2
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=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 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 2
- 229960000752 etoposide phosphate Drugs 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 229960002297 fenofibrate Drugs 0.000 description 2
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 2
- MQOBSOSZFYZQOK-UHFFFAOYSA-N fenofibric acid Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C(=O)C1=CC=C(Cl)C=C1 MQOBSOSZFYZQOK-UHFFFAOYSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 229960002258 fulvestrant Drugs 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 2
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 2
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- 229920000591 gum Polymers 0.000 description 2
- 235000019314 gum ghatti Nutrition 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 230000002439 hemostatic effect Effects 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 2
- 238000003125 immunofluorescent labeling Methods 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 238000012744 immunostaining Methods 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000011221 initial treatment Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 description 2
- 229960004359 iodixanol Drugs 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 229960001320 lapatinib ditosylate Drugs 0.000 description 2
- 239000000171 lavandula angustifolia l. flower oil Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 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
- 229940095570 lescol Drugs 0.000 description 2
- 229960002394 lisinopril Drugs 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 208000037841 lung tumor Diseases 0.000 description 2
- JGCMEBMXRHSZKX-UHFFFAOYSA-N macitentan Chemical compound C=1C=C(Br)C=CC=1C=1C(NS(=O)(=O)NCCC)=NC=NC=1OCCOC1=NC=C(Br)C=N1 JGCMEBMXRHSZKX-UHFFFAOYSA-N 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 2
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 210000003593 megakaryocyte Anatomy 0.000 description 2
- 229960004296 megestrol acetate Drugs 0.000 description 2
- 208000037819 metastatic cancer Diseases 0.000 description 2
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229960001094 midodrine Drugs 0.000 description 2
- OSGPYAHSKOGBFY-KMHHXCEHSA-A mipomersen sodium Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].N1([C@H]2C[C@@H]([C@H](O2)COP([O-])(=O)S[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=O)S[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=O)S[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C(C)=C2)=O)COP([O-])(=O)S[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=O)S[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=O)S[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP([O-])(=O)S[C@H]2[C@H]([C@@H](O[C@@H]2COP([O-])(=O)S[C@H]2[C@H]([C@@H](O[C@@H]2COP([O-])(=O)S[C@H]2[C@H]([C@@H](O[C@@H]2COP([O-])(=O)S[C@H]2[C@H]([C@@H](O[C@@H]2COP([O-])(=O)S[C@H]2[C@H]([C@@H](O[C@@H]2CO)N2C3=C(C(NC(N)=N3)=O)N=C2)OCCOC)N2C(N=C(N)C(C)=C2)=O)OCCOC)N2C(N=C(N)C(C)=C2)=O)OCCOC)N2C(NC(=O)C(C)=C2)=O)OCCOC)N2C(N=C(N)C(C)=C2)=O)OCCOC)SP([O-])(=O)OC[C@H]2O[C@H](C[C@@H]2SP([O-])(=O)OC[C@H]2O[C@H](C[C@@H]2SP([O-])(=O)OC[C@H]2O[C@H](C[C@@H]2SP([O-])(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OCCOC)SP([O-])(=O)OC[C@H]2[C@@H]([C@@H]([C@H](O2)N2C(N=C(N)C(C)=C2)=O)OCCOC)SP([O-])(=O)OC[C@H]2[C@@H]([C@@H]([C@H](O2)N2C3=NC=NC(N)=C3N=C2)OCCOC)SP([O-])(=O)OC[C@H]2[C@@H]([C@@H]([C@H](O2)N2C(N=C(N)C(C)=C2)=O)OCCOC)SP([O-])(=O)OC[C@H]2[C@H](O)[C@@H]([C@H](O2)N2C(N=C(N)C(C)=C2)=O)OCCOC)N2C(N=C(N)C(C)=C2)=O)N2C(NC(=O)C(C)=C2)=O)N2C(NC(=O)C(C)=C2)=O)C=C(C)C(N)=NC1=O OSGPYAHSKOGBFY-KMHHXCEHSA-A 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 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 2
- 239000002088 nanocapsule Substances 0.000 description 2
- 201000011519 neuroendocrine tumor Diseases 0.000 description 2
- 208000029974 neurofibrosarcoma Diseases 0.000 description 2
- 229960001346 nilotinib Drugs 0.000 description 2
- 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 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000010466 nut oil Substances 0.000 description 2
- 229960003347 obinutuzumab Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229960002450 ofatumumab Drugs 0.000 description 2
- 229960002378 oftasceine Drugs 0.000 description 2
- 229960002969 oleic acid Drugs 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 229960000770 ondansetron hydrochloride Drugs 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 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 2
- 229960004390 palbociclib Drugs 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
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 201000002530 pancreatic endocrine carcinoma Diseases 0.000 description 2
- 229960005492 pazopanib hydrochloride Drugs 0.000 description 2
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 229960000292 pectin Drugs 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- RYCSJJXKEWBUTI-YDYAIEMNSA-N perindopril arginine Chemical class OC(=O)[C@@H](N)CCCNC(N)=N.C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 RYCSJJXKEWBUTI-YDYAIEMNSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229960003742 phenol Drugs 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 229940020573 plavix Drugs 0.000 description 2
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229940044519 poloxamer 188 Drugs 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920000056 polyoxyethylene ether Polymers 0.000 description 2
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- BWTNNZPNKQIADY-UHFFFAOYSA-N ponatinib hydrochloride Chemical compound Cl.C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 BWTNNZPNKQIADY-UHFFFAOYSA-N 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 2
- 229940043349 potassium metabisulfite Drugs 0.000 description 2
- 235000010263 potassium metabisulphite Nutrition 0.000 description 2
- 229940096992 potassium oleate Drugs 0.000 description 2
- MLICVSDCCDDWMD-KVVVOXFISA-M potassium;(z)-octadec-9-enoate Chemical compound [K+].CCCCCCCC\C=C/CCCCCCCC([O-])=O MLICVSDCCDDWMD-KVVVOXFISA-M 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 229920003124 powdered cellulose Polymers 0.000 description 2
- 235000019814 powdered cellulose Nutrition 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
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 2
- 229960004197 prasugrel Drugs 0.000 description 2
- 229940089484 pravachol Drugs 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 229960002965 pravastatin Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000007639 printing Methods 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 229940095574 propionic acid Drugs 0.000 description 2
- 229940093625 propylene glycol monostearate Drugs 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- RWRDJVNMSZYMDV-UHFFFAOYSA-L radium chloride Chemical compound [Cl-].[Cl-].[Ra+2] RWRDJVNMSZYMDV-UHFFFAOYSA-L 0.000 description 2
- 229960000424 rasburicase Drugs 0.000 description 2
- 108010084837 rasburicase Proteins 0.000 description 2
- 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 2
- 210000003289 regulatory T cell Anatomy 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 108010051412 reteplase Proteins 0.000 description 2
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 2
- 229960003452 romidepsin Drugs 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
- 235000005713 safflower oil Nutrition 0.000 description 2
- 239000003813 safflower oil Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 150000004760 silicates Chemical class 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 229940001607 sodium bisulfite Drugs 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 235000011083 sodium citrates Nutrition 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 229940001584 sodium metabisulfite Drugs 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 239000001589 sorbitan tristearate Substances 0.000 description 2
- IJCWFDPJFXGQBN-BIFNRIDTSA-N sorbitan tristearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@@H](O)[C@@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-BIFNRIDTSA-N 0.000 description 2
- 229960004129 sorbitan tristearate Drugs 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000002344 surface layer Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 229960003454 tamoxifen citrate Drugs 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940031351 tetravalent vaccine Drugs 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- 229940033663 thimerosal Drugs 0.000 description 2
- 229940064689 tinzaparin sodium Drugs 0.000 description 2
- 229960002190 topotecan hydrochloride 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
- 229960005026 toremifene Drugs 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 229960005032 treprostinil Drugs 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 229940117013 triethanolamine oleate Drugs 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 230000010415 tropism Effects 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 210000005166 vasculature Anatomy 0.000 description 2
- 229940034332 vincristine sulfate liposome Drugs 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 229960000237 vorinostat Drugs 0.000 description 2
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 2
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- YXTKHLHCVFUPPT-YYFJYKOTSA-N (2s)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid;(1r,2r)-1,2-dimethanidylcyclohexane;5-fluoro-1h-pyrimidine-2,4-dione;oxalic acid;platinum(2+) Chemical compound [Pt+2].OC(=O)C(O)=O.[CH2-][C@@H]1CCCC[C@H]1[CH2-].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 YXTKHLHCVFUPPT-YYFJYKOTSA-N 0.000 description 1
- QBADKJRRVGKRHP-JLXQGRKUSA-N (3as)-2-[(3s)-1-azabicyclo[2.2.2]octan-3-yl]-3a,4,5,6-tetrahydro-3h-benzo[de]isoquinolin-1-one;2-[3,5-bis(trifluoromethyl)phenyl]-n,2-dimethyl-n-[6-(4-methylpiperazin-1-yl)-4-[(3z)-penta-1,3-dien-3-yl]pyridin-3-yl]propanamide Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1.C\C=C(\C=C)C1=CC(N2CCN(C)CC2)=NC=C1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 QBADKJRRVGKRHP-JLXQGRKUSA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- QMMJWQMCMRUYTG-UHFFFAOYSA-N 1,2,4,5-tetrachloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl QMMJWQMCMRUYTG-UHFFFAOYSA-N 0.000 description 1
- DTOUUUZOYKYHEP-UHFFFAOYSA-N 1,3-bis(2-ethylhexyl)-5-methyl-1,3-diazinan-5-amine Chemical compound CCCCC(CC)CN1CN(CC(CC)CCCC)CC(C)(N)C1 DTOUUUZOYKYHEP-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 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
- FPKVOQKZMBDBKP-UHFFFAOYSA-N 1-[4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarbonyl]oxy-2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound O=C1C(S(=O)(=O)O)CC(=O)N1OC(=O)C1CCC(CN2C(C=CC2=O)=O)CC1 FPKVOQKZMBDBKP-UHFFFAOYSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- DJMJHIKGMVJYCW-UHFFFAOYSA-N 2-aminoethanol 3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-2-hydroxyphenyl]benzoic acid Chemical compound CC1=C(C=C(C=C1)N2C(=O)C(=C(N2)C)N=NC3=CC=CC(=C3O)C4=CC(=CC=C4)C(=O)O)C.C(CO)N.C(CO)N DJMJHIKGMVJYCW-UHFFFAOYSA-N 0.000 description 1
- RSGFPIWWSCWCFJ-VAXZQHAWSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;phosphoric acid Chemical compound OP(O)(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC(=O)CC(O)(C(O)=O)CC(O)=O RSGFPIWWSCWCFJ-VAXZQHAWSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- BTDNHKQCPIBABF-UTONKHPSSA-N 3-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine;hydrochloride Chemical compound Cl.O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 BTDNHKQCPIBABF-UTONKHPSSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- SATHPVQTSSUFFW-UHFFFAOYSA-N 4-[6-[(3,5-dihydroxy-4-methoxyoxan-2-yl)oxymethyl]-3,5-dihydroxy-4-methoxyoxan-2-yl]oxy-2-(hydroxymethyl)-6-methyloxane-3,5-diol Chemical compound OC1C(OC)C(O)COC1OCC1C(O)C(OC)C(O)C(OC2C(C(CO)OC(C)C2O)O)O1 SATHPVQTSSUFFW-UHFFFAOYSA-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
- OSDLLIBGSJNGJE-UHFFFAOYSA-N 4-chloro-3,5-dimethylphenol Chemical compound CC1=CC(O)=CC(C)=C1Cl OSDLLIBGSJNGJE-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-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
- OZCVMXDGSSXWFT-UHFFFAOYSA-N 6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide;2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoic acid Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O.CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O OZCVMXDGSSXWFT-UHFFFAOYSA-N 0.000 description 1
- KABRXLINDSPGDF-UHFFFAOYSA-N 7-bromoisoquinoline Chemical compound C1=CN=CC2=CC(Br)=CC=C21 KABRXLINDSPGDF-UHFFFAOYSA-N 0.000 description 1
- 239000005660 Abamectin Substances 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 208000036764 Adenocarcinoma of the esophagus Diseases 0.000 description 1
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 1
- 244000251953 Agaricus brunnescens Species 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 244000247812 Amorphophallus rivieri Species 0.000 description 1
- 235000001206 Amorphophallus rivieri Nutrition 0.000 description 1
- 244000144730 Amygdalus persica Species 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 235000011514 Anogeissus latifolia Nutrition 0.000 description 1
- 244000106483 Anogeissus latifolia Species 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 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 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010061692 Benign muscle neoplasm Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229930185605 Bisphenol Natural products 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101800000407 Brain natriuretic peptide 32 Proteins 0.000 description 1
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 1
- 206010058354 Bronchioloalveolar carcinoma Diseases 0.000 description 1
- LVDKZNITIUWNER-UHFFFAOYSA-N Bronopol Chemical compound OCC(Br)(CO)[N+]([O-])=O LVDKZNITIUWNER-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000001736 Calcium glycerylphosphate Substances 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 235000005747 Carum carvi Nutrition 0.000 description 1
- 240000000467 Carum carvi Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 229940124957 Cervarix Drugs 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- 235000010919 Copernicia prunifera Nutrition 0.000 description 1
- 244000180278 Copernicia prunifera Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 description 1
- QZKRHPLGUJDVAR-UHFFFAOYSA-K EDTA trisodium salt Chemical compound [Na+].[Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O QZKRHPLGUJDVAR-UHFFFAOYSA-K 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 108010056764 Eptifibatide Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000588698 Erwinia Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 229940124897 Gardasil Drugs 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 239000005792 Geraniol Substances 0.000 description 1
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 208000012766 Growth delay Diseases 0.000 description 1
- 239000001922 Gum ghatti Substances 0.000 description 1
- 229920000569 Gum karaya Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 235000019487 Hazelnut oil Nutrition 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 102100028999 High mobility group protein HMGI-C Human genes 0.000 description 1
- 240000000950 Hippophae rhamnoides Species 0.000 description 1
- 235000003145 Hippophae rhamnoides Nutrition 0.000 description 1
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 description 1
- 101000986379 Homo sapiens High mobility group protein HMGI-C Proteins 0.000 description 1
- 101001078143 Homo sapiens Integrin alpha-IIb Proteins 0.000 description 1
- 101001015004 Homo sapiens Integrin beta-3 Proteins 0.000 description 1
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 description 1
- 101000652736 Homo sapiens Transgelin Proteins 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 201000003803 Inflammatory myofibroblastic tumor Diseases 0.000 description 1
- IMQLKJBTEOYOSI-GPIVLXJGSA-N Inositol-hexakisphosphate Chemical compound OP(O)(=O)O[C@H]1[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H]1OP(O)(O)=O IMQLKJBTEOYOSI-GPIVLXJGSA-N 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 102100032999 Integrin beta-3 Human genes 0.000 description 1
- 102100040018 Interferon alpha-2 Human genes 0.000 description 1
- 108010078049 Interferon alpha-2 Proteins 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 241000721662 Juniperus Species 0.000 description 1
- 229920002752 Konjac Polymers 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 235000019501 Lemon oil Nutrition 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 239000005949 Malathion Substances 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 208000030070 Malignant epithelial tumor of ovary Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 240000000982 Malva neglecta Species 0.000 description 1
- 235000000060 Malva neglecta Nutrition 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 1
- 206010027193 Meningioma malignant Diseases 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- HBNPJJILLOYFJU-VMPREFPWSA-N Mibefradil Chemical compound C1CC2=CC(F)=CC=C2[C@H](C(C)C)[C@@]1(OC(=O)COC)CCN(C)CCCC1=NC2=CC=CC=C2N1 HBNPJJILLOYFJU-VMPREFPWSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 201000004458 Myoma Diseases 0.000 description 1
- XKLMZUWKNUAPSZ-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl}acetamide Chemical compound COC1=CC=CC=C1OCC(O)CN1CCN(CC(=O)NC=2C(=CC=CC=2C)C)CC1 XKLMZUWKNUAPSZ-UHFFFAOYSA-N 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
- 208000003788 Neoplasm Micrometastasis Diseases 0.000 description 1
- 206010029098 Neoplasm skin Diseases 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 241000772415 Neovison vison Species 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 1
- 201000004404 Neurofibroma Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 229920002292 Nylon 6 Polymers 0.000 description 1
- DFMPTYCSQGZLFA-RJMJUYIDSA-N OP(O)(O)=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O Chemical compound OP(O)(O)=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O DFMPTYCSQGZLFA-RJMJUYIDSA-N 0.000 description 1
- 206010030137 Oesophageal adenocarcinoma Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 description 1
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 206010031112 Oropharyngeal squamous cell carcinoma Diseases 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108010035766 P-Selectin Proteins 0.000 description 1
- 102000008212 P-Selectin Human genes 0.000 description 1
- 239000012270 PD-1 inhibitor Substances 0.000 description 1
- 239000012668 PD-1-inhibitor Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- CZYWHNTUXNGDGR-UHFFFAOYSA-L Pamidronate disodium Chemical compound O.O.O.O.O.[Na+].[Na+].NCCC(O)(P(O)([O-])=O)P(O)([O-])=O CZYWHNTUXNGDGR-UHFFFAOYSA-L 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 206010061332 Paraganglion neoplasm Diseases 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- IMQLKJBTEOYOSI-UHFFFAOYSA-N Phytic acid Natural products OP(O)(=O)OC1C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C1OP(O)(O)=O IMQLKJBTEOYOSI-UHFFFAOYSA-N 0.000 description 1
- 229920001363 Polidocanol Polymers 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 229920001273 Polyhydroxy acid Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HLCFGWHYROZGBI-JJKGCWMISA-M Potassium gluconate Chemical compound [K+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O HLCFGWHYROZGBI-JJKGCWMISA-M 0.000 description 1
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 235000019774 Rice Bran oil Nutrition 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 241000179948 Sarcophaga beta Species 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 208000002669 Sex Cord-Gonadal Stromal Tumors Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000032383 Soft tissue cancer Diseases 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 241000934878 Sterculia Species 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 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 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 208000003217 Tetany Diseases 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 201000009365 Thymic carcinoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 241000276707 Tilapia Species 0.000 description 1
- 241000425037 Toona sinensis Species 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
- GYDJEQRTZSCIOI-UHFFFAOYSA-N Tranexamic acid Chemical compound NCC1CCC(C(O)=O)CC1 GYDJEQRTZSCIOI-UHFFFAOYSA-N 0.000 description 1
- 102100031013 Transgelin Human genes 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- COQLPRJCUIATTQ-UHFFFAOYSA-N Uranyl acetate Chemical compound O.O.O=[U]=O.CC(O)=O.CC(O)=O COQLPRJCUIATTQ-UHFFFAOYSA-N 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 201000003761 Vaginal carcinoma Diseases 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 235000019498 Walnut oil Nutrition 0.000 description 1
- 108010046516 Wheat Germ Agglutinins Proteins 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 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
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- YWXYYJSYQOXTPL-JGWLITMVSA-N [(3r,3ar,6s,6as)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] nitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-JGWLITMVSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XGKPLOKHSA-N [2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XGKPLOKHSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229920006322 acrylamide copolymer Polymers 0.000 description 1
- 229940081664 adempas Drugs 0.000 description 1
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 229940064305 adrucil Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 229960002736 afatinib dimaleate Drugs 0.000 description 1
- 229960002833 aflibercept Drugs 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229940029184 akynzeo Drugs 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 229960002414 ambrisentan Drugs 0.000 description 1
- 150000001414 amino alcohols Chemical group 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 125000005365 aminothiol group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229960001040 ammonium chloride Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229960001694 anagrelide Drugs 0.000 description 1
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 229940003354 angiomax Drugs 0.000 description 1
- 239000000420 anogeissus latifolia wall. gum Substances 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 229960003886 apixaban Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 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
- 238000003556 assay Methods 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 229940089003 atryn Drugs 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical group C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 description 1
- 235000021302 avocado oil Nutrition 0.000 description 1
- 239000008163 avocado oil Substances 0.000 description 1
- 229940106943 azor Drugs 0.000 description 1
- 239000010480 babassu oil Substances 0.000 description 1
- 229940077840 beleodaq Drugs 0.000 description 1
- 229960003094 belinostat Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- MMIMIFULGMZVPO-UHFFFAOYSA-N benzyl 3-bromo-2,6-dinitro-5-phenylmethoxybenzoate Chemical compound [O-][N+](=O)C1=C(C(=O)OCC=2C=CC=CC=2)C([N+](=O)[O-])=C(Br)C=C1OCC1=CC=CC=C1 MMIMIFULGMZVPO-UHFFFAOYSA-N 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 229940108502 bicnu Drugs 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000035587 bioadhesion Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- HOQPTLCRWVZIQZ-UHFFFAOYSA-H bis[[2-(5-hydroxy-4,7-dioxo-1,3,2$l^{2}-dioxaplumbepan-5-yl)acetyl]oxy]lead Chemical compound [Pb+2].[Pb+2].[Pb+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HOQPTLCRWVZIQZ-UHFFFAOYSA-H 0.000 description 1
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 1
- 229960001500 bivalirudin Drugs 0.000 description 1
- 239000010473 blackcurrant seed oil Substances 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 229940101815 blincyto Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000021324 borage oil Nutrition 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- 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 1
- 210000000481 breast Anatomy 0.000 description 1
- 229960003168 bronopol Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 229940067596 butylparaben Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 229960004256 calcium citrate Drugs 0.000 description 1
- 229960002562 calcium glucoheptonate Drugs 0.000 description 1
- UHHRFSOMMCWGSO-UHFFFAOYSA-L calcium glycerophosphate Chemical compound [Ca+2].OCC(CO)OP([O-])([O-])=O UHHRFSOMMCWGSO-UHFFFAOYSA-L 0.000 description 1
- 229940095618 calcium glycerophosphate Drugs 0.000 description 1
- 235000019299 calcium glycerylphosphate Nutrition 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- FATUQANACHZLRT-XBQZYUPDSA-L calcium;(2r,3r,4s,5r,6r)-2,3,4,5,6,7-hexahydroxyheptanoate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C([O-])=O FATUQANACHZLRT-XBQZYUPDSA-L 0.000 description 1
- YZLMERHFSCVBKZ-UHFFFAOYSA-L calcium;pentanoate Chemical compound [Ca+2].CCCCC([O-])=O.CCCCC([O-])=O YZLMERHFSCVBKZ-UHFFFAOYSA-L 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000010495 camellia oil Substances 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 229960001080 cangrelor Drugs 0.000 description 1
- 235000019519 canola oil Nutrition 0.000 description 1
- 239000000828 canola oil Substances 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
- 229960001631 carbomer Drugs 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
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 229940097647 casodex Drugs 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 229940023913 cation exchange resins Drugs 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 1
- 229940052311 cerivastatin sodium Drugs 0.000 description 1
- 229960000800 cetrimonium bromide Drugs 0.000 description 1
- 235000019480 chamomile oil Nutrition 0.000 description 1
- 239000010628 chamomile oil Substances 0.000 description 1
- LQQUHOUXABUDJA-OUFJFOJPSA-N chembl461806 Chemical compound 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 LQQUHOUXABUDJA-OUFJFOJPSA-N 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 238000000701 chemical imaging Methods 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 150000005827 chlorofluoro hydrocarbons Chemical class 0.000 description 1
- 229960005443 chloroxylenol Drugs 0.000 description 1
- 239000010630 cinnamon oil Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 239000001926 citrus aurantium l. subsp. bergamia wright et arn. oil Substances 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940103380 clolar Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 239000010635 coffee oil Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940088547 cosmegen Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229940013361 cresol Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 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
- 229940086555 cyclomethicone Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 229960003850 dabigatran Drugs 0.000 description 1
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 description 1
- 229960004951 dabigatran etexilate mesylate Drugs 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 229960001425 deferoxamine mesylate Drugs 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 229960002923 denileukin diftitox Drugs 0.000 description 1
- 229960001251 denosumab Drugs 0.000 description 1
- 230000002951 depilatory effect Effects 0.000 description 1
- 229940070968 depocyt Drugs 0.000 description 1
- IDDIJAWJANBQLJ-UHFFFAOYSA-N desferrioxamine B mesylate Chemical compound [H+].CS([O-])(=O)=O.CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN IDDIJAWJANBQLJ-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 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 1
- 229960004102 dexrazoxane hydrochloride Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- CGMRCMMOCQYHAD-UHFFFAOYSA-J dicalcium hydroxide phosphate Chemical compound [OH-].[Ca++].[Ca++].[O-]P([O-])([O-])=O CGMRCMMOCQYHAD-UHFFFAOYSA-J 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- JXSJBGJIGXNWCI-UHFFFAOYSA-N diethyl 2-[(dimethoxyphosphorothioyl)thio]succinate Chemical compound CCOC(=O)CC(SP(=S)(OC)OC)C(=O)OCC JXSJBGJIGXNWCI-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- OGGXGZAMXPVRFZ-UHFFFAOYSA-N dimethylarsinic acid Chemical compound C[As](C)(O)=O OGGXGZAMXPVRFZ-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- QLBHNVFOQLIYTH-UHFFFAOYSA-L dipotassium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O QLBHNVFOQLIYTH-UHFFFAOYSA-L 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- WSDISUOETYTPRL-UHFFFAOYSA-N dmdm hydantoin Chemical compound CC1(C)N(CO)C(=O)N(CO)C1=O WSDISUOETYTPRL-UHFFFAOYSA-N 0.000 description 1
- 229940115080 doxil Drugs 0.000 description 1
- 229940063519 doxorubicin hydrochloride liposome Drugs 0.000 description 1
- 229960002084 dronedarone Drugs 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 229960000622 edoxaban Drugs 0.000 description 1
- 230000000235 effect on cancer Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 229940099302 efudex Drugs 0.000 description 1
- 229960001827 eltrombopag olamine Drugs 0.000 description 1
- 210000002308 embryonic cell Anatomy 0.000 description 1
- 229940108890 emend Drugs 0.000 description 1
- 239000010776 emu oil Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 229960000309 enalapril maleate Drugs 0.000 description 1
- OYFJQPXVCSSHAI-QFPUQLAESA-N enalapril maleate Chemical compound OC(=O)\C=C/C(O)=O.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 OYFJQPXVCSSHAI-QFPUQLAESA-N 0.000 description 1
- 201000003908 endometrial adenocarcinoma Diseases 0.000 description 1
- 208000018463 endometrial serous adenocarcinoma Diseases 0.000 description 1
- 208000027858 endometrioid tumor Diseases 0.000 description 1
- 208000029382 endometrium adenocarcinoma Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229940035000 epanova Drugs 0.000 description 1
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 description 1
- 229960002548 epinastine hydrochloride Drugs 0.000 description 1
- CZKPOZZJODAYPZ-LROMGURASA-N eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CNC2=CC=CC=C12 CZKPOZZJODAYPZ-LROMGURASA-N 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229940014684 erivedge Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 208000028653 esophageal adenocarcinoma Diseases 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 125000003916 ethylene diamine group Chemical group 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 235000008524 evening primrose extract Nutrition 0.000 description 1
- 239000010475 evening primrose oil Substances 0.000 description 1
- 229940089020 evening primrose oil Drugs 0.000 description 1
- 229940085363 evista Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 201000009311 eye carcinoma Diseases 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 229940087861 faslodex Drugs 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 201000010972 female reproductive endometrioid cancer Diseases 0.000 description 1
- 229940087476 femara Drugs 0.000 description 1
- 229960000701 fenofibric acid Drugs 0.000 description 1
- 239000010644 fenugreek oil Substances 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 206010016629 fibroma Diseases 0.000 description 1
- 206010049444 fibromatosis Diseases 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- JYEFSHLLTQIXIO-SMNQTINBSA-N folfiri regimen Chemical compound 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 JYEFSHLLTQIXIO-SMNQTINBSA-N 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
- 229940039573 folotyn Drugs 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 description 1
- 229940102767 gardasil 9 Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 230000004077 genetic alteration Effects 0.000 description 1
- 231100000118 genetic alteration Toxicity 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 229940113087 geraniol Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940084910 gliadel Drugs 0.000 description 1
- 108010049491 glucarpidase Proteins 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 208000030316 grade III meningioma Diseases 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 239000008169 grapeseed oil Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940118951 halaven Drugs 0.000 description 1
- 239000010468 hazelnut oil Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 229960004867 hexetidine Drugs 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 239000010903 husk Substances 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 229960005384 hydralazine hydrochloride Drugs 0.000 description 1
- ZUXNZUWOTSUBMN-UHFFFAOYSA-N hydralazine hydrochloride Chemical compound Cl.C1=CC=C2C(NN)=NN=CC2=C1 ZUXNZUWOTSUBMN-UHFFFAOYSA-N 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 229940049235 iclusig Drugs 0.000 description 1
- 229960002600 icosapent ethyl Drugs 0.000 description 1
- 229940099279 idamycin Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229940090411 ifex Drugs 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 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 1
- ZCTXEAQXZGPWFG-UHFFFAOYSA-N imidurea Chemical compound O=C1NC(=O)N(CO)C1NC(=O)NCNC(=O)NC1C(=O)NC(=O)N1CO ZCTXEAQXZGPWFG-UHFFFAOYSA-N 0.000 description 1
- 229940113174 imidurea Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000010569 immunofluorescence imaging Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 238000013383 initial experiment Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940095443 innohep Drugs 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 229940056984 integrilin Drugs 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000002601 intratumoral effect Effects 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
- 229940084651 iressa Drugs 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229940011083 istodax Drugs 0.000 description 1
- 229940045773 jakafi Drugs 0.000 description 1
- 229940025735 jevtana Drugs 0.000 description 1
- 229940119170 jojoba wax Drugs 0.000 description 1
- 229940047695 juxtapid Drugs 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 239000000231 karaya gum Substances 0.000 description 1
- 229940039371 karaya gum Drugs 0.000 description 1
- 229940101712 kengreal Drugs 0.000 description 1
- 229940065223 kepivance Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 235000010485 konjac Nutrition 0.000 description 1
- 239000000252 konjac Substances 0.000 description 1
- 229940098262 kynamro Drugs 0.000 description 1
- 229940000764 kyprolis Drugs 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000010501 lemon oil Substances 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940090243 letairis Drugs 0.000 description 1
- 235000005772 leucine Nutrition 0.000 description 1
- 229940063725 leukeran Drugs 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 229940118199 levulan Drugs 0.000 description 1
- 229940080157 lexxel Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 235000021388 linseed oil Nutrition 0.000 description 1
- 239000000944 linseed oil Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940103064 lipodox Drugs 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 229940034394 liptruzet Drugs 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000001289 litsea cubeba fruit oil Substances 0.000 description 1
- 229940092923 livalo Drugs 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000001325 log-rank test Methods 0.000 description 1
- MBBCVAKAJPKAKM-UHFFFAOYSA-N lomitapide Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1(C(=O)NCC(F)(F)F)CCCCN(CC1)CCC1NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 MBBCVAKAJPKAKM-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 208000016992 lung adenocarcinoma in situ Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 229940087857 lupron Drugs 0.000 description 1
- 208000012804 lymphangiosarcoma Diseases 0.000 description 1
- 229940100352 lynparza Drugs 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229960001039 macitentan Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229960000816 magnesium hydroxide Drugs 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 229960000453 malathion Drugs 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229940034322 marqibo Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 229940103179 mavik Drugs 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 239000010487 meadowfoam seed oil Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 229940090004 megace Drugs 0.000 description 1
- 229940083118 mekinist Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 210000000716 merkel cell Anatomy 0.000 description 1
- 229940101533 mesnex Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BEGLCMHJXHIJLR-UHFFFAOYSA-N methylisothiazolinone Chemical compound CN1SC=CC1=O BEGLCMHJXHIJLR-UHFFFAOYSA-N 0.000 description 1
- 229960004438 mibefradil Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 229940101576 microzide Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 208000024191 minimally invasive lung adenocarcinoma Diseases 0.000 description 1
- 108091060283 mipomersen Proteins 0.000 description 1
- 229960000602 mipomersen sodium Drugs 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004169 mitoxantrone hydrochloride Drugs 0.000 description 1
- 201000010225 mixed cell type cancer Diseases 0.000 description 1
- 208000029638 mixed neoplasm Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 229940074923 mozobil Drugs 0.000 description 1
- 229940087092 multaq Drugs 0.000 description 1
- 229940090009 myleran Drugs 0.000 description 1
- 239000001627 myristica fragrans houtt. fruit oil Substances 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 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 1
- 229960000801 nelarabine Drugs 0.000 description 1
- HPNRHPKXQZSDFX-OAQDCNSJSA-N nesiritide Chemical compound C([C@H]1C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)CNC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CO)C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1N=CNC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 HPNRHPKXQZSDFX-OAQDCNSJSA-N 0.000 description 1
- 229960001267 nesiritide Drugs 0.000 description 1
- WAXQNWCZJDTGBU-UHFFFAOYSA-N netupitant Chemical compound C=1N=C(N2CCN(C)CC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WAXQNWCZJDTGBU-UHFFFAOYSA-N 0.000 description 1
- 229960005163 netupitant Drugs 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 208000016065 neuroendocrine neoplasm Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940080607 nexavar Drugs 0.000 description 1
- 229940033757 niaspan Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- UIAGMCDKSXEBJQ-UHFFFAOYSA-N nimodipine Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-UHFFFAOYSA-N 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 229940085033 nolvadex Drugs 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229940045770 nymalize Drugs 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- JPMIIZHYYWMHDT-UHFFFAOYSA-N octhilinone Chemical compound CCCCCCCCN1SC=CC1=O JPMIIZHYYWMHDT-UHFFFAOYSA-N 0.000 description 1
- 229940024847 odomzo Drugs 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960001199 olmesartan medoxomil Drugs 0.000 description 1
- 229940034999 omega-3 carboxylic acid Drugs 0.000 description 1
- 229940099216 oncaspar Drugs 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 229940100027 ontak Drugs 0.000 description 1
- 229940058799 opsumit Drugs 0.000 description 1
- 229940041678 oral spray Drugs 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 201000002740 oral squamous cell carcinoma Diseases 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 208000022698 oropharynx squamous cell carcinoma Diseases 0.000 description 1
- 239000003346 palm kernel oil Substances 0.000 description 1
- 235000019865 palm kernel oil Nutrition 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 208000007312 paraganglioma Diseases 0.000 description 1
- 201000003913 parathyroid carcinoma Diseases 0.000 description 1
- 208000017954 parathyroid gland carcinoma Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 229940121655 pd-1 inhibitor Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- 229960003076 perindopril arginine Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 235000002949 phytic acid Nutrition 0.000 description 1
- 239000000467 phytic acid Substances 0.000 description 1
- 229940068041 phytic acid Drugs 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 1
- 229960002226 polidocanol Drugs 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 229920000090 poly(aryl ether) Polymers 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920000333 poly(propyleneimine) Polymers 0.000 description 1
- 229940074982 poly(vinylpyrrolidone-co-vinyl-acetate) Drugs 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 229960002183 ponatinib hydrochloride Drugs 0.000 description 1
- 239000010491 poppyseed oil Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229960004109 potassium acetate Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- 239000004224 potassium gluconate Substances 0.000 description 1
- 235000013926 potassium gluconate Nutrition 0.000 description 1
- 229960003189 potassium gluconate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- BHZRJJOHZFYXTO-UHFFFAOYSA-L potassium sulfite Chemical compound [K+].[K+].[O-]S([O-])=O BHZRJJOHZFYXTO-UHFFFAOYSA-L 0.000 description 1
- 235000019252 potassium sulphite Nutrition 0.000 description 1
- 229940066336 pradaxa Drugs 0.000 description 1
- 229960000214 pralatrexate Drugs 0.000 description 1
- 229960001495 pravastatin sodium Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 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
- 229940073270 prestalia Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229940088953 prinivil Drugs 0.000 description 1
- 229960001586 procarbazine hydrochloride Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 229940092597 prolia Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229940021945 promacta Drugs 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- JWHAUXFOSRPERK-UHFFFAOYSA-N propafenone Chemical compound CCCNCC(O)COC1=CC=CC=C1C(=O)CCC1=CC=CC=C1 JWHAUXFOSRPERK-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 229940034080 provenge Drugs 0.000 description 1
- 239000001944 prunus armeniaca kernel oil Substances 0.000 description 1
- 239000008171 pumpkin seed oil Substances 0.000 description 1
- 229940117820 purinethol Drugs 0.000 description 1
- 229960000213 ranolazine Drugs 0.000 description 1
- 229920013730 reactive polymer Polymers 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- 229940107685 reopro Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229940116243 retavase Drugs 0.000 description 1
- 229960002917 reteplase Drugs 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229940061969 rheumatrex Drugs 0.000 description 1
- 239000008165 rice bran oil Substances 0.000 description 1
- WXXSNCNJFUAIDG-UHFFFAOYSA-N riociguat Chemical compound N1=C(N)C(N(C)C(=O)OC)=C(N)N=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1F WXXSNCNJFUAIDG-UHFFFAOYSA-N 0.000 description 1
- 229960001148 rivaroxaban Drugs 0.000 description 1
- 108010017584 romiplostim Proteins 0.000 description 1
- 239000010668 rosemary oil Substances 0.000 description 1
- 229940058206 rosemary oil Drugs 0.000 description 1
- 229960002539 ruxolitinib phosphate Drugs 0.000 description 1
- 229940018498 rythmol Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 201000003804 salivary gland carcinoma Diseases 0.000 description 1
- 239000010671 sandalwood oil Substances 0.000 description 1
- 210000003752 saphenous vein Anatomy 0.000 description 1
- 229940011622 savaysa Drugs 0.000 description 1
- 239000010673 savory oil Substances 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229940053186 sclerosol Drugs 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229960003323 siltuximab Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- VUFNRPJNRFOTGK-UHFFFAOYSA-M sodium;1-[4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarbonyl]oxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)C1CCC(CN2C(C=CC2=O)=O)CC1 VUFNRPJNRFOTGK-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- RWIVSVMMGFFZIJ-VWDRLOGHSA-N sonidegib phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.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 RWIVSVMMGFFZIJ-VWDRLOGHSA-N 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 229940068117 sprycel Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229940090374 stivarga Drugs 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 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 1
- 239000000829 suppository Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 229940110546 sylatron Drugs 0.000 description 1
- 229940053017 sylvant Drugs 0.000 description 1
- 229940022873 synribo Drugs 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- 229940081616 tafinlar Drugs 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 239000010677 tea tree oil Substances 0.000 description 1
- 229940111630 tea tree oil Drugs 0.000 description 1
- 229940061353 temodar Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 229940034915 thalomid Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- CNHYKKNIIGEXAY-UHFFFAOYSA-N thiolan-2-imine Chemical compound N=C1CCCS1 CNHYKKNIIGEXAY-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 239000010496 thistle oil Substances 0.000 description 1
- 239000003634 thrombocyte concentrate Substances 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 1
- 229960002528 ticagrelor Drugs 0.000 description 1
- SYRHIZPPCHMRIT-UHFFFAOYSA-N tin(4+) Chemical compound [Sn+4] SYRHIZPPCHMRIT-UHFFFAOYSA-N 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940035307 toposar Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 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 1
- 229960002051 trandolapril Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 229940066958 treanda Drugs 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- 229940071546 trilipix Drugs 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229940086984 trisenox Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- 229940014025 tyvaso Drugs 0.000 description 1
- 229940022919 unituxin Drugs 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 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
- 229960002381 vardenafil Drugs 0.000 description 1
- 229940079195 varithena Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 239000010679 vetiver oil Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229940061389 viadur Drugs 0.000 description 1
- 229940065658 vidaza Drugs 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 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 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229960005044 vorapaxar Drugs 0.000 description 1
- ZBGXUVOIWDMMJE-QHNZEKIYSA-N vorapaxar Chemical compound C(/[C@@H]1[C@H]2[C@H](C(O[C@@H]2C)=O)C[C@H]2[C@H]1CC[C@H](C2)NC(=O)OCC)=C\C(N=C1)=CC=C1C1=CC=CC(F)=C1 ZBGXUVOIWDMMJE-QHNZEKIYSA-N 0.000 description 1
- NQRYCIGCIAWEIC-CKLVGUEFSA-N vorapaxar sulfate Chemical compound OS(O)(=O)=O.C(/[C@@H]1[C@H]2[C@H](C(O[C@@H]2C)=O)C[C@H]2[C@H]1CC[C@H](C2)NC(=O)OCC)=C\C(N=C1)=CC=C1C1=CC=CC(F)=C1 NQRYCIGCIAWEIC-CKLVGUEFSA-N 0.000 description 1
- 229940110059 voraxaze Drugs 0.000 description 1
- 229940069559 votrient Drugs 0.000 description 1
- 239000008170 walnut oil Substances 0.000 description 1
- 239000010497 wheat germ oil Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229940049068 xalkori Drugs 0.000 description 1
- 229940055725 xarelto Drugs 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229940014556 xgeva Drugs 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- 229940034727 zelboraf Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
- 229940072018 zofran Drugs 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
- 229940087881 zontivity Drugs 0.000 description 1
- 229940095188 zydelig Drugs 0.000 description 1
- 229940052129 zykadia Drugs 0.000 description 1
- 229940051084 zytiga Drugs 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/19—Platelets; Megacaryocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/40—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum bacterial
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0644—Platelets; Megakaryocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Abstract
本公开提供了用于靶向递送治疗剂的组合物和方法。本公开还提供了使用负载有治疗剂(例如,免疫治疗剂)的血小板来治疗或预防癌症转移或复发的方法。
Description
相关申请的交叉引用
本申请要求2016年9月13日提交的美国临时专利申请序列号62/393,839的权益,所述美国临时专利申请明确地通过引用并入本文。
技术领域
本公开提供了用于靶向递送治疗剂的组合物和方法。本公开还提供了使用负载有治疗剂(例如,免疫治疗剂)的血小板来治疗或预防癌症转移或复发的方法。
背景技术
手术是大多数实体瘤的主要治疗选择。尽管手术技术不断改进,肿瘤切除后的残余微肿瘤和/或循环肿瘤细胞(CTC)仍然充满挑战。另外,还有人提出手术可诱导对癌症转移的促进。许多患者在术后发展复发性疾病,这可导致显著的发病率和死亡率。因此,人们对开发预防术后癌症复发的有效策略产生了极大的兴趣。其中,癌症免疫疗法最近受到了相当多的关注。免疫治疗剂不直接攻击肿瘤,而是加强身体的免疫系统以杀伤癌细胞。免疫检查点阻断在一部分患者中引起了持久的抗肿瘤应答和长期缓解。特别是,检查点抑制剂阻断与淋巴细胞上的程序性细胞死亡蛋白1(PD1)的相互作用并且抗原呈递细胞(APC)和肿瘤细胞上的程序性细胞死亡蛋白1配体1(PDL1)在治疗各种类型的癌症方面已经显示出令人兴奋的结果。而且,第一种PD-L1抑制剂阿特珠单抗(atezolizumab)最近获得了FDA的加快审批。尽管取得了显著进展,但目前的检查点阻断治疗方法限制了在许多患者中的治疗益处。在临床试验中观察到的最大限制可能是副作用(诸如自身免疫性病症)的严重程度。用免疫检查点阻断疗法治疗时,有时会发生3/4级不良事件。同时,很大一部分患者对这些剂没有应答。癌症免疫疗法的客观应答率(ORR)仍需提高。如何增强癌症免疫治疗已成为癌症免疫学和免疫治疗领域的核心主题之一。本文公开的组合物和方法解决了这些和其它需要。
发明内容
本公开提供了用于治疗和预防疾病(例如癌症)的血小板组合物和方法。在本文公开的组合物和方法中,治疗剂(例如,免疫治疗剂)与血小板细胞共价连接。发明人已经发现,与血小板细胞的表面缀合的免疫治疗剂(例如,抗PDL1)减少在切除原发肿瘤后的癌症的复发(和/或减少癌症转移)。
一方面,本文提供了一种组合物,其包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接。
另一方面,本文公开了一种预防癌症转移或复发的方法,其包括:
向有需要的受试者施用治疗有效量的组合物,所述组合物包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接。
另一方面,本文公开了一种用于靶向递送治疗剂的方法,其包括:
向受试者施用组合物,所述组合物包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接;
其中所述组合物通过所述血小板细胞的活化而被靶向伤口或手术切除部位。
另一方面,本文提供了一种治疗或预防血管疾病的方法,其包括:
向有需要的受试者施用治疗有效量的组合物,所述组合物包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接。
附图说明
并入本说明书中并构成本说明书的一部分的附图说明了下面描述的几个方面。
图1A-1F。血小板受抗PDL1原位活化(P-aPDL1)促进治疗剂的释放。(图1a)通过血小板向原发肿瘤切除部位递送抗PDL1抗体(aPDL1)的示意图。(图1b)活化之前(i)和之后(ii和iii)P-aPDL1的TEM图像。红色箭头指示PMP从血小板释放。在电子显微镜下观察到大量产生的PMP颗粒。比例尺,0.5μm。(图1c)不同时间点从非活化血小板和活化血小板释放的aPDL1的百分比。(图1d-图1e)不同时间点从非活化血小板和活化血小板释放的TNF-α(图1d)和IL-1β(图1e)的量。(图1f)transwell系统(孔径大小,1μm)中与非活化(左)和活化(右)P-aPDL1共同孵育的B16癌细胞的共聚焦免疫荧光图像。P-aPDL1和B16癌细胞分别在上部和下部隔室中培养。红色表示aPDL1信号,蓝色和绿色荧光分别表示来自DAPI和Alexafluor 488缀合小麦胚芽凝集素的细胞核和质膜。比例尺,20μm。误差线基于一式三份样品的标准偏差(SD)。
图2A-2J。通过P-aPDL1疗法体内减少术床(surgical bed)上的复发性黑素瘤肿瘤。(图2a)通过测量在注射后不同时间点收集的血液中的aPDL1水平制作的小鼠中P-aPDL1、游离aPDL1和血小板+aPDL1混合物的血液循环曲线。误差线基于一式三份样品的标准偏差(SD)(n=3)(图2b)静脉(i.v.)注射P-aPDL1或等效剂量的游离aPDL1注射后2小时小鼠的荧光图像(aPDL1-Cy5.5)。(图2c)P-aPDL1或游离aPDL1静脉注射后2小时有残余肿瘤的伤口的离体图像。(图2d)(c)中所示小鼠的不同伤口中的平均aPDL1-Cy5.5荧光信号强度。误差线基于一式三份样品的平均值的标准误差(s.e.m.)。(图2e)从(b)中所示小鼠取得的残余肿瘤切片的共聚焦图像,其中蓝色和红色分别表示来自DAPI和Cy5.5的细胞核和aPDL1信号。比例尺,20μm。(图2f)用于治疗不完全手术肿瘤模型的P-aPDL1疗法的示意图。(图2g)去除原发肿瘤后不同组的B16F10肿瘤的体内生物发光图像。示出了每个处理组的3只代表性小鼠。(图2h)各种指示处理后不同组小鼠的定量肿瘤信号。(图2i-图2j)经处理的小鼠和对照小鼠的肿瘤生长曲线(i)和存活曲线(j)。示出了用于存活研究的每个处理组的8只小鼠。误差线基于平均值的标准误差(s.e.m.)。P值:*,P<0.05。
图3A-3H。P-aPDL1触发了稳健的、T细胞介导的抗肿瘤免疫应答。(图3a)残余肿瘤的免疫荧光显示CD4+T细胞和CD8+T细胞浸润。比例尺,50μm。(图3b)肿瘤重量和(图3c)每克肿瘤中CD3+细胞的绝对数量。误差线基于平均值的标准误差(s.e.m.)(n=4)。(图3d)总CD3+细胞中CD4+和CD8+T细胞的百分比,以及如所示处理的小鼠残余肿瘤中的代表性点图。所有四个象限中细胞群越大表明肿瘤部位中的CD3+肿瘤浸润淋巴细胞越多。(图3e)总CD3+细胞中CD4+Foxp3+T细胞的百分比,以及如所示处理的小鼠残余肿瘤中的代表性点图。(图3f)各种处理后每克肿瘤中CD8+细胞的绝对数量。(图3g-图3h)在各种处理后,残余肿瘤中肿瘤浸润性CD8+T细胞和有效CD4+T细胞相对于调节性T细胞的比率。误差线基于平均值的标准误差(s.e.m.)(n=4)。使用Tukey事后检验,通过单因素ANOVA计算统计显著性。P值:*,P<0.05;**,P<0.01;***P<0.005。
图4A-4F。P-aPDL1疗法影响局部复发性黑素瘤和转移性疾病的生长。(图4a)用于治疗小鼠不完全手术和转移性肿瘤模型的P-aPDL1疗法的示意图。(图4b)去除原发肿瘤后不同组在不同时间点的B16F10转移瘤的体内生物发光图像。示出了每个处理组的3只代表性小鼠。(图4c)代表性肺部照片和(图4d)在所指示不同处理后从小鼠收集的H&E染色的肺切片。黑色箭头指示肺部转移性肿瘤。比例尺,500μm。(图4e)对经不同处理的小鼠的肺部转移结节进行定量。结果呈现为平均值±SEM(n=3)。(图4f)经处理的小鼠和对照小鼠的存活曲线。示出了用于存活研究的每个处理组的8只小鼠。P值:*,P<0.05。
图5A-5E。用于治疗术后4T1复发性癌症的P-aPDL1。(图5a)去除原发肿瘤后不同组在不同时间点的4T1转移瘤的体内生物发光图像。(图5b)术后2周的代表性小鼠照片。黑色箭头表示术床上的复发肿瘤。(图5c)在所指示不同处理后从小鼠收集的代表性肺部照片。红色箭头指示肺部肿瘤结节。(图5d)对经不同处理的小鼠的肺部转移结节进行定量。结果呈现为平均值±SEM(n=3)。(图5e)经处理的小鼠和对照小鼠的存活曲线。示出了用于存活研究的每个处理组的8只小鼠。P值:*,P<0.05。
图6。aPDL1偶联血小板的共聚焦免疫荧光图像。FITC缀合二抗用于检测血小板上的aPDL1图像。比例尺,20μm。
图7。aPDL1偶联血小板的流式细胞术测定。在不同的实验设置下将血小板与aPDL1一起孵育,并使用山羊抗大鼠IgG(H+L)二抗FITC通过流式细胞术进行分析。通过巯基和马来酰亚胺的结合验证aPDL1成功连接于血小板表面。
图8A-8C。aPDL1偶联血小板的缀合和稳定性。(图8a)将各种量的aPDL1添加到血小板中用于缀合。每个血小板添加0.2pg aPDL1时,aPDL1与血小板的缀合效率(添加的aPDL1/缀合的aPDL1)为约75%。(图8b)aPDL1修饰后血小板的稳定性。基于0小时和24小时的血小板计数分析测量P-aPDL1的数量。(图8c)随时间推移血小板上aPDL1的稳定性。误差线基于一式三份样品的标准偏差(SD)(n=6)。
图9。初次实验血小板和aPDL1缀合血小板上的表面蛋白表达(活化后检查CD62P和CD40L)。
图10A-10B。活化后P-aPDL1的透射电子显微镜检查(TEM)。(图10a)从活化血小板脱落的血小板微粒(PMP)。(图10b)P-aPDL1活化后,可在TEM下发现许多PMP。比例尺,图10a中为100nm,图10b中为2μm。
图11。活化后P-aPDL1的免疫荧光图像。为血小板负载钙黄绿素(calcein)并通过绿色荧光使其可视化。aPDL1用Cy3山羊抗大鼠IgG二抗标记,并通过红色荧光使其可视化。白色箭头指示PMP从血小板释放。
图12A-12B。在transwell系统中与P-aPDL1共同孵育的B16癌细胞的共聚焦免疫荧光图像。(图12a)transwell系统的示意图。P-aPDL1和B16癌细胞分别在上部和下部隔室中培养。(图12b)transwell系统(孔径大小,1μm)中与非活化和活化P-aPDL1共同孵育的B16癌细胞的共聚焦免疫荧光图像。红色(Cy3)荧光表示aPDL1信号,蓝色(DAPI)和绿色(Alexa488)荧光分别表示来自细胞核和细胞膜的信号。比例尺,20μm。
图13A-13C。小鼠体内aPDL1偶联血小板的生物分布。(图13a)游离Cy5.5-aPDL1和P-aPDL1-Cy5.5的荧光光谱。在aPDL1与血小板缀合后,未发现Cy5.5的强度受到显著影响。(图13b)静脉注射P-aPDL1和游离aPDL1后2小时,在小鼠不同器官中的离体Cy5.5-aPDL1荧光图像。L:肝脏,Lu:肺部;Sp:脾脏,H:心脏,K:肾脏。(图13c)(b)中所示小鼠不同器官中的平均Cy5.5荧光信号强度。示出了每个处理组的3只小鼠。结果呈现为平均值±SD。通过t检验计算统计显著性。P值:***,P<0.005。
图14A-14B。残余肿瘤切片的共聚焦图像。(图14a)残余肿瘤切片的共聚焦图像,其中蓝色和红色表示来自DAPI和Cy5.5的细胞核和aPDL1信号。(图14b)(a)的P-aPDL1中残余肿瘤切片的高倍放大图像。白色箭头指示PMP和aPDL1从血小板释放。
图15。小鼠尾部横切放血模型中的止血效果。通过t检验计算统计显著性。n.s.,不显著。误差线基于一式三份样品的标准偏差(SD)(n=10)
图16A-16D。处理后小鼠的细胞因子水平。所指示处理后小鼠的(图16a)局部和(图16b)全身细胞因子水平。(图16c)代表性流式细胞术分析图像和(图16d)PD-L1分析的免疫荧光图像(上,无血小板;下,有血小板)。(针对CD11b+GFP-设门的巨噬细胞,针对GFP+CD45-设门的肿瘤细胞,针对CD20+GFP-设门的B细胞和针对CD11c+GFP-设门的DC)。误差线基于一式三份样品的s.e.m.。使用Tukey事后检验,通过单因素ANOVA计算统计显著性。P值:*,P<0.05,n.s.,不显著。
图17。残余肿瘤的免疫荧光显示CD4+T细胞和CD8+T细胞浸润。比例尺,50μm。
图18。经所指示的不同处理,表达Ki67的CD8+、CD4+Foxp3和CD4+Foxp3+T细胞的百分比。使用Tukey事后检验,通过单因素ANOVA计算统计显著性。P值:*,P<0.05;**,P<0.01;***P<0.005。
图19A-19C。去除原发肿瘤后PMP-aPDL1和高剂量aPDL1的抗肿瘤功效。(图19a)去除原发肿瘤后不同组的B16F10肿瘤的体内生物发光图像。(图19b)各种所指示处理后不同组小鼠的肿瘤生长曲线。(图19c)各种所指示处理后60天内小鼠的存活曲线。示出了每个处理组的5只小鼠。
图20。肺组织的荧光图像。蓝色和绿色荧光分别表示来自DAPI和GFP癌细胞的细胞核。比例尺,100μm。
具体实施方式
本公开提供了用于治疗和预防疾病(例如癌症)的血小板组合物和方法。在本文公开的组合物和方法中,治疗剂(例如,免疫治疗剂)与血小板细胞共价连接。发明人已经发现,与血小板细胞的表面缀合的免疫治疗剂(例如,抗PDL1)减少在切除原发肿瘤后的癌症复发(和/或减少癌症转移)。
现在将详细参考本发明的实施方案,其实例在附图和实施例中示出。然而,本发明可以许多不同形式体现且不应被解释为限于本文所阐述的实施方案。
除非另外定义,否则本文使用的所有技术和科学术语均具有与本公开所属领域中的普通技术人员通常所理解的相同含义。如本文所用的术语“包含”及其变型与术语“包括”及其变型同义地使用,并且是开放的、非限制性术语。虽然术语“包含”和“包括”在本文中用于描述各种实施方案,但是可以使用术语“基本上由......组成”和“由...组成”来代替“包含”和“包括”以提供更具体的实施方案并且也被公开。
术语
如说明书和权利要求书中所用,除非上下文另外明确指出,否则单数形式“一”、“一种(个)”和“所述(该)”包括复数指示物。例如,术语“细胞”包括多个细胞,包括其混合物。
如本文所用,术语“可以”、“任选地”和“可任选地”可互换使用,并且意在包括病症发生的情况以及不发生病症的情况。因此,例如,制剂“可包括赋形剂”的陈述意在包括制剂包括赋形剂的情况以及制剂不包括赋形剂的情况。
如本文所用,术语“有益剂”和“活性剂”在本文中可互换使用,是指具有有益生物效应的化学化合物或组合物。有益生物效应包括治疗效果,即治疗病症或其他不期望的生理状况;和预防效果,即预防病症或其它不期望的生理状况(例如,癌症)。该术语还涵盖本文具体提到的有益剂的药学上可接受的药理学活性衍生物,包括但不限于盐、酯、酰胺、前药、活性代谢物、异构体、片段、类似物等。使用术语“有益剂”或“活性剂”时,或明确标识特定药剂时,应理解该术语包括药剂本身以及药学上可接受的药理学活性盐、酯、酰胺、前药、缀合物、活性代谢物、异构体、片段、类似物等。
如本文所用,术语受试者的“治疗”包括向受试者施用药物以达到预防、治愈、愈合、减轻、缓和、改变、补救、缓解、改善、稳定或影响疾病或病症,或疾病或病症的症状的目的。术语“治疗”还可以指降低症状的严重程度和/或频率,消除症状和/或潜在病因,预防症状和/或其潜在病因的发生,以及改善或补救损伤。
如本文所用,术语“预防”受试者的病症或有害生理事件具体指预防症状和/或其潜在病因的发生,其中受试者可能或可能不表现出对病症或事件增高的易感性。
术语治疗剂的“有效量”意指有益剂提供预期效果的无毒但足够的量。有益剂“有效”的量将因受试者而异,这取决于受试者的年龄和总体状况、一种或多种特定的有益剂等。因此,并不总是能够指定确切的“有效量”。然而,本领域的普通技术人员可以使用常规实验测确定任何受试者情况下的适当“有效”量。同样,如本文所用,并且除非另有特别说明,有益剂的“有效量”也可以指涵盖治疗有效量和预防有效量的量。
达到治疗效果所必需的药物的“有效量”可以根据诸如受试者的年龄、性别和体重等因素而变化。可以调整剂量方案以提供最佳治疗应答。例如,如治疗情境的紧急情况所指示,可以每天施用几个分剂量或按比例减少剂量。
如本文所用,治疗剂的“治疗有效量”是指有效达到预期治疗结果的量,并且治疗剂的“预防有效量”是指有效预防有害生理状况的量。给定治疗剂的治疗有效量和预防有效量通常会根据诸如所治病症或疾病的类型和严重程度以及受试者的年龄、性别和体重等因素而变化。
术语“治疗有效量”也可以指有效促进预期治疗效果的治疗剂的量,或治疗剂的递送速率(例如,随时间而变化的量)。精确的预期治疗效果将根据待治病症、受试者的耐受性、待施用的药物和/或药物制剂(例如,治疗剂(药物)的效力、制剂中药物的浓度等)以及本领域普通技术人员所理解的多种其他因素而变化。
如本文所用,术语“药学上可接受的”组分可以指不是生物学上或其他方面不合需要的组分,即该组分可以掺入本发明的药物制剂中并如本文所述施用于受试者而不会引起任何显著的不合需要的生物效应或以有害的方式与含有该组分的制剂的任何其他组分相互作用。当术语“药学上可接受的”用于指赋形剂时,通常暗示该组分符合所要求的毒理学和生产测试标准,或者包括在由美国食品和药物管理局准备的非活性成分指南中。
同样,如本文所用,术语“药理学活性”(或简称“活性”),如同在“药理学活性”衍生物或类似物中,可以指具有与母体化合物相同类型的药理活性并且程度大致相等的衍生物或类似物(例如,盐、酯、酰胺、缀合物、代谢物、异构体、片段等)。
如本文所用,术语“混合物”可包括其中混合物的组分可完全混溶的溶液,以及其中混合物的组分不完全混溶的悬浮液和乳液。
如本文所用,术语“受试者”可以指活生物体,诸如哺乳动物,包括但不限于人、牲畜、狗、猫和其他哺乳动物。治疗剂的施用可以按治疗受试者有效的剂量和时间段进行。在一些实施方案中,受试者为人。在一些实施方案中,本发明系统的药代动力学特征对于男性和女性受试者而言是相似的。
如本文所用的短语“并行施用”、“组合施用”、“同时施用”或“同时地施用”意指在相同时间点或紧接着彼此施用化合物。在后一种情况下,两种化合物的施用时间足够接近,使得观察到的结果与在相同时间点施用化合物时所达到的结果无区别。
如本文所用的术语“抗体”是指由四条多肽链组成的免疫球蛋白分子,两条重链(H)和两条轻链(L)通过二硫键相互连接。如本文所用的术语“抗体”包括但不限于通过如本领域已知的重组技术产生的重组抗体。“抗体”可以是任何来源的,包括来自哺乳动物物种,诸如人、非人灵长类动物(例如人,诸如来自黑猩猩、狒狒、恒河猴或食蟹猴)、啮齿动物(例如来自小鼠、大鼠、兔或豚鼠)、山羊、牛或马;或鸟类,诸如鸡抗体或鱼类,诸如鲨鱼抗体。“抗体”包括任何同种型的抗体,包括人同种型IgA1、IgA2、IgD、IgG1、IgG2a、IgG2b、IgG3、IgG4、IgE和IgM及其修饰变体。本文的抗体是针对目标“抗原”。优选地,抗原是生物学上重要的多肽,并且将抗体施用给患有疾病或病症的哺乳动物可以在该哺乳动物中产生治疗益处。然而,也考虑了针对非多肽抗原的抗体。
如本文所用的术语“抗体片段”是指缺少一个或多个结构域或一个或多个氨基酸的天然存在的抗体。通常,抗体片段含有此类天然存在的抗体的整个抗原结合区或其可变区。抗体片段的实例包括缺少Fc部分的任何抗体。抗体片段的实例还包括Fab、Fab'、F(ab')2、Fv和scFv片段;双抗体(diabodies);三抗体(triabodies);四抗体(tetrabodies);微抗体(minibodies);基本上由单个、两个或三个免疫球蛋白结构域组成的抗体,诸如Domain抗体TM;单链抗体;任何上述抗体的双特异性、三特异性、四特异性或多特异性变体。
组合物
一方面,本文提供了一种组合物,其包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接。
在一个实施方案中,治疗剂是免疫治疗剂。在一个实施方案中,免疫治疗剂选自抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体或其组合。在一个实施方案中,免疫治疗剂是抗PDL1抗体。
在一个实施方案中,化学接头部分选自马来酰亚胺接头、PEG接头、PASylation和HESylation。在一个实施方案中,化学接头部分是马来酰亚胺接头。
在一个实施方案中,血小板细胞是人血小板细胞。在一个实施方案中,血小板细胞是自体血小板细胞。
在一个实施方案中,本文提供了一种组合物,其包含:
血小板细胞;
化学接头部分;和
免疫治疗剂;
其中所述免疫治疗剂通过所述化学接头部分与所述血小板细胞共价连接。
在一个实施方案中,本文提供了一种组合物,其包含:
血小板细胞;
化学接头部分;和
抗PDL1抗体;
其中所述抗PDL1抗体通过所述化学接头部分与所述血小板细胞共价连接;
在一个实施方案中,本文提供了一种组合物,其包含:
血小板细胞;
马来酰亚胺接头;和
免疫治疗剂;
其中所述免疫治疗剂通过所述化学接头部分与所述血小板细胞共价连接。
在一个实施方案中,本文提供了一种组合物,其包含:
血小板细胞;
马来酰亚胺接头;和
抗PDL1抗体;
其中所述抗PDL1抗体通过所述化学接头部分与所述血小板细胞共价连接。
公开了含有治疗有效量的一种或多种所公开的血小板组合物和药学上可接受的载体的药物组合物。适于施用本文提供的组合物的药物载体包括本领域技术人员已知的适于特定施用模式的任何此类载体。另外,组合物可以配制成药物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。
如本文所述,包含活性化合物(例如,与血小板细胞缀合的免疫治疗剂)和某类赋形剂的组合物可用于多种应用。
“赋形剂”包括适于所期望特定剂型的任何和所有溶剂、稀释剂或其他液体媒介物、分散或悬浮助剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。配制和/或生产中的一般考虑因素可以例如在Remington's PharmaceuticalSciences,第十六版,E.W.Martin(Mack Publishing Co.,Easton,Pa.,1980)和Remington:The Science and Practice of Pharmacy,第21版(Lippincott Williams&Wilkins,2005)中找到。药学上可接受的赋形剂还可包括以下的一种或多种:填充剂、粘合剂、润滑剂、助流剂、崩解剂等。
示例性赋形剂包括但不限于任何类型的任何无毒的、惰性固体、半固体或液体填充剂、稀释剂、封装材料或配制助剂。可用作赋形剂的材料的一些实例包括但不限于糖,诸如乳糖、葡萄糖和蔗糖;淀粉,诸如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,诸如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;黄蓍胶粉;麦芽;明胶;滑石;赋形剂,诸如可可脂和栓剂蜡;油,诸如花生油、棉籽油;红花油;芝麻油;橄榄油;玉米油和大豆油;二醇,诸如丙二醇;酯类,诸如油酸乙酯和月桂酸乙酯;琼脂;洗涤剂,诸如Tween80;缓冲剂,诸如氢氧化镁和氢氧化铝;海藻酸;无热原水;等渗盐水;林格氏溶液(Ringer's solution);乙醇;和磷酸盐缓冲溶液,以及其他无毒的相容性润滑剂,诸如月桂基硫酸钠和硬脂酸镁,以及着色剂、脱模剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂根据配方设计师的判断也可以存在于组合物中。如本领域技术人员所理解的,可以基于组合物可用的用途来选择赋形剂。例如,对于药物组合物,赋形剂的选择将取决于施用途径、递送的药剂、药剂递送时程等,并且可以经口服、直肠、肠胃外、脑池内、阴道内、鼻内、腹膜内、局部(如通过粉末、乳膏、软膏或滴剂)、经颊或作为口腔或鼻腔喷雾剂向人和/或动物施用。在特定的实施方案中,在肿瘤切除部位或附近注射组合物。
示例性的稀释剂包括碳酸钙、碳酸钠、磷酸钙、磷酸二钙、硫酸钙、磷酸氢钙、磷酸钠乳糖、蔗糖、纤维素、微晶纤维素、高岭土、甘露糖醇、山梨糖醇、肌醇、氯化钠、干淀粉、玉米淀粉、糖粉等及其组合。
示例性的制粒剂和/或分散剂包括马铃薯淀粉、玉米淀粉、木薯淀粉、羟基乙酸淀粉钠、粘土、海藻酸、瓜尔胶、柑桔渣、琼脂、膨润土、纤维素和木制品、天然海绵、阳离子交换树脂、碳酸钙、硅酸盐、碳酸钠、交联聚(乙烯基吡咯烷酮)(交聚维酮)、羧甲基淀粉钠(羟基乙酸淀粉钠)、羧甲基纤维素、交联羧甲基纤维素钠(交联羧甲纤维素)、甲基纤维素、预胶凝淀粉(淀粉1500)、微晶淀粉、水不溶性淀粉、羧甲基纤维素钙、硅酸镁铝(Veegum)、月桂基硫酸钠、季铵化合物等,及其组合。
示例性的表面活性剂和/或乳化剂包括天然乳化剂(例如阿拉伯胶、琼脂、海藻酸、海藻酸钠、黄蓍胶、角叉菜胶(chondrux)、胆固醇、黄原胶、果胶、明胶、蛋黄、酪蛋白、羊毛脂、胆固醇、蜡和卵磷脂)、胶质粘土(例如膨润土[硅酸铝]和Veegum[硅酸镁铝])、长链氨基酸衍生物、高分子量醇(例如硬脂醇、鲸蜡醇、油醇、单硬脂酸三醋精、乙二醇二硬脂酸酯、单硬脂酸甘油酯和丙二醇单硬脂酸酯、聚乙烯醇)、卡波姆(carbomer)(例如聚羧乙烯、聚丙烯酸、丙烯酸聚合物和羧乙烯基聚合物)、卡拉胶、纤维素衍生物(例如羧甲基纤维素钠、粉末状纤维素、羟甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素)、脱水山梨糖醇脂肪酸酯(例如聚氧乙烯脱水山梨糖醇单月桂酸酯[Tween20]、聚氧乙烯脱水山梨糖醇[Tween60]、聚氧乙烯脱水山梨糖醇单油酸酯[Tween80]、脱水山梨糖醇单棕榈酸酯[Span40]、脱水山梨糖醇单硬脂酸酯[Span60]、脱水山梨糖醇三硬脂酸酯[Span65]、单油酸甘油酯、脱水山梨糖醇单油酸酯[Span80])、聚氧乙烯酯(例如聚氧乙烯单硬脂酸酯[Myrj45]、聚氧乙烯氢化蓖麻油、聚乙氧基化蓖麻油、聚甲醛硬脂酸酯和Solutol)、蔗糖脂肪酸酯、聚乙二醇脂肪酸酯(例如Cremophor)、聚氧乙烯醚(例如聚氧乙烯月桂基醚[Brij30])、聚(乙烯基-吡咯烷酮)、二乙二醇单月桂酸酯、三乙醇胺油酸酯、油酸钠、油酸钾、油酸乙酯、油酸、月桂酸乙酯、月桂基硫酸钠、Pluronic F 68、Poloxamer 188、西曲溴铵(cetrimonium bromide)、西吡氯铵(cetylpyridinium chloride)、苯扎氯铵(benzalkonium chloride)、多库酯钠(docusate sodium)等和/或其组合。
示例性的粘合剂包括淀粉(例如玉米淀粉和淀粉糊)、明胶、糖(例如蔗糖、葡萄糖、右旋糖、糊精、糖蜜、乳糖、乳糖醇、甘露糖醇等)、天然和合成树胶(例如阿拉伯树胶、海藻酸钠、爱尔兰藓(Irish moss)提取物、潘瓦尔(panwar)胶、印度树胶(ghatti gum)、芒麻胶(mucilage of isapol husks)、羧甲基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、微晶纤维素、醋酸纤维素、聚(乙烯基-吡咯烷酮)、硅酸镁铝(Veegum)和落叶松阿拉伯半乳聚糖)、海藻酸盐、聚环氧乙烷、聚乙二醇、无机钙盐、硅酸、聚甲基丙烯酸酯、蜡、水、醇等,和/或其组合。
示例性的防腐剂包括抗氧化剂、螯合剂、抗微生物防腐剂、抗真菌防腐剂、醇防腐剂、酸性防腐剂和其他防腐剂。
示例性的抗氧化剂包括α生育酚、抗坏血酸、抗坏血酸棕榈酸酯、丁羟茴香醚、丁羟甲苯、单硫代甘油、焦亚硫酸钾、丙酸、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、焦亚硫酸钠和亚硫酸钠。
示例性的螯合剂包括乙二胺四乙酸(EDTA)及其盐和水合物(例如乙二胺四乙酸钠、乙二胺四乙酸二钠、乙二胺四乙酸三钠、乙二胺四乙酸二钠钙、乙二胺四乙酸二钾等)、柠檬酸及其盐和水合物(例如柠檬酸一水合物)、富马酸及其盐和水合物、苹果酸及其盐和水合物、磷酸及其盐和水合物以及酒石酸及其盐和水合物。示例性的抗微生物防腐剂包括苯扎氯铵、苄索氯铵、苯甲醇、溴硝丙二醇、西曲溴铵(cetrimide)、西吡氯铵、氯己定、氯丁醇、氯甲酚、氯二甲酚、甲酚、乙醇、甘油、海克替啶(hexetidine)、咪脲、苯酚、苯氧乙醇、苯乙醇、硝酸苯汞、丙二醇和硫柳汞(thimerosal)。
示例性的抗真菌防腐剂包括对羟苯甲酸丁酯、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、苯甲酸、羟基苯甲酸、苯甲酸钾、山梨酸钾、苯甲酸钠、丙酸钠和山梨酸。
示例性的醇防腐剂包括乙醇、聚乙二醇、苯酚、酚类化合物、双酚、氯丁醇、羟基苯甲酸酯和苯乙醇。
示例性的酸性防腐剂包括维生素Α、维生素C、维生素Ε、β-胡萝卜素、柠檬酸、乙酸、脱氢乙酸、抗坏血酸、山梨酸和植酸。
其他防腐剂包括生育酚、生育酚乙酸酯、甲磺酸去铁胺(deteroxime mesylate)、西曲溴铵、丁羟茴香醚(BHA)、丁羟甲苯(BHT)、乙二胺、月桂基硫酸钠(SLS)、月桂基醚硫酸钠(SLES)、亚硫酸氢钠、焦亚硫酸钠、亚硫酸钾、焦亚硫酸钾、Glydant Plus、Phenonip、对羟基苯甲酸甲酯、Germall 115、Germaben II、Neolone、Kathon和Euxyl。在某些实施方案中,防腐剂是抗氧化剂。在其他实施方案中,防腐剂是螯合剂。
示例性的缓冲剂包括柠檬酸盐缓冲溶液、乙酸盐缓冲溶液、磷酸盐缓冲溶液、氯化铵、碳酸钙、氯化钙、柠檬酸钙、葡乳醛酸钙、葡庚糖酸钙、葡糖酸钙、D-葡糖酸、甘油磷酸钙、乳酸钙、丙酸、戊酮酸钙、戊酸、磷酸氢钙、磷酸、磷酸钙、磷酸氢氧化钙、乙酸钾、氯化钾、葡糖酸钾、钾混合物、磷酸氢二钾、磷酸二氢钾、磷酸钾混合物、乙酸钠、碳酸氢钠、氯化钠、柠檬酸钠、乳酸钠、磷酸氢二钠、磷酸二氢钠、磷酸钠混合物、氨丁三醇(tromethamine)、氢氧化镁、氢氧化铝、海藻酸、无热原水、等渗盐水、林格氏溶液、乙醇及其组合。
示例性的润滑剂包括硬脂酸镁、硬脂酸钙、硬脂酸、二氧化硅、滑石、麦芽、山嵛酸甘油酯、氢化植物油、聚乙二醇、苯甲酸钠、乙酸钠、氯化钠、亮氨酸、月桂基硫酸镁、月桂基硫酸钠等及其组合。
示例性的天然油包括扁桃仁油、杏仁油、鳄梨油、巴巴苏油、香柠檬油、黑加仑籽油、琉璃苣油、杜松油、春黄菊油、芥花籽油、葛缕子油、巴西棕榈油、蓖麻油、肉桂油、可可脂、椰子油、鱼肝油、咖啡油、玉米油、棉籽油、鸸鹋油、桉树油、月见草油、鱼油、亚麻籽油、香叶醇、葫芦油、葡萄籽油、榛子油、海索草油、豆蔻酸异丙酯、荷荷巴油、夏威夷核油、杂薰衣草油、熏衣草油、柠檬油、山苍子油、澳洲坚果油、锦葵油、芒果籽油、白芒花籽油、貂油、肉豆蔻油、橄榄油、橙油、罗非鱼油、棕榈油、棕榈仁油、桃仁油、花生油、罂粟籽油、南瓜籽油、菜籽油、米糠油、迷迭香油、红花油、檀香油、茶花油、香薄荷油、沙棘油、芝麻油、牛油脂、硅油、大豆油、向日葵油、茶树油、蓟油、椿(tsubaki)油、香根油、胡桃油和小麦胚芽油。示例性的合成油包括但不限于硬脂酸丁酯、辛酸甘油三酯、癸酸甘油三酯、环甲硅油、癸二酸二乙酯、二甲硅油360、肉豆蔻酸异丙酯、矿物油、辛基十二烷醇、油醇、硅油及其组合。
另外,该组合物还可包含聚合物。本文考虑的示例性聚合物包括但不限于纤维素聚合物和共聚物,例如纤维素醚诸如甲基纤维素(MC)、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、甲基羟乙基纤维素(MHEC)、甲基羟丙基纤维素(MHPC)、羧甲基纤维素(CMC)及其各种盐(包括例如钠盐)、羟乙基羧甲基纤维素(HECMC)及其各种盐、羧甲基羟乙基纤维素(CMHEC)及其各种盐;其他多糖和多糖衍生物(诸如淀粉、葡聚糖、葡聚糖衍生物、壳聚糖)和海藻酸及其各种盐、角叉菜胶、各种树胶(包括黄原胶、瓜尔胶、阿拉伯树胶、刺梧桐树胶、印度树胶、魔芋和黄蓍胶);糖胺聚糖和蛋白多糖(诸如透明质酸及其盐);蛋白质(诸如明胶、胶原蛋白、白蛋白和纤维蛋白);其他聚合物,例如,多羟基酸诸如聚丙交酯、聚乙交酯、聚(丙交酯-共-乙交酯)和聚(.ε.-己内酯-共-乙交酯)-、羧乙烯基聚合物及其盐(例如卡波姆)、聚乙烯吡咯烷酮(PVP)、聚丙烯酸及其盐、聚丙烯酰胺、聚丙烯酸/丙烯酰胺共聚物、聚环氧烷诸如聚环氧乙烷、聚环氧丙烷、聚(环氧乙烷-环氧丙烷)和Pluronic聚合物、聚氧乙烯(聚乙二醇)、聚酐、聚乙烯醇、聚乙烯胺和聚吡啶、聚乙二醇(PEG)聚合物诸如聚乙二醇化脂质(例如PEG-硬脂酸酯、1,2-二硬脂酰基-sn-甘油基-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)-1000]、1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)-2000]和1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)-5000]),其共聚物和盐。
另外,该组合物还可包含乳化剂。示例性的乳化剂包括但不限于聚乙二醇(PEG)、聚丙二醇、聚乙烯醇、聚-N-乙烯吡咯烷酮及其共聚物、泊洛沙姆非离子表面活性剂、中性水溶性多糖(例如,葡聚糖、Ficoll、纤维素)、非阳离子聚(甲基)丙烯酸酯、非阳离子聚丙烯酸酯(诸如聚(甲基)丙烯酸)及其酯酰胺和羟烷基酰胺、天然乳化剂(例如阿拉伯胶、琼脂、海藻酸、海藻酸钠、黄蓍胶、角叉菜胶、胆固醇、黄原胶、果胶、明胶、蛋黄、酪蛋白、羊毛脂、胆固醇、蜡和卵磷脂)、胶质粘土(例如膨润土[硅酸铝]和Veegum[硅酸镁铝])、长链氨基酸衍生物、高分子量醇(例如硬脂醇、鲸蜡醇、油醇、单硬脂酸三醋精、乙二醇二硬脂酸酯、单硬脂酸甘油酯和丙二醇单硬脂酸酯、聚乙烯醇)、卡波姆(例如聚羧乙烯、聚丙烯酸、丙烯酸聚合物和羧乙烯基聚合物)、卡拉胶、纤维素衍生物(例如羧甲基纤维素钠、粉末状纤维素、羟甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素)、脱水山梨糖醇脂肪酸酯(例如聚氧乙烯脱水山梨糖醇单月桂酸酯[Tween20]、聚氧乙烯脱水山梨糖醇[Tween60]、聚氧乙烯脱水山梨糖醇单油酸酯[Tween80]、脱水山梨糖醇单棕榈酸酯[Span40]、脱水山梨糖醇单硬脂酸酯[Span60]、脱水山梨糖醇三硬脂酸酯[Span65]、单油酸甘油酯、脱水山梨糖醇单油酸酯[Span80])、聚氧乙烯酯(例如聚氧乙烯单硬脂酸酯[Myrj45]、聚氧乙烯氢化蓖麻油、聚乙氧基化蓖麻油、聚甲醛硬脂酸酯和Solutol)、蔗糖脂肪酸酯、聚乙二醇脂肪酸酯(例如Cremophor)、聚氧乙烯醚(例如聚氧乙烯月桂基醚[Brij30])、聚(乙烯基-吡咯烷酮)、二乙二醇单月桂酸酯、三乙醇胺油酸酯、油酸钠、油酸钾、油酸乙酯、油酸、月桂酸乙酯、月桂基硫酸钠、Pluronic F 68、Poloxamer 188、西曲溴铵、西吡氯铵、苯扎氯铵、多库酯钠等和/或其组合。在某些实施方案中,乳化剂是胆固醇。
液体组合物包括乳剂、微乳剂、溶液、混悬液、糖浆剂和酏剂。除活性化合物(例如,与血小板细胞缀合的免疫治疗剂)(与血小板细胞缀合的免疫治疗剂)外,所述液体组合物可含有本领域常用的惰性稀释剂,例如如水或其他溶剂、增溶剂和乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(具体而言,棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯及其混合物。除了惰性稀释剂外,口服组合物还可包括佐剂,诸如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和芳香剂。
可注射组合物,例如,可注射水性或油性混悬液可根据已知技术,使用合适的分散剂或湿润剂和悬浮剂进行配制。无菌可注射制剂可为无毒的胃肠外可接受的稀释剂或溶剂中的可注射溶液、混悬液或乳液,例如,1,3-丁二醇溶液。可以使用的用于药物或美容组合物可接受的媒介物和溶剂中有水、林格氏溶液、U.S.P.和等渗氯化钠溶液。另外,通常采用无菌不挥发性油作为溶剂或悬浮介质。可以使用任何温和的不挥发性油,包括合成单甘油酯或二甘油酯。另外,脂肪酸诸如油酸用于制备注射剂。在某些实施方案中,将颗粒悬浮在包含1%(w/v)羧甲基纤维素钠和0.1%(v/v)Tween80的载液中。可注射组合物可通过以下进行灭菌,例如,通过细菌截留过滤器(bacterial-retaining filter)过滤或通过掺入无菌固体组合物形式的灭菌剂,该灭菌剂可在使用前溶解或分散于无菌水或其他无菌可注射介质中。
在一些实施方案中,组合物或治疗剂(例如,与本文公开的组合物组合给予的另外的治疗剂)可以以固体组合物施用。固体组合物包括胶囊、片剂、丸剂、粉末和颗粒。在此类固体组合物中,将颗粒与至少一种赋形剂和/或以下物质混合:a)填充剂或增量剂,诸如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;b)粘合剂,诸如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;c)保湿剂,诸如甘油;d)崩解剂,诸如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶液缓凝剂,诸如石蜡;f)吸收促进剂,诸如季铵化合物;g)润湿剂,诸如鲸蜡醇和单硬脂酸甘油酯;h)吸收剂,诸如高岭土和膨润土;和i)润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物。在胶囊、片剂和丸剂的情况下,该剂型还可包含缓冲剂。相似类型的固体组合物也可用作软填充和硬填充的明胶胶囊中的填充剂,其使用赋形剂诸如乳糖(lactose)或乳糖(milk sugar)以及高分子量聚乙二醇等。
片剂、胶囊、丸剂和颗粒可以使用包衣和壳诸如肠溶衣和制药领域熟知的其他包衣来制备。它们可任选地含有乳浊剂并且也可具有使其仅在或优先在肠道的某一部分,任选地以延迟的方式释放活性成分的组合物。可以使用的包埋组合物的实例包括聚合物质和蜡。
相似类型的固体组合物也可用作软填充和硬填充的明胶胶囊中的填充剂,其使用赋形剂诸如乳糖(lactose)或乳糖(milk sugar)以及高分子量聚乙二醇等。
供局部或透皮施用的组合物包括软膏剂、糊剂、霜剂、洗剂、凝胶剂、粉末、溶液、喷雾剂、吸入剂或贴剂。将活性化合物(例如,与血小板细胞缀合的免疫治疗剂)与赋形剂和任何需要的防腐剂或可能需要的缓冲剂混合。
除活性化合物(例如,与血小板细胞缀合的免疫治疗剂)之外,软膏剂、糊剂、霜剂和凝胶剂可以含有赋形剂,诸如动植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石和氧化锌,或其混合物。
除了活性化合物/组合物之外,粉剂和喷雾剂可以含有赋形剂,诸如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。喷雾剂可另外含有常规推进剂,诸如氯氟烃。
透皮贴剂具有向身体提供化合物的受控递送的附加优点。此类剂型可以通过将纳米颗粒溶解或分配在适当的介质中来制备。吸收增强剂也可用于增加化合物通过皮肤的通量。速率可以通过提供速率控制膜或通过将颗粒分散在聚合物基质或凝胶中来控制。
在一些实施方案中,治疗剂可以封装在纳米颗粒中。在一个实施方案中,本文提供了一种组合物,其包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂封装在纳米颗粒内。
在一些实施方案中,纳米颗粒通过化学接头部分共价连接。在一些实施方案中,化学接头部分是任选的,并且纳米颗粒不与血小板细胞共价连接。
纳米颗粒可以由一种或多种聚合物制成。在一些实例中,聚合物包括多元羧酸或其盐、羧酸酐(例如马来酸酐)与其他单体(例如,(甲基)丙烯酸甲酯、丙烯酸等)的共聚物,亲水性乙烯基聚合物,诸如聚乙酸乙烯酯、聚乙烯醇、聚乙烯吡咯烷酮(PVP)、聚环氧乙烷(PEO)、聚(乙烯基吡咯烷酮-共-乙酸乙烯酯)、聚甲基丙烯酸酯、聚氧乙烯烷基醚、聚氧乙烯蓖麻油、聚己内酰胺、聚乳酸、聚乙醇酸、聚(乳酸-乙醇酸)、聚(乳酸共-乙醇酸)(PLGA),纤维素衍生物,诸如羟甲基纤维素、羟丙基纤维素等。在一个实例中,聚合物为50:50 PLGA共聚物。在其他实例中,聚合物包括天然聚合物,诸如壳聚糖、胶原、海藻酸盐、明胶、透明质酸及其无毒金属盐。在一些实施方案中,聚合物为水凝胶,例如海藻酸盐水凝胶。亲水性聚合物和其他媒介物可以单独使用或组合使用,并且可以通过部分结晶、离子键合、交联等赋予媒介物增强的结构完整性。
将药物或治疗剂封装入颗粒的方法是本领域已知的。常用封装技术包括但不限于喷雾干燥、界面聚合、热熔封装、相分离封装(乳液自发微封装、溶剂蒸发微封装和溶剂去除微封装)、凝聚、低温微球形成和相转化纳米封装(PIN)。下面介绍这些方法的简要概述。
在某些实施方案中,掺入本文讨论的组合物中的纳米颗粒是多壁纳米颗粒。可用于本文公开的组合物的多壁纳米颗粒可以例如使用“序贯相转化纳米封装”(sPIN)制备。
1.喷雾干燥
使用喷雾干燥技术形成微球/纳米球的方法在Mathiowitz等人的美国专利第6,620,617号中有描述。在该方法中,将聚合物溶于有机溶剂诸如二氯甲烷或水中。将要掺入颗粒中的已知量的一种或多种活性剂悬浮(在不溶性活性剂的情况下)或共溶(在可溶性活性剂的情况下)于聚合物溶液中。将溶液或分散体泵送通过受压缩气体流驱动的微粉化喷嘴,并且将所得气溶胶悬浮在加热的空气旋流器中,使溶剂从微滴中蒸发,形成颗粒。使用该方法可以获得介于0.1-10微米范围的微球/纳米球。
2.界面聚合
界面聚合也可用于封装一种或多种活性剂。使用该方法,使单体和活性剂溶解在溶剂中。将第二单体溶解在与第一溶剂不混溶的第二溶剂(通常为水性)中。通过拌入第二溶液中使第一溶液悬浮而形成乳液。一旦乳液稳定,就将引发剂添加到水相中,在每滴乳液的界面处引起界面聚合。
3.热熔微封装
可以使用如Mathiowitz等人,Reactive Polymers,6:275(1987)所描述的热熔微封装法由诸如聚酯和聚酸酐的聚合物形成微球。在该方法中,优选使用分子量为3-75,000道尔顿的聚合物。在该方法中,首先使聚合物熔化,然后与一种或多种待掺入的活性剂的固体颗粒混合,所述固体颗粒已筛至小于50微米。将混合物悬浮在不混溶的溶剂(如硅油)中,并在连续搅拌下,加热至5℃,此高于聚合物熔点。一旦乳液稳定,就将其冷却直至聚合物颗粒固化。通过用石油醚倾析洗涤所得微球,得到自由流动的粉末。
4.相分离微封装
在相分离微封装技术中,任选地在一种或多种待封装的活性剂存在下搅拌聚合物溶液。在通过搅拌继续使材料均匀悬浮的同时,将聚合物的非溶剂缓慢添加到溶液中以降低聚合物的溶解度。根据聚合物在溶剂和非溶剂中的溶解度,聚合物沉淀或相分离成富聚合物相和贫聚合物相。在适当的条件下,富聚合物相中的聚合物将迁移到与连续相的界面,将活性剂封装在具有聚合物外壳的液滴中。
in.自发乳液微封装
自发乳化涉及通过改变温度,蒸发溶剂或添加化学交联剂来固化上面形成的乳化液体聚合物液滴。封装材料的物理和化学性质以及任选掺入新生颗粒中的一种或多种活性剂的性质决定了合适的封装方法。诸如疏水性、分子量、化学稳定性和热稳定性等因素会影响封装。
ii.溶剂蒸发微封装
使用溶剂蒸发技术形成微球的方法在E.Mathiowitz等人,J.ScanningMicroscopy,4:329(1990);L.R.Beck等人,Fertil.Steril.,31:545(1979);L.R.Beck等人Am J Obstet Gynecol 135(3)(1979);S.Benita等人,J.Pharm.Sci.,73:1721(1984);和Morishita等人的美国专利第3,960,757号中有描述。将聚合物溶于挥发性有机溶剂诸如二氯甲烷中。任选地将一种或多种待掺入的活性剂添加到溶液中,并将混合物悬浮在含有表面活性剂诸如聚(乙烯醇)的水溶液中。搅拌所得乳液直至大部分有机溶剂蒸发,留下固体微球/纳米球。该方法可用于相对稳定的聚合物,诸如聚酯和聚苯乙烯。然而,由于存在水,不稳定的聚合物,诸如聚酸酐,可能在制造过程中降解。对于这些聚合物,一些在完全无水的有机溶剂中进行的下列方法更有用。
iii.溶剂去除微封装
溶剂去除微封装技术主要被设计用于聚酸酐,并且在例如Brown UniversityResearch Foundation的WO93/21906中有描述。在该方法中,将待掺入的物质分散或溶解在所选聚合物于挥发性有机溶剂诸如亚甲基氯中的溶液中。通过拌入有机油诸如硅油中,使该混合物悬浮形成乳液。通过该程序可以获得介于1-300微米范围的微球。可以掺入微球中的物质包括药品、杀虫剂、营养素、显像剂和金属化合物。
5.凝聚
使用凝聚技术的各种物质的封装方法是本领域已知的,例如GB-B-929 406;GB-B-929 40 1;和美国专利第3,266,987、4,794,000和4,460,563号。凝聚涉及将大分子溶液分离成两个不混溶的液相。一相是致密凝聚层相,其含有高浓度的聚合物封装材料(和任选一种或多种活性剂),而第二相含有低浓度的聚合物。在致密凝聚层相中,聚合物封装材料形成纳米级或微米级液滴。可以通过温度变化,添加非溶剂或添加微盐(简单凝聚),或通过添加另一种聚合物从而形成聚合物间复合物(复合凝聚)来诱导凝聚。
6.微球的低温铸造
用于控制释放微球的极低温铸造的方法在Gombotz等人的美国专利第5,019,400号中有描述。在该方法中,将聚合物任选地溶解在含有一种或多种溶解或分散的活性剂的溶剂中。然后在低于使聚合物液滴冻结的聚合物-物质溶液的凝固点的温度下,将混合物雾化到含有液体非溶剂的容器中。当聚合物的液滴和非溶剂升温时,液滴中的溶剂解冻并被萃取到非溶剂中,引起微球硬化。
7.相转化纳米封装(PIN)
还可以使用相转化纳米封装(PIN)方法形成纳米颗粒,其中将聚合物溶解在“良好”溶剂中,将待掺入物质(诸如药物)的细小颗粒混合或溶解在聚合物溶液中,并将混合物倒入聚合物的强非溶剂中,以在有利条件下自发地产生聚合物微球,其中聚合物被颗粒包被或颗粒分散在聚合物中。参见,例如,Mathiowitz等人的美国专利第6,143,211号。该方法可用于生产各种尺寸(包括例如约100纳米至约10微米)的纳米颗粒和微粒的单分散群。
有利地,在沉淀之前无需形成乳液。该方法可用于由热塑性聚合物形成微球。
8.序贯相转化纳米封装(sPIN)
多壁纳米颗粒也可以通过本文称为“序贯相转化纳米封装”(sPIN)的方法形成。sPIN特别适用于形成纳米颗粒的单分散群,避免了为获得纳米颗粒的单分散群而对额外分离步骤的需要。
在sPIN中,将核聚合物溶解在第一溶剂中。将活性剂溶解或分散在核聚合物溶剂中。核聚合物、核聚合物溶剂和待封装的剂形成具有连续相的混合物,其中核聚合物溶剂为连续相。将壳聚合物溶解在壳聚合物溶剂中,壳聚合物溶剂是核聚合物的非溶剂。将核聚合物和壳聚合物的溶液混合在一起。由于壳聚合物溶剂的存在而引起的核聚合物在其浊点的溶解度降低导致核聚合物优先相分离和任选地封装所述剂。将核聚合物和壳聚合物的非溶剂添加到这种不稳定的混合物中时,壳聚合物在完成相转化时吞没核聚合物以形成双壁纳米颗粒。
sPIN提供了制备多壁颗粒(诸如双壁纳米颗粒)的一步法,这几乎是瞬时的,并且不需要乳化溶剂。在Cho等人的美国公开号2012-0009267中公开了形成多壁颗粒的方法。其公开内容通过引用并入本文。
颗粒可以是树状大分子(dendrimer)颗粒。树状大分子是通过将支化分子的壳或层连续添加到中心核中而生长的三维聚合物。树状大分子具有优于线性聚合物的若干优点,因为它们具有可控的结构,单分子量而不是分子量分布,以及大量可控的表面官能度,并且一旦达到一定大小就倾向于呈球状构象。它们通过使高度支化的单体一起反应以制备单分散、树状和/或代际结构的聚合物结构来制备。单个树状大分子由中心核分子组成,有树状楔形物连接到每个功能位点。根据制备过程中使用的组装单体,树状表层可具有置于其上的各种官能团。通常,树状大分子官能团决定了单个树状大分子类型的性质。由于其设计,树状大分子核是宽大的,并且通过改变核、壳,尤其是表层的化学性质,可以精细地调整它们的物理性质。可调性质包括溶解度、毒性、免疫原性和生物附着能力。
聚酰胺-胺、聚丙烯亚胺、聚芳醚和聚乙烯亚胺是已经研究用于生物制药应用的树状大分子的实例。聚酰胺-胺树状大分子基于乙二胺核和酰氨基胺重复分支结构。它们可以以各种明确定义的分子量合成。其大小和表面官能度(伯胺)由单体单元的受控重复添加的数量限定,产生不同的半代或全代。它们是水溶性的并且据报道它们是唯一一类单分散的树状大分子。此外,它们显示出限于分子表面的高电荷密度。
已通过将药物包埋在树状大分子内的空腔中,或者通过将药物分子共价连接到表面上,将树状大分子用作治疗性化合物的载体。这在Svenson,S.,Eur J Pharm Biopharm(2009)71:445-462和Cheng,Y.,J.Pharm.Sci.(2007)97:123-143中进行了评论。包埋在树状大分子空腔内限于小分子,并且共价连接方法迄今仅限于其中小药物从树状大分子表面水解或酶促裂解的系统。
方法
一方面,本文公开了一种预防癌症转移或复发的方法,其包括:
向有需要的受试者施用治疗有效量的组合物,所述组合物包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接。
在一个实施方案中,治疗剂是免疫治疗剂。在一个实施方案中,免疫治疗剂选自抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体或其组合。在一个实施方案中,免疫治疗剂是抗PDL1抗体。
在一个实施方案中,化学接头部分选自马来酰亚胺接头、PEG接头、PASylation和HESylation。在一个实施方案中,化学接头部分是马来酰亚胺接头。
在一个实施方案中,血小板细胞是人血小板细胞。在一个实施方案中,血小板细胞是自体血小板细胞。
在一个实施方案中,癌症是实体瘤。在一个实施方案中,癌症是黑素瘤。在一个实施方案中,癌症是乳腺癌。在一个实施方案中,所述组合物与另外的治疗剂组合施用。在一个实施方案中,另外的治疗剂是抗肿瘤剂。
一方面,本文公开了一种治疗或预防癌症的方法,其包括:
向有需要的受试者施用治疗有效量的组合物,所述组合物包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接。
另一方面,本文公开了一种用于靶向递送治疗剂的方法,其包括:
向受试者施用组合物,所述组合物包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接;
其中所述组合物通过所述血小板细胞的活化而靶向伤口或手术切除部位。
在一个实施方案中,所述方法提供了在所述血小板细胞活化后在伤口或切除部位处在源自血小板的微粒中进一步释放的治疗剂。
在一个实施方案中,治疗剂是免疫治疗剂。在一个实施方案中,免疫治疗剂选自抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体或其组合。在一个实施方案中,免疫治疗剂是抗PDL1抗体。
在一个实施方案中,化学接头部分选自马来酰亚胺接头、PEG接头、PASylation和HESylation。在一个实施方案中,化学接头部分是马来酰亚胺接头。
在一个实施方案中,血小板细胞是人血小板细胞。在一个实施方案中,血小板细胞是自体血小板细胞。
癌症和实体瘤
在一些实施方案中,本文所述的血小板组合物和方法可用于治疗或预防癌症转移或复发。在一些实施方案中,本文所述的血小板组合物和方法可用于预防切除的实体瘤的复发。在一些实施方案中,本文所述的组合物和方法可用于预防切除的实体瘤的转移。在另一个实施方案中,要预防的复发癌症是黑素瘤。在另一个实施方案中,要预防的复发癌症是乳腺癌。在再一个实施方案中,要预防的复发癌症是前列腺癌。
一方面,本文所述的方法用于预防实体瘤复发或转移,例如,黑素瘤、肺癌(包括肺腺癌、基底细胞癌、鳞状细胞癌、大细胞癌、细支气管肺泡癌、支气管癌、非小细胞癌、小细胞癌、间皮瘤);乳腺癌(包括导管癌、小叶癌、炎性乳腺癌、透明细胞癌、粘液癌、浆膜腔乳腺癌);结直肠癌(结肠癌、直肠癌、结直肠腺癌);肛门癌;胰腺癌(包括胰腺腺癌、胰岛细胞癌、神经内分泌瘤);前列腺癌;前列腺腺癌;卵巢癌(卵巢上皮癌或表面上皮间质瘤,包括浆液性肿瘤、子宫内膜样肿瘤和粘液性囊腺癌、性索-间质肿瘤);肝和胆管癌(包括肝细胞癌、胆管癌、血管瘤);食管癌(包括食管腺癌和鳞状细胞癌);口腔和口咽鳞状细胞癌;唾液腺腺样囊性癌;膀胱癌(bladder cancer);膀胱癌(bladder carcinoma);子宫癌(包括子宫内膜腺癌、眼癌、子宫乳头状浆液性癌、子宫透明细胞癌、子宫肉瘤、平滑肌肉瘤、苗勒管混合瘤);胶质瘤、胶质母细胞瘤、成神经管细胞瘤和其他脑肿瘤;肾癌(包括肾细胞癌,透明细胞癌,维尔姆氏瘤(Wilm's tumor));头颈癌(包括鳞状细胞癌);胃癌(胃癌、胃腺癌、胃肠道间质瘤);睾丸癌;生殖细胞肿瘤;神经内分泌肿瘤;宫颈癌;胃肠道、乳房和其他器官的类癌;印戒细胞癌;间质细胞瘤包括肉瘤、纤维肉瘤、血管瘤、血管瘤病、血管外皮细胞瘤、假血管瘤性间质增生、肌纤维母细胞瘤、纤维瘤病、炎性肌纤维母细胞瘤、脂肪瘤、血管脂肪瘤、颗粒细胞瘤、神经纤维瘤、神经鞘瘤、血管肉瘤、脂肪肉瘤、横纹肌肉瘤、骨肉瘤、平滑肌瘤、平滑肌肉瘤、皮肤肿瘤(包括黑素瘤)、宫颈癌、视网膜母细胞瘤、头颈癌、胰腺癌、脑癌、甲状腺癌、睾丸癌、肾癌、膀胱癌、软组织癌、肾上腺癌、尿道癌、阴茎癌、粘液肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、恶性纤维组织细胞瘤、淋巴管肉瘤、间皮瘤,鳞状细胞癌;表皮样癌、恶性皮肤附件肿瘤、腺癌、肝癌、肝细胞癌、肾细胞癌、肾上腺样瘤、胆管癌、移行细胞癌、绒毛膜癌、精原细胞瘤、胚胎细胞癌、退行性神经胶质瘤;多形性胶质母细胞瘤、神经母细胞瘤、髓母细胞瘤、恶性脑膜瘤、恶性神经鞘瘤、神经纤维肉瘤、甲状旁腺癌、甲状腺髓样癌、支气管类癌、嗜铬细胞瘤、胰岛细胞癌、恶性类癌,恶性副神经节瘤、黑素瘤、梅克尔细胞肿瘤(Merkel cellneoplasm)、叶状囊肉瘤、唾液腺癌、胸腺癌和阴道癌等。
在一些实施方案中,本文所述的血小板组合物和方法可用于治疗或预防癌症。在一些情况下,癌症是循环癌细胞(循环肿瘤细胞)。在一些情况下,癌症是转移性癌细胞。
在一些实施方案中,本文所述的血小板组合物可以消除或减少体内的循环肿瘤细胞(CTC)。在一些实施方案中,本文所述的血小板组合物可以显著抑制肿瘤转移。在一些实施方案中,本文所述的血小板组合物可以显著抑制癌症的复发(例如,在切除实体瘤后)。
血小板
血小板是从巨核细胞释放的无核细胞片段,并且因其在止血方面的功能而最为人熟知。循环血小板的平均寿命为8至9天,这可以大大改善静脉注射的治疗剂的药代动力学。而且,输注的血小板可以迁移到手术伤口部位,在该部位残余肿瘤可以在术后存活。另一方面,有证据表明血小板具有识别循环肿瘤细胞(CTC)并与之相互作用的能力,循环肿瘤细胞已经从原发肿瘤流入脉管系统并导致转移。除了它们的固有的伤口和CTC向性特性外,还可以将血小板视为引发和改善许多炎症病症的免疫“细胞”。
在一些情况下,血小板组合物是自体的,即由获自受试者的血小板产生。在一些情况下,血小板组合物是异源的,即由获自除治疗的受试者以外的来源的血小板产生。
在一些实施方案中,整个血小板细胞可以与治疗剂缀合。在一些实施方案中,治疗剂可以在源自血小板的微粒中递送。源自血小板的微粒(PMPS)源自血小板活化后的质膜;活化血小板释放携带粘附分子和趋化因子的PMP,促进在PMP沉积位点的单核细胞截留。这些PMP在血小板活化后(例如,通过凝血酶)从血小板上释放。
治疗剂
在一个实施方案中,通过接头与血小板缀合的治疗剂可选自由以下组成的组:肽、多肽、蛋白质、抗体、抗体片段、核酸或治疗性药物(例如,小分子)。
在一个实施方案中,治疗剂是免疫治疗剂。在一个实施方案中,治疗剂是抗体或抗体片段。在一些实施方案中,治疗剂是抗肿瘤剂。在一些实施方案中,血小板组合物可以靶向递送治疗剂以治疗血管疾病。
免疫治疗剂
在一个实施方案中,免疫治疗剂选自抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体或其组合。
在一个实施方案中,免疫治疗剂是抗PDL1抗体。在一个实施方案中,抗PDL1抗体选自阿特珠单抗、德瓦鲁单抗(durvalumab)或阿维鲁单抗(avelumab)。在一个实施方案中,抗PDL1抗体是阿特珠单抗(MPDL3280A)(Roche)。在一个实施方案中,抗PDL1抗体是德瓦鲁单抗(MEDI4736)。在一个实施方案中,抗PDL1抗体是阿维鲁单抗(MS0010718C)。
在一个实施方案中,免疫治疗剂是程序性死亡蛋白1(PD-1)抑制剂或程序性死亡蛋白配体1或2抑制剂。PD-1抑制剂是本领域已知的,包括例如纳武单抗(nivolumab)(BMS)、派姆单抗(pembrolizumab)(Merck)、匹利珠单抗(pidilizumab)(CureTech/Teva)、AMP-244(Amplimmune/GSK)、BMS-936559(BMS)和MEDI4736(Roche/Genentech)。
在一个实施方案中,免疫治疗剂是抗PD1抗体。在一个实施方案中,抗PD1抗体是纳武单抗。在一个实施方案中,抗PD1抗体是派姆单抗。
在一个实施方案中,免疫治疗剂是抗CTLA4抗体。在一个实施方案中,抗CTLA4抗体是伊匹单抗(ipilimumab)。
在一些实施方案中,免疫治疗剂与另外的治疗剂组合施用。在一些实施方案中,免疫治疗剂与抗肿瘤剂组合施用。
抗肿瘤剂
在一些实施方案中,治疗剂是抗肿瘤剂。例如,抗肿瘤剂可以选自由以下组成的组:醋酸阿比特龙(Abiraterone Acetate)、Abitrexate(甲氨蝶呤)、Abraxane(紫杉醇白蛋白稳定化纳米颗粒制剂)、ABVD、ABVE、ABVE-PC、AC、AC-T、Adcetris(本妥昔单抗瑞他汀(Brentuximab Vedotin))、ADE、Ado-曲妥珠单抗美坦新(Ado-Trastuzumab Emtansine)、阿霉素(盐酸多柔比星)、Adrucil(氟尿嘧啶(Fluorouracil))、马来酸阿法替尼(AfatinibDimaleate)、Afinitor(依维莫司(Everolimus))、Akynzeo(奈妥吡坦(Netupitant)和盐酸帕洛诺司琼(Palonosetron Hydrochloride))、Aldara(咪喹莫特(Imiquimod))、阿地白介素(Aldesleukin)、阿仑单抗(Alemtuzumab)、Alimta(培美曲塞二钠)、Aloxi(盐酸帕洛诺司琼)、Ambochlorin(苯丁酸氮芥(Chlorambucil))、Amboclorin(苯丁酸氮芥)、氨基乙酰丙酸(Aminolevulinic Acid)、阿那曲唑(Anastrozole)、阿瑞匹坦(Aprepitant)、Aredia(帕米膦酸二钠)、Arimidex(阿那曲唑)、Aromasin(依西美坦(Exemestane))、Arranon(奈拉滨(Nelarabine))、三氧化二砷、Arzerra(奥法木单抗(Ofatumumab))、天冬酰胺酶菊欧文氏菌(Asparaginase Erwinia chrysanthemi)、Avastin(贝伐单抗(Bevacizumab))、阿西替尼(Axitinib)、阿扎胞苷、BEACOPP、Becenum(卡莫司汀(Carmustine))、Beleodaq(贝利司他(Belinostat))、贝利司他、盐酸苯达莫司汀(Bendamustine Hydrochloride)、BEP、贝伐单抗、蓓萨罗丁(Bexarotene)、Bexxar(托西莫单抗(Tositumomab)和碘I 131托西莫单抗)、比卡鲁胺(Bicalutamide)、BiCNU(卡莫司汀)、博来霉素(Bleomycin)、博纳吐单抗(Blinatumomab)、Blincyto(博纳吐单抗)、硼替佐米(Bortezomib)、Bosulif(博舒替尼(Bosutinib))、博舒替尼、本妥昔单抗瑞他汀、白消安(busulfan)、Busulfex(白消安)、卡巴他赛(Cabazitaxel)、苹果酸卡博替尼(Cabozantinib-S-Malate)、CAF、Campath(阿仑单抗)、Camptosar(盐酸伊立替康(Irinotecan Hydrochloride))、卡培他滨(Capecitabine)、CAPOX、卡铂(Carboplatin)、卡铂-紫杉醇、卡非佐米(Carfilzomib)、Carmubris(卡莫司汀)、卡莫司汀、卡莫司汀植入物、Casodex(比卡鲁胺(Bicalutamide))、CeeNU(洛莫司汀(Lomustine))、色瑞替尼(Ceritinib)、Cerubidine(盐酸柔红霉素)、Cervarix(重组HPV二价疫苗)、西妥昔单抗(Cetuximab)、苯丁酸氮芥、苯丁酸氮芥-强的松、CHOP、顺铂(Cisplatin)、Clafen(环磷酰胺)、氯法拉滨(Clofarabine),Clofarex(氯法拉滨)、Clolar(氯法拉滨)、CMF、Cometriq(苹果酸卡博替尼)、COPP、COPP-ABV、Cosmegen(放线菌素D(Dactinomycin))、克唑替尼(Crizotinib)、CVP、环磷酰胺、Cyfos(异环磷酰胺)、Cyramza(雷莫芦单抗(Ramucirumab))、阿糖胞苷(Cytarabine)、阿糖胞苷、脂质体、Cytosar-U(阿糖胞苷)、Cytoxan(环磷酰胺)、达拉菲尼(Dabrafenib)、达卡巴嗪(Dacarbazine)、Dacogen(地西他滨(Decitabine))、放线菌素D、达沙替尼(Dasatinib)、盐酸柔红霉素、地西他滨、地加瑞克(Degarelix)、地尼白介素(Denileukin Diftitox)、地诺单抗(Denosumab)、DepoCyt(脂质体阿糖胞苷)、DepoFoam(脂质体阿糖胞苷)、盐酸右雷佐生(DexrazoxaneHydrochloride)、达妥昔单抗(Dinutuximab)、多西他赛(Docetaxel)、Doxil(盐酸多柔比星脂质体)、盐酸多柔比星、盐酸多柔比星脂质体、Dox-SL(盐酸多柔比星脂质体)、DTIC-Dome(达卡巴嗪)、Efudex(氟尿嘧啶)、Elitek(拉布立酶(Rasburicase))、Ellence(盐酸表柔比星(Epirubicin Hydrochloride))、Eloxatin(奥沙利铂(Oxaliplatin))、艾曲波帕乙醇胺(Eltrombopag Olamine)、Emend(阿瑞匹坦)、恩杂鲁胺(Enzalutamide)、盐酸表柔比星、EPOCH、Erbitux(西妥昔单抗)、甲磺酸艾日布林(Eribulin Mesylate)、Erivedge(维莫德吉(Vismodegib))、盐酸埃罗替尼(Erlotinib Hydrochloride)、Erwinaze(天冬酰胺酶菊欧文氏菌)、Etopophos(磷酸依托泊苷(Etoposide Phosphate))、依托泊苷、磷酸依托泊苷、Evacet(盐酸多柔比星脂质体)、依维莫司、Evista(盐酸雷洛昔芬(RaloxifeneHydrochloride))、依西美坦、Fareston(托瑞米芬(Toremifene))、Farydak(帕比司他(Panobinostat))、Faslodex(氟维司群((Fulvestrant)))、FEC、Femara(来曲唑(Letrozole))、非格司亭(Filgrastim)、Fludara(磷酸氟达拉滨(FludarabinePhosphate))、磷酸氟达拉滨、Fluoroplex(氟尿嘧啶)、氟尿嘧啶、Folex(甲氨蝶呤)、FolexPFS(甲氨蝶呤)、FOLFIRI、FOLFIRI-贝伐单抗、FOLFIRI-西妥昔单抗、FOLFIRINOX、FOLFOX、Folotyn(普拉曲沙(Pralatrexate))、FU-LV、Fulvestrant、Gardasil(重组HPV四价疫苗)、Gardasil9(重组HPV无价疫苗)、Gazyva(奥比妥珠单抗(Obinutuzumab))、吉非替尼(Gefitinib)、盐酸吉西他滨(Gemcitabine Hydrochloride)、吉西他滨-顺铂、吉西他滨-奥沙利铂、吉妥珠单抗奥唑米星(Gemtuzumab Ozogamicin)、Gemzar(盐酸吉西他滨)、Gilotrif(马来酸阿法替尼)、Gleevec(甲磺酸伊马替尼)、Gliadel(卡莫司汀植入物)、Gliadel晶片(卡莫司汀植入物)、谷卡匹酶(Glucarpidase)、醋酸戈舍瑞林(GoserelinAcetate)、Halaven(甲磺酸艾日布林)、Herceptin(曲妥珠单抗)、重组HPV二价疫苗、重组HPV无价疫苗、重组HPV四价疫苗、Hycamtin(盐酸拓扑替康)、Hyper-CVAD、Ibrance(帕博西尼(Palbociclib))、替坦异贝莫单抗(Ibritumomab Tiuxetan)、依鲁替尼(Ibrutinib)、ICE、Iclusig(盐酸帕纳替尼(Ponatinib Hydrochloride))、Idamycin(盐酸伊达比星(Idarubicin Hydrochloride))、盐酸伊达比星、艾代拉里斯(Idelalisib)、Ifex(异环磷酰胺)、异环磷酰胺、Ifosfamidum(异环磷酰胺)、甲磺酸伊马替尼、Imbruvica(依鲁替尼(Ibrutinib))、咪喹莫特、Inlyta(阿西替尼)、重组干扰素α-2b、干扰素A(重组干扰素α-2b),碘I 131托西莫单抗和托西莫单抗、伊匹单抗(Ipilimumab)、Iressa(吉非替尼(Gefitinib))、盐酸伊立替康、Istodax(罗米地辛(Romidepsin))、伊沙匹隆(Ixabepilone)、Ixempra(伊沙匹隆)、Jakafi(磷酸鲁索替尼(Ruxolitinib Phosphate))、Jevtana(卡巴他赛(Cabazitaxel))、Kadcyla(Ado-曲妥珠单抗美坦新)、Keoxifene(盐酸雷洛昔芬)、Kepivance(帕利夫明(Palifermin))、Keytruda(派姆单抗)、Kyprolis(卡非佐米)、醋酸兰瑞肽(Lanreotide Acetate)、二甲苯磺酸拉帕替尼(Lapatinib Ditosylate)、来那度胺(Lenalidomide)、甲磺酸乐伐替尼(Lenvatinib Mesylate)、Lenvima(甲磺酸乐伐替尼)、来曲唑、甲酰四氢叶酸钙、Leukeran(苯丁酸氮芥)、醋酸亮丙瑞林(LeuprolideAcetate)、Levulan(氨基乙酰丙酸)、Linfolizin(苯丁酸氮芥)、LipoDox(盐酸多柔比星脂质体)、脂质体阿糖胞苷、洛莫司汀、Lupron(醋酸亮丙瑞林)、储库型Lupron(醋酸亮丙瑞林)、储库型Lupron-Ped(醋酸亮丙瑞林)、储库型Lupron-3个月(醋酸亮丙瑞林)、储库型Lupron-4个月(醋酸亮丙瑞林)、Lynparza(奥拉帕尼(Olaparib))、Marqibo(硫酸长春新碱脂质体)、Matulane(盐酸丙卡巴肼)、盐酸氮芥、Megace(醋酸甲地孕酮)、醋酸甲地孕酮、Mekinist(曲美替尼(Trametinib))、巯基嘌呤、美司钠(Mesna)、Mesnex(美司钠)、Methazolastone(替莫唑胺(Temozolomide))、甲氨蝶呤、甲氨蝶呤LPF(甲氨蝶呤)、Mexate(甲氨蝶呤)、Mexate-AQ(甲氨蝶呤)、丝裂霉素C、盐酸米托蒽醌、Mitozytrex(丝裂霉素C)、MOPP、Mozobil(普乐沙福(Plerixafor))、Mustargen(盐酸氮芥)、Mutamycin(丝裂霉素C)、Myleran(白消安)、Mylosar(阿扎胞苷)、Mylotarg(吉妥珠单抗奥唑米星)、纳米颗粒紫杉醇(紫杉醇白蛋白稳定化纳米颗粒制剂)、Navelbine(酒石酸长春瑞滨(VinorelbineTartrate))、奈拉滨(Nelarabine)、Neosar(环磷酰胺)、奈妥吡坦和盐酸帕洛诺司琼、Neupogen(非格司亭)、Nexavar(甲苯磺酸索拉非尼(Sorafenib Tosylate))、尼罗替尼(Nilotinib)、纳武单抗(Nivolumab)、Nolvadex(柠檬酸他莫昔芬)、Nplate(罗米司亭(Romiplostim))、奥比妥珠单抗(Obinutuzumab)、Odomzo(索尼德吉(Sonidegib))、OEPA、奥法木单抗(Ofatumumab)、OFF、奥拉帕尼(Olaparib)、高三尖杉酯碱(OmacetaxineMepesuccinate)、Oncaspar(培门冬酶(Pegaspargase))、盐酸昂丹司琼(OndansetronHydrochloride)、Ontak(地尼白介素)、Opdivo(纳武单抗)、OPPA、奥沙利铂、紫杉醇、紫杉醇白蛋白稳定化纳米颗粒制剂、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吡坦、帕米膦酸二钠、帕尼单抗(Panitumumab)、帕比司他(Panobinostat)、Paraplat(卡铂)、Paraplatin(卡铂)、盐酸帕唑帕尼(Pazopanib Hydrochloride)、培门冬酶、聚乙二醇干扰素α-2b(Peginterferon Alfa-2b)、PEG-干扰素(聚乙二醇干扰素α-2b)、派姆单抗、培美曲塞二钠(Pemetrexed Disodium)、Perjeta(帕妥珠单抗(Pertuzumab))、帕妥珠单抗、Platinol(顺铂)、Platinol-AQ(顺铂)、普乐沙福、泊马度胺(Pomalidomide)、Pomalyst(泊马度胺)、盐酸帕纳替尼、普拉曲沙(Pralatrexate)、强的松(Prednisone)、盐酸丙卡巴肼、Proleukin(阿地白介素(Aldesleukin))、Prolia(地诺单抗)、Promacta(艾曲波帕乙醇胺)、Provenge(西普鲁塞(Sipuleucel)-T)、Purinethol(巯基嘌呤)、Purixan(巯基嘌呤)、二氯化镭223、盐酸雷洛昔芬、雷莫芦单抗(Ramucirumab)、拉布立酶(Rasburicase)、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)无价疫苗、重组人乳头瘤病毒(HPV)四价疫苗、重组干扰素α-2b、瑞戈非尼(Regorafenib)、R-EPOCH、Revlimid(来那度胺)、Rheumatrex(甲氨蝶呤)、Rituxan(利妥昔单抗(Rituximab))、利妥昔单抗、罗米地辛、罗米司亭、Rubidomycin(盐酸柔红霉素)、磷酸鲁索替尼、司兰索胸腔内气溶胶(Sclerosol Intrapleural Aerosol)(滑石)、司妥昔单抗(Siltuximab)、西普鲁塞-T、Somatuline Depot(醋酸兰瑞肽)、索尼德吉、甲苯磺酸索拉非尼、Sprycel(达沙替尼)、STANFORD V,无菌滑石粉(滑石)、Steritalc(滑石)、Stivarga(瑞戈非尼)、苹果酸舒尼替尼(Sunitinib Malate)、Sutent(苹果酸舒尼替尼)、Sylatron(聚乙二醇干扰素α-2b)、Sylvant(司妥昔单抗)、Synovir(沙利度胺)、Synribo(高三尖杉酯碱),TAC、Tafinlar(达拉菲尼)、滑石、柠檬酸他莫昔芬、Tarabine PFS(阿糖胞苷)、Tarceva(盐酸埃罗替尼)、Targretin(蓓萨罗丁)、Tasigna(尼罗替尼)、Taxol(紫杉醇)、Taxotere(多西他赛)、Temodar(替莫唑胺)、替莫唑胺、替西罗莫司(Temsirolimus)、沙利度胺、Thalomid(沙利度胺)、噻替派(Thiotepa)、Toposar(依托泊苷)、盐酸拓扑替康、托瑞米芬(Toremifene)、Torisel(替西罗莫司)、托西莫单抗(Tositumomab)和碘I 131托西莫单抗、Totect(盐酸右雷佐生)、TPF、曲美替尼(Trametinib)、曲妥珠单抗、Treanda(盐酸苯达莫司汀)、Trisenox(三氧化二砷)、Tykerb(二甲苯磺酸拉帕替尼)、Unituxin(达妥昔单抗)、凡德他尼(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)、威罗菲尼(Vemurafenib)、VePesid(依托泊苷)、Viadur(醋酸亮丙瑞林)、Vidaza(阿扎胞苷)、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、维莫德吉、Voraxaze(谷卡匹酶)、伏立诺他(Vorinostat)、Votrient(盐酸帕唑帕尼)、Wellcovorin(甲酰四氢叶酸钙)、Xalkori(克唑替尼)、Xeloda(卡培他滨)、XELIRI、XELOX、Xgeva(地诺单抗)、Xofigo(二氯化镭223)、Xtandi(恩杂鲁胺)、Yervoy(伊匹单抗)、Zaltrap(阿柏西普(Ziv-Aflibercept))、Zelboraf(威罗菲尼)、Zevalin(替坦异贝莫单抗)、Zinecard(盐酸右雷佐生)、阿柏西普、Zofran(盐酸昂丹司琼)、Zoladex(醋酸戈舍瑞林)、唑来膦酸(Zoledronic Acid)、Zolinza(伏立诺他)、Zometa(唑来膦酸)、Zydelig(艾代拉里斯)、Zykadia(色瑞替尼)和Zytiga(醋酸阿比特龙)。
治疗血管疾病的方法
由于血小板还通过形成封闭受损血管并阻止出血的栓塞在若干生理和病理过程(诸如止血和血栓形成)中起关键作用,因此该平台也可用于治疗相关的血管疾病。
本文公开了一种治疗受试者的血管疾病的方法,该方法涉及向受试者施用本文公开的血小板组合物。在这些实施方案中,血小板递送药物以治疗血管疾病,例如凝血功能障碍或冠状动脉再狭窄。例如,药物可以是肝素或多柔比星。
一方面,本文提供了一种治疗或预防血管疾病的方法,其包括:
向有需要的受试者施用治疗有效量的组合物,所述组合物包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接。
在一个实施方案中,化学接头部分选自马来酰亚胺接头、PEG接头、PASylation和HESylation。在一个实施方案中,化学接头部分是马来酰亚胺接头。
在一个实施方案中,血小板细胞是人血小板细胞。在一个实施方案中,血小板细胞是自体血小板细胞。
在一个实施方案中,血管疾病是组织损伤、炎症或心血管疾病。在一个实施方案中,所述组合物与另外的治疗剂组合施用。
在一些实施方案中,血小板组合物可以靶向递送治疗剂,以治疗或预防血管疾病,例如凝血功能障碍或冠状动脉再狭窄。
例如,在一些情况下,治疗剂可以选自由以下组成的组:Adcirca(他达拉非(tadalafil))、Adempas(利奥西呱(riociguat))、Agrylin(盐酸阿那格雷(anagrelideHCL))、Angiomax(比伐卢定(bivalirudin))、Atacand(坎地沙坦西酯(candesartancilexetil))、Atryn(用于重构的抗凝血酶重组冻干粉)、Azor(苯磺酸氨氯地平(amlodipine besylate);奥美沙坦酯(olmesartan medoxomil))、Baycol(西立伐他汀钠(cerivastatin sodium))、BiDil(硝酸异山梨酯(isosorbide dinitrate)/盐酸肼屈嗪(hydralazine hydrochloride))、Brilinta(替格瑞洛(ticagrelor))、Caduet(氨氯地平(amlodipine)/阿托伐他汀(atorvastatin))、卡托普利(Captopril)、Cardizem(R)(注射用盐酸地尔硫卓(Diltiazem HC1))Monvial(R)、CellCept、Cleviprex(氯维地平(clevidipine))、Corlanor(伊伐布雷定(ivabradine))、Corlopam、Corvert注射剂(富马酸伊布利特(ibutilide fumarate)注射剂)、Covera-HS(维拉帕米(verapamil))、Crestor(瑞舒伐他汀钙(rosuvastatin calcium))、盐酸地尔硫卓、Diovan(缬沙坦(valsartan))、多柔比星、DynaCirc CR、Edarbi(阿齐沙坦酯(azilsartan medoxomil))、Edarbyclor(阿齐沙坦酯和氯噻酮(chlorthalidone))、Efient(普拉格雷(prasugrel))、Eliquis(阿哌沙班(apixaban))、Entresto(沙库必曲(sacubitril)和缬沙坦)、Epanova(ω-3-羧酸)、非诺贝特(Fenofibrate)、肝素、Innohep(亭扎肝素钠(tinzaparin sodium))注射剂、Integrilin、Juxtapid(洛美他派(lomitapide))、Kengreal(坎格雷洛(cangrelor))、Kynamro(米泊美生钠(mipomersen sodium))、Lescol(氟伐他汀钠(fluvastatin sodium))、Lescol(氟伐他汀钠)胶囊、Rx、Letairis(安立生坦(ambrisentan))、Levitra(伐地那非(vardenafil))、Lexxel(马来酸依那普利-非洛地平ER(enalapril maleate-felodipine ER))、Lipitor(阿托伐他汀钙(atorvastatin calcium))、Liptruzet(依替米贝(ezetimibe)和阿托伐他汀(atorvastatin))、Livalo(匹伐他汀(pitavastatin))、Mavik(群多普利(trandolapril))、Micardis(替米沙坦(telmisartan))、Micardis HCT(替米沙坦和氢氯噻嗪(hydrochlorothiazide))、Microzide(氢氯噻嗪)、Multaq(决奈达隆(dronedarone))、Natrecor(奈西立肽(nesiritide))、Niaspan、Normiflo、Nymalize(尼莫地平(nimodipine))、Opsumit(马西替坦(macitentan))、Pentoxifylline、Pindolol、Plavix(硫酸氢氯吡格雷(clopidogrel bisulfate))、Plavix(硫酸氢氯吡格雷)、Posicor、Pradaxa(甲磺酸达比加群(dabigatran etexilate mesylate))、Pravachol(普伐他汀钠(pravastatin sodium))、Pravachol(普伐他汀钠)、Prestalia(培哚普利精氨酸盐(perindopril arginine)和苯磺酸氨氯地平(amlodipine besylate))、Prinivil或Zestril(赖诺普利(Lisinopril))、ProAmatine(米多君(midodrine))、Ranexa(雷诺嗪(ranolazine))、Remodulin(曲前列尼尔(treprostinil))、ReoPro、REPRONEX(注射用尿促性素,USP)、Retavase(瑞替普酶(reteplase))、Rythmol、Savaysa(依度沙班(edoxaban))、Soliris(依库丽单抗(eculizumab))、Teczem(马来酸依那普利(enalapril maleate)/苹果酸地尔硫卓(diltiazem malate))、Tekamlo(阿利吉仑(aliskiren)+氨氯地平)、Tekturna(阿利吉仑)、Teveten(甲磺酸依普罗沙坦(eprosartan mesylate)加上氢氯噻嗪)、Teveten(甲磺酸依普罗沙坦)、Tiazac(盐酸地尔硫卓)、Tiazac(盐酸地尔硫卓)、Tiazac(盐酸地尔硫卓)、Toprol-XL(琥珀酸美托洛尔(metoprolol succinate))、Tribenzor(奥美沙坦酯+氨氯地平+氢氯噻嗪)、Tricor(非诺贝特(fenofibrate))、Trilipix(非诺贝特酸(fenofibricacid))、Tyvaso(曲前列尼尔(treprostinil))、Varithena(聚多卡醇(polidocanol)注射泡沫)、Vascepa(二十碳五烯酸乙酯(icosapent ethyl))、Visipaque(碘克沙醇(iodixanol))、Xarelto(利伐沙班(rivaroxaban))、Xarelto(利伐沙班)、Zocor、Zontivity(沃拉帕沙(vorapaxar))。
接头
可以采用共价方法通过化学接头来修饰血小板。使用化学接头的好处之一是回避了对遗传变化的需要。这种双官能化学接头可以将治疗剂连至血小板细胞。双官能接头基团的实例包括但不限于诸如糖、氨基酸、氨基醇、羧基醇、氨基硫醇等部分。
在一些实施方案中,化学接头部分选自马来酰亚胺接头、PEG接头、PASylation和HESylation。在一个实施方案中,化学接头部分是马来酰亚胺接头。
实施例
下面阐述了以下实施例以说明根据所公开的主题的组合物、方法和结果。这些实施例并非旨在包括本文所公开的主题的所有方面,而是旨在说明代表性方法和结果。这些实施例并非旨在排除对本领域的技术人员显而易见的本发明的等同形式和变型。
实施例1.血小板受用于术后癌症免疫疗法的检查点抑制剂的原位活化
手术是大多数实体瘤的主要治疗选择。尽管手术技术不断改进,肿瘤切除后的残余微肿瘤和/或CTC仍然充满挑战1-3。另外,还有人提出手术可诱导对癌症转移的促进4,5。许多患者在术后发展复发性疾病,这可导致显著的发病率和死亡率。因此,人们对开发预防术后癌症复发的有效策略产生了极大的兴趣。其中,癌症免疫疗法最近受到了相当多的关注6。免疫治疗剂不直接攻击肿瘤,而是加强身体的免疫系统以杀伤癌细胞7。免疫检查点阻断在一部分患者中引起了持久的抗肿瘤应答和长期缓解8-10。特别是,检查点抑制剂阻断与淋巴细胞上的程序性细胞死亡蛋白1(PD1)的相互作用并且抗原呈递细胞(APC)和肿瘤细胞上的程序性细胞死亡1配体1(PDL1)在治疗各种类型的癌症方面已经显示出令人兴奋的结果11-14。而且,第一种PD-L1抑制剂阿特珠单抗最近获得了美国食品和药物管理局(FDA)的加快审批15。尽管取得了显著进展,但目前的检查点阻断治疗方法限制了在许多患者中的治疗益处。在临床试验中观察到的最大限制可能是副作用,诸如自身免疫性病症的严重程度16-18。用免疫检查点阻断疗法治疗时,有时会发生3/4级不良事件15,19。同时,很大一部分患者对这些药剂没有应答8,10,15。抗PD疗法的客观应答率仍需提高。如何增强抗PD疗法已成为癌症免疫学和免疫治疗领域的核心主题之一6,11。
可能导致抗PD疗法的疗效受损的一种机制是静脉输注时正常组织的抗体脱靶16,18,20,21。在这种情况下,期望未来的癌症免疫疗法特异性集中在肿瘤部位而不是免疫系统的全身性活化20。而且,功效有限也可能是由于肿瘤淋巴细胞浸润不足和T细胞炎性肿瘤微环境,该微环境含有较高的PDL1表达,这与抗PD疗法的临床益处正相关22-25
基于细胞的系统最近已成为生物药物载体,包括红细胞、细菌菌影(bacterialghost)和基因工程改造的干细胞和免疫细胞。26,27其中,血小板是从巨核细胞释放的无核细胞片段,并且因其在止血方面的功能而最为人熟知28-31。循环血小板的平均寿命为8至9天27,32,这可以大大改善静脉注射的治疗剂的药代动力学。而且,输注的血小板可以迁移到手术伤口部位33,在该部位残余肿瘤可以在术后存活。另一方面,新出现的证据表明,血小板具有识别CTC并与CTC相互作用的能力34-36,CTC已经从原发肿瘤流入脉管系统并导致转移。在血小板的帮助下,aPDL1可以在术后靶向癌细胞,同时减少治疗剂的脱靶效应。除了它们的固有伤口和CTC向性特性外,还将血小板视为引发和改善许多炎症病症的免疫“细胞”37-39。血小板源趋化因子募集并唤醒T细胞以及其他免疫细胞。作为可溶性CD40L(sCD40L)的主要来源,血小板可以加强T细胞免疫,并且是诱导树突细胞(DC)成熟和B细胞同种型转换以产生免疫球蛋白G所必需的40。还有报道称,PDL1和PDL2响应于炎症而上调,41,42这产生PDL1阳性肿瘤,使肿瘤对抗PD疗法更敏感并且可能改善ORR。
在这个实例中,将抗PDL1(aPDL1)负载到血小板表面以防止术后肿瘤复发(图1a)。令人惊讶的是,本发明人发现aPDL1与未活化血小板的结合高度稳定,而在血小板活化后可显著促进aPDL1的释放。因此,aPDL1释放可以由源自血小板的微粒(PMP)引起,源自血小板的微粒由活化血小板的质膜产生43。此类结构改变可以促进aPDL1与APC和肿瘤细胞结合。通过在切除原发肿瘤后向带有B16黑素瘤和4T1乳腺癌肿瘤的小鼠静脉注射aPDL1缀合的血小板(P-aPD1),证明血小板可以帮助aPDL1向具有残余微肿瘤以及血液中具有CTC的术床运输并积聚。T细胞炎性肿瘤微环境也由血小板在活化后产生,伴有肿瘤部位的PDL1表达增加。同时,血小板活化后可以释放aPDL1以阻断免疫细胞和肿瘤细胞上的PDL1。这些结果表明,血小板可以用作以靶向和控制释放方式进行治疗剂(例如,aPDL1)递送的载体,以预防术后癌症复发。
经aPDL1修饰的工程改造的血小板
采用共价方法方便地通过双官能马来酰亚胺接头用aPDL1修饰血小板,回避了对遗传修饰的需要44。通过免疫荧光检查aPDL1与血小板的结合(图6)。另外,不含马来酰亚胺的aPDL1显示出与血小板最低限度的非特异性结合(图7)。酶联免疫吸附测定(ELISA)显示血小板可以容易地与aPDL1偶联,达到每个血小板约0.3pg(图8a)。还发现每个血小板偶联0.1和0.2pg的aPDL1对其活力无显著影响(图8b)。此类共价结合高度稳定,并且在两天内未显示出显著释放(图8c)。而且,检查了调节细胞粘附和迁移的血小板的几种表面蛋白(图9)。总的来说,与aPDL1的缀合不会对那些血小板细胞引起显著损伤。
血小板活化促进治疗剂的释放
在出现粘附后发生血小板活化45。血小板含有约60个颗粒,这些颗粒含有许多具有免疫功能的分子38。活化后,这些颗粒将其内部货物(cargo)释放到细胞外环境中。许多这些内含物起到免疫分子的作用。例如,它们可以募集和活化其他免疫细胞,诱导T细胞迁移,并增加单核细胞向DC的分化。另外,PMP源自血小板活化后的质膜43;活化血小板释放携带粘附分子和趋化因子的PMP,促进在PMP沉积位点的单核细胞截留46。为了研究aPDL1修饰的血小板(P-aPDL1)是否可以在刺激后活化,使用凝血酶活化体外P-aPDL1。通过观察活化前后P-aPDL1的透射电子显微镜检查(TEM)图像,在电子显微镜下检测到大量产生的PMP(图1b、图10)。还观察到血小板的树突状和扩散形态变化。更有趣的是,通过ELISA测定监测到aPDL1从活化血小板的显著释放(图1c)。明显的aPDL1释放归因于血小板活化后从质膜解离的PMP。为了测试这种假设,进行了活化P-aPDL1的免疫荧光成像。血小板用钙黄绿素染色,aPDL1用荧光二抗染色(图11)。在血小板活化后检测到PMP上存在aPDL1。
值得注意的是,几种促炎细胞因子也在活化后与aPDL1一起释放(图1d-e)。为了进一步检查通过产生PMP从血小板释放aPDL1,引入了transwell培养系统。将aPDL1缀合的血小板在transwell培养系统的上部隔室中培养,而使B16癌细胞在下部隔室中生长(图12)。插入膜上的微孔直径为1μm,允许PMP自由穿过该膜。在免疫染色前12小时,将B16癌细胞与非活化和活化血小板共同孵育。如图1f和图12所示,当血小板活化时,发现aPDL1与癌细胞膜结合。至于和非活化血小板一起孵育的癌细胞,可以在下部隔室中的癌细胞上检测到很少的信号。总的来说,数据显示aPDL1可以从活化血小板上释放并与癌细胞结合。
对复发肿瘤的体内P-aPDL1疗法
aPDL1与血小板表面的偶联有可能改变其体内行为。因此,在健康小鼠中评价全身施用之后P-aPDL1的体内药代动力学。将aPDL1、P-aPDL1和共同注射的未缀合的血小板+a-PDL1以等效aPDL1剂量静脉注射到小鼠体内。来自血液的aPDL1的ELISA分析显示,与游离aPDL1(5.2小时)和混合物(5.5小时)相比,与血小板连接的aPDL1实现了大大延长的血液循环半衰期(34.8小时)(图2a)。与临床上的治疗性抗体相比,相对较短的血液循环时间归因于大鼠抗小鼠IgG的较高免疫原性和非特异性结合。然后在通过手术不完全去除原发肿瘤后测试其伤口向性能力。aPDL1经Cy5.5标记,然后与血小板缀合。在注射P-aPDL1或游离aPDL1后2小时进行体内荧光成像,收集主要器官进行离体荧光成像(图13)。当aPDL1与血小板缀合时观察到aPDL1富集在具有残余肿瘤的手术伤口周围,而对于游离aPDL1而言,在伤口部位检测到不显著的荧光信号(图2b)。主要器官以及具有残余微肿瘤的伤口的离体成像进一步证实了P-aPDL1的伤口向性能力(图2c、图13)。显示在注射游离aPDL1的小鼠肝脏中检测到主要的aPDL1荧光信号,而P-aPDL1在肝脏中显示出的aPDL1信号显著低于按相同aPDL1剂量注射游离aPDL1的小鼠,显示P-aPDL1的血液循环时间更长。同时,在具有残余微肿瘤的手术伤口周围检测到显著强烈的aPDL1信号,而在与游离aPDL1相关的样品中检测到不显著的信号。荧光信号的定量显示静脉注射后两小时,伤口处P-aPDL1的积聚与游离aPDL1相比效率高9.4倍(图2d)。微肿瘤切片的共聚焦图像也证实当缀合到血小板上时aPDL1的肿瘤摄取显著增加(图2e、图14a)。而且,通过荧光成像清楚地观察到体内从血小板释放的aPDL1(图14b)。还检查了经修饰的血小板的止血作用。输注后小鼠尾部出血时间显示,与输注初次实验的血小板进行处理的小鼠相比,经P-aPDL1处理的小鼠的出血时间无统计学显著差异(图15)。
为研究体内促炎环境,评估手术部位的细胞因子水平。手术去除原发肿瘤后,对小鼠静脉注射血小板。两小时后,收集伤口组织并在培养基中培养24小时。然后测试来自伤口组织的培养基的细胞因子活性。发现与未处理的对照和带伤口的小鼠相比,IL-1β、IL-6、TNF-α和sCD40L的水平均表现出明显升高(图16a)。还测试了来自血清的细胞因子。有趣的是,血小板不会诱导血清中这些促炎细胞因子的分泌(图16b)。这些结果表明,血小板注射可以诱导局部炎症环境,而不是全身性炎症。通过在肿瘤部位将静止前体淋巴细胞转化为活化淋巴细胞,局部促炎环境有利于aPDL1免疫疗法47。另外,还研究了肿瘤部位的PDL1表达。发现血小板诱导的炎症负荷可以使肿瘤浸润免疫细胞和肿瘤细胞的PDL1表达上调(图16c-d)。肿瘤内PDL1阳性细胞的增加可进一步增强抗PDL1免疫疗法并增加ORR。41,42
为了治疗术后留下的残余微肿瘤,使用B16F10小鼠黑素瘤不完全肿瘤切除模型来模拟术后局部复发(图2f)。手术去除大部分肿瘤(约99%)后,对小鼠静脉注射单剂量的PBS、血小板、aPDL1或P-aPDL1(aPDL1=1mg/kg)。通过B16F10细胞的生物发光信号监测肿瘤生长。证明接受P-aPDL1的小鼠显示出最小的复发肿瘤体积。8只小鼠中有6只显示出强烈响应而没有任何可检测到的肿瘤。而经游离aPD1处理的小鼠显示出适度的肿瘤生长延迟但不能阻止术床中的肿瘤复发。仅用血小板处理的小鼠中对肿瘤复发的预防显示出与PBS对照相似的效果(图2g-h)。小鼠的肿瘤大小也与其存活率相关。在用P-aPDL1处理后60天,约75%的小鼠存活。相比之下,60天后所有对照组中没有小鼠存活(图2i)。
由P-aPDL1疗法触发的T细胞介导的免疫应答
另外,收获来自复发肿瘤的肿瘤浸润淋巴细胞(TIL)并在第16天通过免疫荧光和流式细胞术分析。免疫荧光染色揭示对照组中的残余肿瘤具有有限的T细胞浸润。相比之下,来自经P-aPDL1处理的小鼠的残余肿瘤受CD8+和CD4+T细胞显著浸润(图3a、图17)。在第10天,经P-aPDL1处理的小鼠中肿瘤重量显著较低(图3b),这也与残余肿瘤中CD3+细胞绝对数量的增加相对应(图3c)。更值得注意的是,经P-aPDL1处理的小鼠中每克肿瘤的CD8+T细胞绝对数量与PBS对照相比增加近10倍并且比经游离aPDL1处理的小鼠高3倍(图3d-f)。另外,研究了肿瘤浸润的CD4+FoxP3+T细胞(图3e)。在P-aPDL1疗法后,小鼠中T效应细胞与调节性T(Treg)细胞的瘤内比率显著提高(图3f-h)。另外,如通过细胞周期相关蛋白Ki67的表达测量,观察到P-aPDL1小鼠的肿瘤内的高CD8+和CD4+效应T细胞增殖。与效应T细胞相反,用P-aPDL1疗法,肿瘤浸润Treg细胞的增殖无显著增加(图18)。总的来说,这些观察结果表明P-aPDL1可以有效地将aPDL1递送至肿瘤微环境,从而触发稳健的T细胞介导的抗肿瘤免疫应答。
用于转移性疾病的P-aPDL1疗法
为了进一步证明P-aPDL1治疗CTC的效力,首先在实验转移肿瘤模型中通过在术后静脉注射B16F10细胞而攻击小鼠,模拟CTC从原发肿瘤逃逸到血液循环中,来对P-aPDL1进行测试48(图4a、图19)。术后立即为小鼠静脉注射单剂量的PBS、血小板、aPDL1(aPDL1=1mg/kg或2mg/kg)或P-aPDL1(aPDL1=1mg/kg)。根据小鼠B16F10细胞的生物发光信号(图4b、图19),证明游离aPDL1处理可预防转移癌,但即使在2mg/kg的较高剂量下,也无法预防手术部位的局部肿瘤复发,这可能是由于术后aPDL1向这些残余微肿瘤的积聚不足(图13)。相比之下,如通过全肺照片连同其苏木精-伊红(H&E)染色图像(图4c-d)以及肺组织的荧光图像(图20)证实,在P-aPDL1疗法后实现了术床肿瘤以及肺转移的复发的明显降低。当用P-aPDL1处理时,肺部转移部位的平均数量显著减少(图4e)。此外,与对照组相比,经处理的小鼠的存活时间显著增加(图4f)。与游离aPDL1相比,P-aPDL1的抗癌作用更佳部分归因于癌细胞周围抗体的局部浓度增加(图13)。同时,血小板活化也是抗癌作用的功能组成部分,因为活化不但可以释放缀合的aPDL1,而且还有助于募集许多其他免疫细胞浸润物到TME中。随着PDL1阻断,这些免疫细胞可以诱导强烈的抗癌免疫应答。
为进一步验证P-aPDL1的原位活化是否有助于抗癌作用,收集PMP并用aPDL1修饰(图19)。清楚地表明,与完整血小板相比,直接注射这些微粒限制了抗癌作用,甚至与游离aPDL1一样(图4)。这可以通过先前的研究来解释,这些研究验证PMP在引入循环后可以被快速清除49,50。这些结果证实肿瘤部位中P-aPDL1的原位活化是增强P-aPDL1抗癌作用的必需组成部分。
用于术后4T1复发性癌症的P-aPDL1。
为了评估P-aPDL1在预防术后另一种类型的癌症复发方面的效力,在三阴性乳腺癌(TNBC)4T1癌肿瘤模型中进行了试验。在该实验中,为BABL/c小鼠皮下(s.c.)注射4T1肿瘤细胞。皮下肿瘤接种后十四天,通过手术去除原发肿瘤,留下约1%的残余微肿瘤。术后立即对小鼠静脉注射与aPDL1偶联的治疗性血小板。在该模型中,单个疗程的P-aPDL1疗法足够显著以影响术后残余肿瘤的生长(图5a-b)。另外,所述疗法对肺部转移的影响也令人印象深刻,因为在经P-aPDL1处理的小鼠的肺部仅发现很少结节,与在经游离aPDL1处理的小鼠中发现的16个结节的中位数和在经血小板处理和未处理的小鼠中发现的约30个结节完全不同。(图5c-d)。与对照组相比,术后用P-aPDL1疗法的小鼠得到了实质性存活益处。肿瘤接种后60天,75%的小鼠存活(图5e)。
概括地说,该实施例使用了原位活化血小板以促进aPDL1的递送,这样可在术后基本上根除残余肿瘤细胞并防止癌症复发。P-aPDL1疗法可以使手术干预的有效性最大化,并降低原发肿瘤切除后癌症复发和转移的风险。除了使用血小板进行aPDL1递送之外,该递送方法还适用于其他治疗剂和应用生物微粒进行治疗剂靶向递送和生物响应性释放的治疗。51
方法和材料
细胞系
小鼠黑素瘤细胞系B16F10和小鼠乳腺癌细胞系4T1购自美国模式培养物保藏中心(American Type Culture Collection)。B16F10-luc-GFP和4T1-luc-GFP细胞是来自北卡罗来纳大学教堂山分校(The University of North Carolina at Chapel Hill.)的LeafHuang博士的礼馈赠。将B16F10细胞保持在补充有10%胎牛血清(Invitrogen,Carlsbad,CA)、100 U/mL青霉素(Invitrogen)和100 U/mL链霉素(Invitrogen)的杜尔贝科改良伊格尔培养基(Dulbecco’s Modified Eagle Medium)(Gibco,Invitrogen)中。将4T1细胞保持在补充有10%胎牛血清(Invitrogen,Carlsbad,CA)、100 U/mL青霉素(Invitrogen)和100U/mL链霉素(Invitrogen)的RPMI-1640培养基(Gibco,Invitrogen)中。收到后立即生成主细胞库和工作细胞库。将第三和第四代用于肿瘤实验。每三个月检验一次细胞中的潜在支原体。收到后未进行细胞重新鉴定。
小鼠
C57BL/6小鼠和BALB/c小鼠购自Jackson Lab(USA)。所有实验全部使用年龄匹配的(6-10周)雌性动物。所有小鼠研究均在北卡罗来纳大学教堂山分校和北卡罗来纳州立大学(North Carolina State University)的机构动物护理和使用委员会(InstitutionalAnimal Care and Use Committee)批准的动物方案的背景下进行。实验组大小在为平衡统计功效、可行性和道德方面而限定后,经动物福利监管机构批准。所有小鼠根据联邦和州动物研究政策保存在北卡罗来纳大学教堂山分校和北卡罗来纳州立大学。
抗体
体内使用的抗PDL1抗体(aPDL1)购自Biolegend Inc(目录号124329,克隆:10F.9G2)。染色抗体,包括CD3(Thermo Fisher Scientific,目录号A18644)、CD4(ThermoFisher Scientific,目录号A18667)、CD8(Thermo Fisher Scientific,目录号A18609)、PD1(Biolegend,目录号135227)、CD11c(Biolegend,目录号117309)、PDL1(Biolegend,目录号124311)、CD20(Biolegend,目录号150411)、CD11b(Biolegend,目录号101211)、CD9(Biolegend,目录号124805)、CD41(Biolegend,目录号133905)、CD61(Biolegend,目录号104307)、CD62P(Biolegend,目录号148305)、CD40L(Biolegend,目录号106505)、细胞内Ki67(Biolegend,目录号652405)和细胞内Foxp3(eBioscience,目录号71-5775-40)按照制造商的说明进行荧光激活细胞分选(FACS)分析。在Calibur FACS仪器(BD)上分析染色细胞,并使用FlowJo软件(版本10)进行分析。二抗,包括山羊抗大鼠IgG(H+L)二抗(ThermoFisher Scientific,目录号A18866)、兔抗大鼠IgG(H+L)二抗(Thermo FisherScientific,目录号A18920)、山羊抗大鼠IgG(最小x反应性)抗体(Biolegend,目录号405408)用于免疫染色。
aPDL-1缀合血小板的制备
如所述分离鼠血小板。52简言之,从C57BL/6(或BALB/c)小鼠收集全血(从眶窦或隐静脉进行非终端采血,20只小鼠用于采血)到含有1.0mL柠檬酸盐-磷酸盐-右旋糖(16mM柠檬酸、90mM柠檬酸钠,16mM NaH2PO4、142mM右旋糖,pH7.4)的塑料注射器中并在室温下以100g旋转20分钟,无刹车(no brake)。使用移液管(宽口)将富含血小板的血浆(PRP)转移到单独的管中,并向每支管中添加PGE1至1μm的最终浓度。(注意:如果PRP颜色微红,请弃去这些样品)。通过以800g旋转10分钟(无刹车)从PRP中分离血小板。弃去血浆,小心缓慢地将血小板重新悬浮在Tyrode缓冲液(134mM NaCl、12mM NaHCO3、2.9mM KCl、0.34mM Na2HPO4、1mMMgCl2、10mM HEPES,pH7.4)或包含PGE1(1μm最终浓度)的PBS中(注意:沿管壁缓慢释放缓冲液并将搅拌量减到最少)。每次体内注射需要500-600μl全血。
然后,用aPDL-1分三步使血小板表面官能化。首先,将100μL血小板(1x 108)重新悬浮于400μL包含PGE1(1μm)的PBS(pH=8)中,并与Traut试剂(0.1mg/ml)(2-亚氨基硫烷,Pierce)在室温(RT)下孵育30分钟。反应30分钟后,通过以800g离心10分钟去除过量的Traut试剂,并用Tyrode缓冲液(包括PGE1(1μm))洗涤三次(不重新悬浮,以免不必要的血小板活化)。与此同时,将aPDL-1与磺基琥珀酰亚胺基-4-(N-马来酰亚胺基甲基)-环己烷-1-羧酸酯(Sulfo-SMCC,Pierce)以1:1.2的摩尔比混合在PBS(pH=7.4)中,在4℃下保持2小时。使用离心过滤装置(截留分子量(MWCO)=10kDa)去除过量的磺基-SMCC,以纯化SMCC活化抗体。最后,将血小板和抗体混合在Tyrode缓冲液(包括PGE1(1μm))中。在室温下反应2小时后,通过离心(800g,10分钟)去除过量的抗体。保留沉淀级分并用Tyrode缓冲液(包括PGE1(1μm))洗涤两次。基于血小板计数分析,在缀合后血小板回收率高于80%。将获得的aPDL1-血小板于室温下储存在Tyrode缓冲液(包含PGE1(1μm))中直至使用。将未缀合的血小板未与缀合的血小板分离。通过ELISA(大鼠IgG总ELISA试剂盒,eBioscience,目录号88-50490-22)测量aPDL1与血小板的最终缀合量。新鲜分离的血小板在6小时内使用。血小板活化标记物CD62P用于评价血小板活化。所有血小板操作均在室温下进行。为了研究缀合效率,将各种量的aPDL1添加到血小板中用于缀合。在上清液中通过离心(800g,10分钟)去除未缀合的aPDL1。然后通过离心(800g,10分钟)用Tyrode缓冲液(包含PGE1(1μm))洗涤沉淀物P-aPDL1两次。之后,将P-aPDL1溶解在100μl去离子水中并用超声波处理进行细胞裂解以释放aPDL1。通过ELISA分析测量aPDL1与血小板的缀合量。每个血小板添加0.2pg aPDL1时,aPDL1与血小板的缀合效率(添加的aPDL1/缀合的aPDL1)为约75%。为了研究aPDL1修饰后血小板的稳定性,基于0小时和24小时时的血小板计数分析测量P-aPDL1的数量。为了研究随时间推移血小板上aPDL1的稳定性,将P-aPDL1于室温下储存在Tyrode缓冲液(包含PGE1(1μm))中。在不同时间取50μl的P-aPDL1。通过离心(800g,10分钟)去除上清液中释放的aPDL1。将P-aPDL1溶解在100μl去离子水中并用超声波处理进行裂解以释放aPDL1。通过ELISA分析测量aPDL1与血小板的缀合量。为了活化血小板,将0.5U凝血酶/mL添加到血小板悬浮液中。在血小板活化之前去除PGE1。将血小板在37℃下活化30分钟。
如先前所述,由血小板制备PMP。53在实验之前,用凝血酶(2U/mL)活化血小板浓缩物30分钟并以800g离心10分钟,并且收集富含PMP的上清液。使用抗小鼠aIIbb3抗体和抗小鼠CD62P(P选择素)抗体通过流式细胞术分析来检查上清液。接下来,如上所述使PMP与aPDL1偶联。通过ELISA检查偶联效率和稳定性。
透射电子显微镜检查(TEM)
通过将血小板与10%缓冲甲醛溶液混合来进行血小板的预固定,以避免后续制备步骤对血小板的形状改变。预固定后立即将样品在室温下以800g离心10分钟。弃去上清液后,在4℃下用于二甲胂酸盐缓冲液(pH7.2)中的2.5%戊二醛固定血小板90分钟(对于活化血小板,还收集上清液用于TEM成像)。固定后,通过在4℃下以800g离心10分钟来洗涤血小板两次。然后将血小板用2%乙酸铀酰和柠檬酸铅按顺序步骤染色5分钟,然后转移到铜网格中。54通过JEOL 2000FX TEM仪器在80kV下获得血小板的TEM图像。
抗PDL1和细胞因子从血小板上释放
为了活化P-aPDL1,将0.5U凝血酶/mL添加到P-aPDL1悬浮液(500μL Tyrode缓冲液中约1x 108个血小板,n=3)中,在37℃下保持30分钟。在不同时间取50μl的P-aPDL1。通过以800g离心10分钟收集上清液中从血小板上释放的aPDL1和细胞因子。非活化的P-aPDL1作为对照。通过ELISA测定测量上清液中释放的aPDL1和细胞因子的量。(eBioscience,目录号88-50490-22(大鼠IgG)、88-7013-22(IL1β)、88-7064-22(IL6)、88-7324-22(TNF-α)、BMS6010(sCD40L))。在200 PRO酶标仪上读取吸光度。
体内药代动力学
对三只小鼠静脉注射游离aPDL1、P-aPDL1或未缀合的血小板+a-PDL1混合物(每只小鼠2mg/kg的aPDL1,2×108个血小板,于200μL PBS中)。在不同时间点使用抗凝管从尾部取10μL血液。将每个样品溶解在100μl水中(Sigma,目录号W4502)并用超声波处理进行细胞裂解以释放缀合的aPDL1。通过大鼠IgG总ELISA试剂盒(eBioscience,目录号88-50490-22)测量aPDL1。对于体内生物分布研究,在去除原发肿瘤而留下约1%的残余组织后,为小鼠静脉注射Cy5.5标记的游离aPDL1或P-aPDL1。通过IVIS系统(具有提供的Cy5.5的激发/发射滤光片,曝光时间为1秒)记录体内荧光图像。对于离体成像,在注射后2小时处死经处理的小鼠。收集主要器官和组织并在IVIS成像系统(具有提供的Cy5.5的激发/发射滤光片,曝光时间为1秒)(Perkin Elmer Ltd)下成像。
体内肿瘤模型
为了测量对癌症复发的影响,在将1×106个B16F10(或4T1)或荧光素酶标记的B16F10(或4T1)肿瘤细胞移植到小鼠右肋腹7天(肿瘤达到~300mm3)后;切除肿瘤,留下约1%的残余组织,以模拟术床上的残余微量肿瘤3。简言之,通过腔室诱导用异氟烷(1-3%用于维持;高达5%用于诱导)麻醉来麻醉动物并通过鼻锥保持。夹住肿瘤区域并做无菌准备。使用无菌器械去除大约99%的肿瘤。伤口用Autoclip伤口夹系统封闭。对于实验转移模型,切除原发肿瘤后通过尾静脉将1×105个于200μL PBS中的荧光素酶标记的B16F10(或4T1)肿瘤细胞静脉输注到小鼠体内。将小鼠称重并随机分成不同的组(n=8)。手术之后,立即对小鼠静脉注射不同的药物制剂(每只小鼠aPDL1=1mg/kg,1-2x108个血小板于200μL PBS中)(这里使用的新鲜制备的血小板是从相同品系的健康小鼠中收集的)。通过癌细胞的生物发光信号监测肿瘤负荷。在成像之前,将小鼠夹住并使用脱毛膏剃毛。使用IVIS Lumina成像系统(Caliper,USA)拍摄图像。还用数字卡尺测量肿瘤。按(长径×短径)2)/2计算肿瘤体积(mm3)。用生物发光评估转移负荷。对肺部称重并对微转移进行计数。当表现出健康受损的迹象或当肿瘤体积超过2cm3时,对动物实施安乐死。
对于图5c中的肺转移瘤,使用印度墨汁(India ink)以按照标准方案使肺部转移更好地可视化。55在气管内注射墨汁(85ml H2O,15ml墨汁,两滴氨水)并用Fekete溶液(5ml70%乙醇,0.5ml福尔马林和0.25ml冰醋酸)固定之后将小鼠处死并对肿瘤负荷进行非盲性量化。2-6小时后,肿瘤病变被漂白,而正常肺组织仍然染色。
另外,在处理后从小鼠解剖肿瘤并在最佳切割培养基(O.C.T.)中快速冷冻用于免疫荧光染色。使用荧光标记的二抗检测aPDL1和血小板或PMP。对于H&E染色,处死有肺部肿瘤的动物用于分析。按照标准方案用H&E对肺组织切片进行染色。在Leica显微镜(LeicaDM5500 B)下检查所有H&E染色切片。
细胞因子检测
通过ELISA(eBioscience)测量IL-1β、IL-6、TNF-α和sCD40L的局部和血浆水平。为了测定在血小板注射后6小时伤口处不同细胞因子的浓度,收集伤口组织并在37℃下培养12小时。取出100μL培养基并在-80℃下冷冻用于分析。为了测定血小板注射后6小时血浆中的细胞因子水平,在各种处理后从小鼠中分离血浆样品并稀释用于分析。通过ELISA(Thermo Scientific)测定IL-1β、IL-6、TNF-α和sCD40L浓度。所有测量一式三份进行。
共聚焦显微镜检查
从小鼠切下肿瘤并在O.C.T.中快速冷冻。使用低温切片机切割几微米的切片并固定在载玻片上。将切片在冰冷的丙酮中固定10分钟,然后用PBS再水合。用BSA(3%)封闭后,在4℃下将切片用一抗染色过夜。在添加荧光标记的二抗后,使用共聚焦显微镜(Zeiss LSM710)分析载玻片。
体内生物发光和成像
用IVIS光谱成像系统(Perkin Elmer Ltd)收集生物发光图像。向动物腹腔注射(10μL/g体重)于DPBS(15mg/mL)中的d-萤光素(Thermo ScientificTM PierceTM,目录号PI88291)后10分钟,使用Living Image软件(Perkin Elmer Ltd)获取数据。生物发光成像的曝光时间为5分钟。(为了优化读数时间,使用IVIS成像系统,以1分钟的曝光时间获取生物发光强度持续30分钟。)将目标区域(ROI)量化为平均辐射率(光子数s-1cm-2sr-1,用彩色条表示)(IVIS Living Image4.2)。
尾部出血测定
通过从小鼠尾部远端的尖端取下3mm并立即将尾部浸入37℃PBS中来测定尾部出血时间。将完全停止出血定义为出血时间的终点。
统计分析
所有结果均表示为平均值±s.d.,如所示的平均值±s.e.m.。除非另有说明,否则在所有实验中均使用生物学重复。当比较两组以上时进行单因素方差分析(ANOVA),并且当确定显著时(P≤0.05),使用Tukey事后检验进行多重比较。通过对数秩检验确定存活益处。用GraphPad Prism(5.0)进行所有统计学分析。*P≤0.05,**P≤0.01,***P≤0.001。没有统计学方法用于预先确定动物或其他实验的样品大小。
参考文献
1.Baker,D.,Masterson,T.,Pace,R.,Constable,W.&Wanebo,H.The influenceof the surgical wound on local tumor recurrence.Surgery 106,525-532(1989).
2.Lukianova-Hleb,E.Y.et al.Intraoperative diagnostics and eliminationof residual microtumors with plasmonic nanobubbles.Nat.Nanotechnol.(2016).
3.Stephan,S.B.et al.Biopolymer implants enhance the efficacy ofadoptive T-cell therapy.Nat.Biotechnol.33,97-101(2015).
4.Demicheli,R.,Retsky,M.,Hrushesky,W.,Baum,M.&Gukas,I.The effects ofsurgery on tumor growth:a century of investigations.Ann.Oncol.,mdn386(2008).
5.Ceelen,W.,Pattyn,P.&Mareel,M.Surgery,wound healing,and metastasis:Recent insights and clinical implications.Crit.Rev.Oncol.Hematol.89,16-26(2014).
6.Klevorn,L.E.&Teague,R.M.Adapting Cancer Immunotherapy Models forthe Real World.Trends Immunol.(2016).
7.O′Sullivan,D.&Pearce,E.L.Targeting T cell metabolism fortherapy.Trends Immunol.36,71-80(2015).
8.Robert,C.et al.Pembrolizumab versus Ipilimumab in AdvancedMelanoma.N.Engl,J.Med.372,2521-2532(2015).
9.Postow,M.A.et al.Nivolumab and ipilimumab versus ipilimumab inuntreated melanoma.N.Engl.J.Med.372,2006-2017(2015).
10.Sharma,P.&Allison,J.P.The future of immune checkpointtherapy.Science 348,56-61(2015).
11.Wang,C.,Ye,Y.,Hochu,G.M.,Sadeghifar,H.&Gu,Z.Enhanced CancerImmunotherapy by Microneedle Patch-Assisted Delivery of Anti-PD1Antibody.Nano Lett.16,2334-2340(2016).
12.Zou,W.,Wolchok,J.D.&Chen,L.PD-L1(B7-H1)and PD-1 pathway blockadefor cancer therapy:Mechanisms,response biomarkers,andcombinations.Sci.Transl.Med.8,328rv324(2016).
13.Buchbinder,E.I.&Hodi,F.S.Melanoma in 2015:Immune-checkpointblockade-durable cancer control.Nat.Rev.Clin.Oncol.13,77-78(2016).
14.Smyth,E.C.&Cunningham,D.Encouraging results for PD-1 inhibition ingastric cancer.Lancet Oncol.(2016).
15.Rosenberg,J.E.et al.Atezolizumab in patients with locally advancedand metastatic urothelial carcinoma who have progressed following treatmentwith platinum-based chemotherapy:a single-arm,multicentre,phase 2 trial.TheLancet387,1909-1920(2016).
16.Naidoo,J.et al.Toxicities of the anti-PD-1 and anti-PD-L1 immunecheckpoint antibodies.Ann.Oncol.,mdv383(2015).
17.Mellati,M.et al.Anti-PD-1 and Anti-PDL-1 Monoclonal AntibodiesCausing Type 1 Diabetes.Diabetes Care 38,e137-138(2015).
18.Boutros,C.et al.Safety profiles of anti-CTLA-4 and anti-PD-1antibodies alone and in combination.Nat.Rev.Clin.Oncol.(2016).
19.Larkin,J.et al.Combined Nivolumab and Ipilimumab or Monotherapy inUntreated Melanoma.N.Engl.J.Med.373,23-34(2015).
20.Chen,L.&Han,X.Anti-PD-1/PD-L1 therapy of human cancer:past,present,and future.J.Clin.Invest.125,3384-3391(2015).
21.Weber,J.S.,Kahler,K.C.&Hauschild,A.Management of immune-relatedadverse events and kinetics of response with ipilimumab,J.Clin.Oncol.30,2691-2697(2012).
22.Woo,S.R.,Corrales,L.&Gajewski,T.F.The STING pathway and the Tcell-inflamed tumor microenvironment.Trends Immunol.36,250-256(2015).
23.Hegde,P.S.,Karanikas,V.&Evers,S.The where,the when,and the how ofimmune monitoring for cancer immunotherapies in the era of checkpointinhibition.Clin.Cancer Res.22,1865-1874(2016).
24.Spranger,S.et al.Up-regulation of PD-L1,IDO,and Tregs in themelanoma tumor microenvironment is driven by CD8+T cells.Sci.Transl.Med.5,200ra116-200ra116(2013).
25.Gajewski,T.F.,Schreiber,H.&Fu,Y.X.Innate and adaptive immune cellsin the tumor microenvironment.Nat.Immunol.14,1014-1022(2013).
26.Fesnak,A.D.,June,C.H.&Levine,B.L.Engineered T cells:the promiseand challenges of cancer immunotherapy.Nat.Rev.Cancer 16,566-581(2016).
27.Yoo,J.W.,Irvine,D.J.,Discher,D.E.&Mitragotri,S.Bio-inspired,bioengineered and biomimetic drug delivery carriers.Nat.Rev.Drug Discov.10,521-535(2011).
28.Tamagawa-Mineoka,R.Important roles of platelets as immune cells inthe skin.J.Dermatol.Sci.77,93-101(2015).
29.Franco,A.T.,Corken,A.&Ware,J.Platelets at the interface ofthrombosis,inflammation,and cancer.Blood 126,582-588(2015).
30.Hu,C.M.et al.Nanoparticle biointerfacing by platelet membranecloaking.Nature 526,118-121(2015).
31.Textor,J.in Platelet-Rich Plasma 61-94(Springer,2014).
32.Harker,L.A.et al.Effects of megakaryocyte growth and developmentfactor on platelet production,platelet life span,and platelet function inhealthy human volunteers.Blood 95,2514-2522(2000).
33.Nurden,A.T.,Nurden,P.,Sanchez,M.,Andia,I.&Anitua,E.Platelets andwound healing.Front Biosci.13,3532-3548(2008).
34.Gay,L.J.&Felding-Habermann,B.Contribution of platelets to tumormetastasis.Nat.Rev.Cancer 11,123-134(2011).
35.Nash,G.F.,Turner,L.F.,Scully,M.F.&Kakkar,A.K.Platelets andcancer.Lancet Oncol.3,425-430(2002).
36.Hu,Q.et al.Anticancer Platelet-MimickingNanovehicles.Adv.Mater.27,7043-7050(2015).
37.Garraud,O.Editorial:Platelets as immune cells in physiology andimmunopathology.Front Immunol.6,1-3(2015).
38.Morrell,C.N.,Aggrey,A.A.,Chapman,L.M.&Modjeski,K.L.Emerging rolesfor platelets as immune and inflammatory cells.Blood 123,2759-2767(2014).
39.Semple,J.W.,Italiano,J.E.&Freedman,J.Platelets and the immunecontinuum.Nat.Rev.Immunol.11,264-274(2011).
40.Elzey,B.D.et al.Platelet-mediated modulation of adaptive immunity:A communication link between innate and adaptive immune compartments.Immunity19,9-19(2003).
41.Seifert,L.et al.The necrosome promotes pancreatic oncogenesis viaCXCL1 and Mincle-induced immune suppression.Nature 532,245-249(2016).
42.Topalian,S.L.,Drake,C.G.&Pardoll,D.M.Targeting the PD-1/B7-H1(PD-L1)pathway to activate anti-tumor immunity.Curr:Opin.Immunol.24,207-212(2012).
43.Siljander,PR.M.Platelet-derived microparticles-an updatedperspective.Thromb.Res.127,S30-S33(2011).
44.Li,J.,Sharkey,C.C.,Wun,B.,Liesveld,J.L.&King,M.R.Geneticengineering of platelets to neutralize circulating tumor cells.J.ControlRelease 228,38-47(2016).
45.Ruggeri,Z.M.&Mendolicchio,G.L.Adhesion mechanisms in plateletfunction.Circ.Res.100,1673-1685(2007).
46.Mause,S.F.,von Hundelshausen,P.,Zernecke,A.,Koenen,R.R.&Weber,C.Platelet microparticles-A transcellular delivery system for RANTESpromoting monocyte recruitment on endothelium.Arterioscler.Thromb.Vasc.Biol.25,1512-1518(2005).
47.Tripathi,S.&Guleria,I.Role of PD1/PDL1 pathway,and TH17 and tregcells in maternal tolerance to the fetus.Biomed.J.38,25-31(2015).
48.Headley,M.B.et al.Visualization of immediate immune responses topioneer metastatic cells in the lung.Nature531,513-517(2016).
49.Flaumenhaft,R.Formation and fate of platelet microparticles.BloodCells Mol.Dis.36,182-187(2006).
50.Rand,M.L.,Wang,H.,Bang,KW.,Packham,M.A.&Freedman,J.Rapid clearanceof procoagulant platelet-derived microparticles from the circulation ofrabbits.J.Thromb Haemost 4,1621-1623(2006).
51.Lu,Y.,Aimetti,A.A.,Langer,R.&Gu,Z.Bioresponsive materials.NatureReviews Materials 1,16075(2016).
52.Cazenave,J.-P.et al.Preparation of washed platelet suspensionsfrom human and rodent blood.Platelets and Megakaryocytes:Volume 1:FunctionalAssays,13-28(2004).
53.Janowska-Wieczorek,A.et al.Platelet-derived microparticles bind tohematopoietic stem/progenitor cells and enhance their engraftment aftertransplantation.Blood98,645a-645a(2001).
54.Cheville,N.F.&Stasko,J.Techniques in electron microscopy of animaltissue.Veterinary pathology 51,28-41(2014).
55.Zimmerman,M.,Hu,X.&Liu,K.Experimental metastasis and CTL adoptivetransfer immunotherapy mouse model.Journal of visualized experiments:JoVE(2010).
56.Wang,C.et al.Dataset for In situ Activation of Platelets withCheckpoint Inhibitors for Post-Surgical Cancer Immunotherapy.Figshare http://dx.doi.org/10.6084/m9.figshare.4231766(2016).
除非另有定义,否则如本文使用的所有技术和科学术语具有与公开的发明所属领域中的技术人员通常所理解的相同含义。本文引用的出版物及其引用的材料通过引用明确并入。
本领域的技术人员将理解,可以对本发明的优选实施方案进行许多变化和修改,并且可以在不脱离本发明的精神的情况下进行此类变化和修改。因此,所附权利要求旨在覆盖落入本发明的真实精神和范围内的所有此类等同变型。
Claims (24)
1.一种组合物,其包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接,
其中所述治疗剂是免疫治疗剂,以及
其中所述免疫治疗剂选自抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体或其组合。
2.如权利要求1所述的组合物,其中所述免疫治疗剂是抗PDL1抗体。
3.如权利要求1所述的组合物,其中所述化学接头部分选自马来酰亚胺接头、PEG接头、PASylation和HESylation。
4.如权利要求3所述的组合物,其中所述化学接头部分是马来酰亚胺接头。
5.如权利要求1至4中任一项所述的组合物,其中所述血小板细胞是人血小板细胞。
6.如权利要求1至4中任一项所述的组合物,其中所述血小板细胞是自体血小板细胞。
7.组合物在制备用于预防有需要的受试者的癌症转移或复发的药物中的用途,所述组合物包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接,
其中所述治疗剂是免疫治疗剂,以及
其中所述免疫治疗剂选自抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体或其组合。
8.如权利要求7所述的用途,其中所述免疫治疗剂是抗PDL1抗体。
9.如权利要求7所述的用途,其中所述化学接头部分选自马来酰亚胺接头、PEG接头、PASylation和HESylation。
10.如权利要求9所述的用途,其中所述化学接头部分是马来酰亚胺接头。
11.如权利要求7至10中任一项所述的用途,其中所述血小板细胞是人血小板细胞。
12.如权利要求7至10中任一项所述的用途,其中所述血小板细胞是人自体血小板细胞。
13.如权利要求7至10中任一项所述的用途,其中所述癌症是实体瘤。
14.如权利要求7至10中任一项所述的用途,其中所述癌症为黑素瘤。
15.如权利要求7至10中任一项所述的用途,其中所述癌症为乳腺癌。
16.如权利要求7至10中任一项所述的用途,其中所述组合物与另外的治疗剂组合施用。
17.如权利要求16所述的用途,其中所述另外的治疗剂是抗肿瘤剂。
18.组合物在制备用于向受试者靶向递送治疗剂的药物中的用途,所述组合物包含:
血小板细胞;
化学接头部分;和
治疗剂;
其中所述治疗剂通过所述化学接头部分与所述血小板细胞共价连接;
其中所述治疗剂是免疫治疗剂,
其中所述组合物通过所述血小板细胞的活化而被靶向伤口或手术切除部位,以及
其中所述免疫治疗剂选自抗PDL1抗体、抗PD1抗体、抗CTLA4抗体、抗CD47抗体或其组合。
19.如权利要求18所述的用途,其中所述组合物在所述血小板细胞活化后在所述伤口或切除部位处在源自血小板的微粒中进一步释放。
20.如权利要求18所述的用途,其中所述免疫治疗剂是抗PDL1抗体。
21.如权利要求18所述的用途,其中所述化学接头部分选自马来酰亚胺接头、PEG接头、PASylation和HESylation。
22.如权利要求21所述的用途,其中所述化学接头部分是马来酰亚胺接头。
23.如权利要求18至22中任一项所述的用途,其中所述血小板细胞是人血小板细胞。
24.如权利要求18至22中任一项所述的用途,其中所述血小板细胞是自体血小板细胞。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662393839P | 2016-09-13 | 2016-09-13 | |
US62/393,839 | 2016-09-13 | ||
PCT/US2017/051376 WO2018053010A1 (en) | 2016-09-13 | 2017-09-13 | Platelet compositions and methods for the delivery of therapeutic agents |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109890420A CN109890420A (zh) | 2019-06-14 |
CN109890420B true CN109890420B (zh) | 2024-04-09 |
Family
ID=61620161
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780066511.5A Active CN109890420B (zh) | 2016-09-13 | 2017-09-13 | 用于递送治疗剂的血小板组合物和方法 |
Country Status (8)
Country | Link |
---|---|
US (1) | US11730765B2 (zh) |
EP (1) | EP3512554B1 (zh) |
JP (2) | JP7262774B2 (zh) |
KR (2) | KR102557336B1 (zh) |
CN (1) | CN109890420B (zh) |
AU (1) | AU2017327360A1 (zh) |
CA (1) | CA3036693A1 (zh) |
WO (1) | WO2018053010A1 (zh) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11073462B2 (en) | 2017-12-06 | 2021-07-27 | Lightintegra Technology Inc. | Non-activated platelet transfusion methods for enhancement of patient treatment outcomes |
CN112135639B (zh) * | 2018-04-06 | 2023-10-20 | 北卡罗莱纳州立大学 | 细胞组装介导的癌症免疫治疗检查点抑制剂的递送 |
US20210252070A1 (en) * | 2018-06-29 | 2021-08-19 | Platelet Biogenesis, Inc. | Compositions for Drug Delivery and Methods of Use Thereof |
AU2019321429B2 (en) * | 2018-08-15 | 2022-12-08 | Aiviva Biopharma, Inc. | Multi-kinase inhibitors of VEGF and TGF beta and uses thereof |
WO2020077037A1 (en) * | 2018-10-10 | 2020-04-16 | North Carolina State University | Pd-l1 presenting platelets reverse new-onset type 1 diabetes |
WO2022006011A1 (en) * | 2020-07-01 | 2022-01-06 | Cello Therapeutics, Inc. | Platelet membrane coated nanoparticles and uses thereof |
CN112826941A (zh) * | 2020-08-14 | 2021-05-25 | 南京邮电大学 | 一种用于递送蛋白药物的磁性血小板复合物的制备方法 |
CN112891317A (zh) * | 2021-02-05 | 2021-06-04 | 东南大学 | 一种血小板载药系统的制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08109142A (ja) * | 1994-08-16 | 1996-04-30 | S R L:Kk | 血小板薬物送達システム |
CN1822765A (zh) * | 2003-05-16 | 2006-08-23 | 北卡罗来纳查佩尔山大学 | 用再水化血细胞进行化合物的递送 |
CN102083447A (zh) * | 2007-05-16 | 2011-06-01 | 恩特格利昂公司 | 微米和纳米颗粒与血小板一起的递送 |
CN105102978A (zh) * | 2013-02-02 | 2015-11-25 | 杜克大学 | 分离循环肿瘤细胞的方法 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB929401A (en) | 1958-12-22 | 1963-06-19 | Upjohn Co | Encapsulated emulsions and processes for their preparation |
GB929406A (en) | 1958-12-22 | 1963-06-19 | Upjohn Co | A process for the production of encapsulated material |
GB969808A (en) | 1962-06-08 | 1964-09-16 | Boots Pure Drug Co Ltd | Anthelmintic compositions and compounds |
GB1413186A (en) | 1973-06-27 | 1975-11-12 | Toyo Jozo Kk | Process for encapsulation of medicaments |
IT1148784B (it) | 1980-04-09 | 1986-12-03 | Eurand Spa | Procedimento per la preparazione di microcapsule in un veicolo liquido |
US4794000A (en) | 1987-01-08 | 1988-12-27 | Synthetic Blood Corporation | Coacervate-based oral delivery system for medically useful compositions |
US5019400A (en) | 1989-05-01 | 1991-05-28 | Enzytech, Inc. | Very low temperature casting of controlled release microspheres |
US6197346B1 (en) | 1992-04-24 | 2001-03-06 | Brown Universtiy Research Foundation | Bioadhesive microspheres and their use as drug delivery and imaging systems |
CA2190121A1 (en) | 1994-03-15 | 1995-09-21 | Edith Mathiowitz | Polymeric gene delivery system |
US6143211A (en) | 1995-07-21 | 2000-11-07 | Brown University Foundation | Process for preparing microparticles through phase inversion phenomena |
US20060141482A1 (en) | 2004-12-23 | 2006-06-29 | Awdalla Essam T | Method and multicomponent conjugates for treating cancer |
WO2006073446A2 (en) | 2004-04-28 | 2006-07-13 | The Trustees Of The University Of Pennsylvania | Peptide-mediated protein transduction into cells the hematopoietic lineage |
LT2439273T (lt) * | 2005-05-09 | 2019-05-10 | Ono Pharmaceutical Co., Ltd. | Žmogaus monokloniniai antikūnai prieš programuotos mirties 1(pd-1) baltymą, ir vėžio gydymo būdai, naudojant vien tik anti-pd-1 antikūnus arba derinyje su kitais imunoterapiniais vaistais |
US20070178107A1 (en) * | 2006-01-31 | 2007-08-02 | Awdalla Essam T | Method and means for treating solid tumors |
AU2007243412A1 (en) | 2006-04-25 | 2007-11-08 | Immune Disease Institute Inc. | Targeted delivery to leukocytes using non-protein carriers |
EP2111869A1 (en) | 2008-04-23 | 2009-10-28 | Stichting Sanquin Bloedvoorziening | Compositions and methods to enhance the immune system |
WO2010014784A2 (en) | 2008-08-01 | 2010-02-04 | Bristol-Myers Squibb Company | Combination of anti-ctla4 antibody with diverse therapeutic regimens for the synergistic treatment of proliferative diseases |
SI2376535T1 (sl) * | 2008-12-09 | 2017-07-31 | F. Hoffmann-La Roche Ag | Protitelesa anti-pd-l1 in njihova uporaba za izboljšanje funkcije celic t |
US8673359B2 (en) | 2010-07-08 | 2014-03-18 | Brown University | Nanoparticle compositions and methods for improved oral delivery of active agents |
US9856320B2 (en) * | 2012-05-15 | 2018-01-02 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
WO2016057898A1 (en) * | 2014-10-10 | 2016-04-14 | Idera Pharmaceuticals, Inc. | Treatment of cancer using tlr9 agonist with checkpoint inhibitors |
-
2017
- 2017-09-13 WO PCT/US2017/051376 patent/WO2018053010A1/en unknown
- 2017-09-13 AU AU2017327360A patent/AU2017327360A1/en active Pending
- 2017-09-13 KR KR1020197009451A patent/KR102557336B1/ko active IP Right Grant
- 2017-09-13 KR KR1020237022734A patent/KR20230109771A/ko not_active Application Discontinuation
- 2017-09-13 CA CA3036693A patent/CA3036693A1/en active Pending
- 2017-09-13 EP EP17851460.0A patent/EP3512554B1/en active Active
- 2017-09-13 JP JP2019513929A patent/JP7262774B2/ja active Active
- 2017-09-13 US US16/332,939 patent/US11730765B2/en active Active
- 2017-09-13 CN CN201780066511.5A patent/CN109890420B/zh active Active
-
2023
- 2023-04-05 JP JP2023061666A patent/JP2023085470A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08109142A (ja) * | 1994-08-16 | 1996-04-30 | S R L:Kk | 血小板薬物送達システム |
CN1822765A (zh) * | 2003-05-16 | 2006-08-23 | 北卡罗来纳查佩尔山大学 | 用再水化血细胞进行化合物的递送 |
CN102083447A (zh) * | 2007-05-16 | 2011-06-01 | 恩特格利昂公司 | 微米和纳米颗粒与血小板一起的递送 |
CN105102978A (zh) * | 2013-02-02 | 2015-11-25 | 杜克大学 | 分离循环肿瘤细胞的方法 |
Non-Patent Citations (1)
Title |
---|
Drug delivery using platelet cancer cell interaction;SARKAR,S等;《PHARM.RES.》;20131130;第30卷(第11期);摘要部分 * |
Also Published As
Publication number | Publication date |
---|---|
US20190247438A1 (en) | 2019-08-15 |
EP3512554A4 (en) | 2020-06-17 |
CN109890420A (zh) | 2019-06-14 |
JP2023085470A (ja) | 2023-06-20 |
KR20230109771A (ko) | 2023-07-20 |
US11730765B2 (en) | 2023-08-22 |
KR20190053206A (ko) | 2019-05-17 |
JP2019530673A (ja) | 2019-10-24 |
KR102557336B1 (ko) | 2023-07-18 |
EP3512554A1 (en) | 2019-07-24 |
WO2018053010A1 (en) | 2018-03-22 |
EP3512554B1 (en) | 2022-07-27 |
JP7262774B2 (ja) | 2023-04-24 |
AU2017327360A1 (en) | 2019-03-28 |
CA3036693A1 (en) | 2018-03-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109890420B (zh) | 用于递送治疗剂的血小板组合物和方法 | |
CN108136023B (zh) | 血小板膜包覆的药物递送系统 | |
CA2873404C (en) | Membrane encapsulated nanoparticles and method of use | |
CN111787945A (zh) | 作为癌症免疫治疗的检查点阻断剂的工程化纳米囊泡 | |
Garizo et al. | p28-functionalized PLGA nanoparticles loaded with gefitinib reduce tumor burden and metastases formation on lung cancer | |
Mills et al. | Nanoparticle based medicines: approaches for evading and manipulating the mononuclear phagocyte system and potential for clinical translation | |
RU2734930C2 (ru) | Режимы дозирования мелфлуфена для раковых заболеваний | |
TWI603731B (zh) | 透明質酸奈米顆粒在製備治療於一個體中之淋巴系統中之腫瘤之藥物的用途 | |
WO2019195819A1 (en) | Cell assembly-mediated delivery of checkpoint inhibitors for cancer immunotherapy | |
JP7470988B2 (ja) | 生物応答性ヒドロゲルマトリックス及び使用方法 | |
Zhao et al. | Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review | |
US20210260187A1 (en) | In situ sprayed bioresponsive immunotherapeutic gel for post-surgical treatment | |
KR20150054543A (ko) | 간 표적화 나노입자, 이의 제조방법 및 이를 포함하는 약학적 조성물 | |
US20230000784A1 (en) | Nanoparticles for medical and diagnositc applications | |
US20230364259A1 (en) | Kidney targeted delivery of drugs | |
WO2022235941A1 (en) | Double sided chimeric antigen receptor (car) engineered cell membrane based drug delivery systems | |
Li et al. | Triptolide Self-Assembling Nanoparticles Engineering with Modified Erythrocyte Membranes for Targeting and Remodeling Inflammatory Microenvironment in Arthritis | |
EP4178988A1 (en) | In situ thiol-maleimide crosslinked hydrogel for immune checkpoint blockade delivery |
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 | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40009575 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |