CN113840798A - 官能化酶驱动的纳米马达 - Google Patents
官能化酶驱动的纳米马达 Download PDFInfo
- Publication number
- CN113840798A CN113840798A CN201980080190.3A CN201980080190A CN113840798A CN 113840798 A CN113840798 A CN 113840798A CN 201980080190 A CN201980080190 A CN 201980080190A CN 113840798 A CN113840798 A CN 113840798A
- Authority
- CN
- China
- Prior art keywords
- nanomotor
- enzyme
- nanomotors
- urease
- particles
- 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.)
- Granted
Links
- 102000004190 Enzymes Human genes 0.000 title claims abstract description 70
- 108090000790 Enzymes Proteins 0.000 title claims abstract description 70
- 239000002245 particle Substances 0.000 claims abstract description 76
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 239000012491 analyte Substances 0.000 claims abstract description 7
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 5
- 238000003745 diagnosis Methods 0.000 claims abstract description 4
- 238000004393 prognosis Methods 0.000 claims abstract description 4
- 229940088598 enzyme Drugs 0.000 claims description 66
- 108010046334 Urease Proteins 0.000 claims description 54
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 47
- 239000002105 nanoparticle Substances 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 24
- 239000011859 microparticle Substances 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 239000000377 silicon dioxide Substances 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 22
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 17
- 206010005003 Bladder cancer Diseases 0.000 claims description 16
- 230000008685 targeting Effects 0.000 claims description 16
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 16
- 102000004169 proteins and genes Human genes 0.000 claims description 12
- 108090000623 proteins and genes Proteins 0.000 claims description 12
- 238000000338 in vitro Methods 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 8
- 210000000170 cell membrane Anatomy 0.000 claims description 6
- 210000005056 cell body Anatomy 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000003550 marker Substances 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 229920000642 polymer Polymers 0.000 claims description 4
- 108010053835 Catalase Proteins 0.000 claims description 3
- 239000004366 Glucose oxidase Substances 0.000 claims description 3
- 108010015776 Glucose oxidase Proteins 0.000 claims description 3
- 239000003575 carbonaceous material Substances 0.000 claims description 3
- 235000019420 glucose oxidase Nutrition 0.000 claims description 3
- 229940116332 glucose oxidase Drugs 0.000 claims description 3
- 229910044991 metal oxide Inorganic materials 0.000 claims description 3
- 150000004706 metal oxides Chemical class 0.000 claims description 3
- 108010015428 Bilirubin oxidase Proteins 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- 102000004882 Lipase Human genes 0.000 claims description 2
- 108090001060 Lipase Proteins 0.000 claims description 2
- 239000004367 Lipase Substances 0.000 claims description 2
- 108091005804 Peptidases Proteins 0.000 claims description 2
- 102000003992 Peroxidases Human genes 0.000 claims description 2
- 239000004365 Protease Substances 0.000 claims description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 2
- 102000004142 Trypsin Human genes 0.000 claims description 2
- 108090000631 Trypsin Proteins 0.000 claims description 2
- 102100033220 Xanthine oxidase Human genes 0.000 claims description 2
- 108010093894 Xanthine oxidase Proteins 0.000 claims description 2
- 229930195712 glutamate Natural products 0.000 claims description 2
- 235000019421 lipase Nutrition 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- 150000002739 metals Chemical class 0.000 claims description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 claims description 2
- 239000012588 trypsin Substances 0.000 claims description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 claims 1
- 102000012440 Acetylcholinesterase Human genes 0.000 claims 1
- 102000016938 Catalase Human genes 0.000 claims 1
- 102000005548 Hexokinase Human genes 0.000 claims 1
- 108700040460 Hexokinases Proteins 0.000 claims 1
- 229940022698 acetylcholinesterase Drugs 0.000 claims 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 103
- 108020004414 DNA Proteins 0.000 description 58
- 239000004202 carbamide Substances 0.000 description 51
- 229920001223 polyethylene glycol Polymers 0.000 description 50
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 47
- 239000002202 Polyethylene glycol Substances 0.000 description 33
- 230000033001 locomotion Effects 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 29
- 239000000243 solution Substances 0.000 description 26
- 229910021529 ammonia Inorganic materials 0.000 description 24
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 23
- 230000000694 effects Effects 0.000 description 23
- 239000002953 phosphate buffered saline Substances 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- -1 haramycin Chemical compound 0.000 description 20
- 239000003094 microcapsule Substances 0.000 description 19
- 238000004458 analytical method Methods 0.000 description 18
- 238000009792 diffusion process Methods 0.000 description 17
- 239000000523 sample Substances 0.000 description 17
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 15
- 238000007306 functionalization reaction Methods 0.000 description 15
- 230000035899 viability Effects 0.000 description 14
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 210000002700 urine Anatomy 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000009826 distribution Methods 0.000 description 11
- 238000005259 measurement Methods 0.000 description 11
- 239000000446 fuel Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 9
- 239000008107 starch Substances 0.000 description 9
- 229940032147 starch Drugs 0.000 description 9
- 235000019698 starch Nutrition 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000004793 Polystyrene Substances 0.000 description 8
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 description 8
- 230000003993 interaction Effects 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 230000003287 optical effect Effects 0.000 description 8
- 239000003755 preservative agent Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 102000053602 DNA Human genes 0.000 description 7
- 238000005119 centrifugation Methods 0.000 description 7
- 229920002223 polystyrene Polymers 0.000 description 7
- 235000012239 silicon dioxide Nutrition 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 6
- 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 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 239000011148 porous material Substances 0.000 description 6
- 238000011002 quantification Methods 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 description 5
- 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 5
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 206010020843 Hyperthermia Diseases 0.000 description 5
- 102000008986 Janus Human genes 0.000 description 5
- 108050000950 Janus Proteins 0.000 description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 5
- 108020004682 Single-Stranded DNA Proteins 0.000 description 5
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 5
- 238000003349 alamar blue assay Methods 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 231100000433 cytotoxic Toxicity 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002296 dynamic light scattering Methods 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 229940126864 fibroblast growth factor Drugs 0.000 description 5
- 230000036031 hyperthermia Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 244000045232 Canavalia ensiformis Species 0.000 description 4
- 235000010520 Canavalia ensiformis Nutrition 0.000 description 4
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 4
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 4
- 108091008794 FGF receptors Proteins 0.000 description 4
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 4
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 4
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 229940121375 antifungal agent Drugs 0.000 description 4
- 230000002210 biocatalytic effect Effects 0.000 description 4
- 239000001506 calcium phosphate Substances 0.000 description 4
- 239000001569 carbon dioxide Substances 0.000 description 4
- 230000010261 cell growth Effects 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 230000021615 conjugation Effects 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 210000002744 extracellular matrix Anatomy 0.000 description 4
- 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 4
- 239000010931 gold Substances 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000004626 scanning electron microscopy Methods 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000007704 transition Effects 0.000 description 4
- 238000004627 transmission electron microscopy Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 201000011177 bladder transitional cell papilloma Diseases 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 229960003563 calcium carbonate Drugs 0.000 description 3
- 235000010216 calcium carbonate Nutrition 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000006911 enzymatic reaction Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 229960000628 fidaxomicin Drugs 0.000 description 3
- ZVGNESXIJDCBKN-UUEYKCAUSA-N fidaxomicin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@H]([C@H]1O)OC)OCC\1=C/C=C/C[C@H](O)/C(C)=C/[C@@H]([C@H](/C(C)=C/C(/C)=C/C[C@H](OC/1=O)[C@@H](C)O)O[C@H]1[C@H]([C@@H](O)[C@H](OC(=O)C(C)C)C(C)(C)O1)O)CC)C(=O)C1=C(O)C(Cl)=C(O)C(Cl)=C1CC ZVGNESXIJDCBKN-UUEYKCAUSA-N 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 3
- 238000007654 immersion Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 108010082117 matrigel Proteins 0.000 description 3
- 239000012621 metal-organic framework Substances 0.000 description 3
- 238000002887 multiple sequence alignment Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 238000001139 pH measurement Methods 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000012360 testing method Methods 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
- NMWKYTGJWUAZPZ-WWHBDHEGSA-N (4S)-4-[[(4R,7S,10S,16S,19S,25S,28S,31R)-31-[[(2S)-2-[[(1R,6R,9S,12S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,53S,56S,59S,62S,65S,68S,71S,76S,79S,85S)-47-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-18-(4-aminobutyl)-27,68-bis(3-amino-3-oxopropyl)-36,71,76-tribenzyl-39-(3-carbamimidamidopropyl)-24-(2-carboxyethyl)-21,56-bis(carboxymethyl)-65,85-bis[(1R)-1-hydroxyethyl]-59-(hydroxymethyl)-62,79-bis(1H-imidazol-4-ylmethyl)-9-methyl-33-(2-methylpropyl)-8,11,17,20,23,26,29,32,35,38,41,48,54,57,60,63,66,69,72,74,77,80,83,86-tetracosaoxo-30-propan-2-yl-3,4,44,45-tetrathia-7,10,16,19,22,25,28,31,34,37,40,49,55,58,61,64,67,70,73,75,78,81,84,87-tetracosazatetracyclo[40.31.14.012,16.049,53]heptaoctacontane-6-carbonyl]amino]-3-methylbutanoyl]amino]-7-(3-carbamimidamidopropyl)-25-(hydroxymethyl)-19-[(4-hydroxyphenyl)methyl]-28-(1H-imidazol-4-ylmethyl)-10-methyl-6,9,12,15,18,21,24,27,30-nonaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29-nonazacyclodotriacontane-4-carbonyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](Cc4ccccc4)NC3=O)[C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3CCC[C@H]3C(=O)N[C@@H](C)C(=O)N2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)C(C)C)C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(=O)N[C@@H](C)C(O)=O NMWKYTGJWUAZPZ-WWHBDHEGSA-N 0.000 description 2
- OBYNJKLOYWCXEP-UHFFFAOYSA-N 2-[3-(dimethylamino)-6-dimethylazaniumylidenexanthen-9-yl]-4-isothiocyanatobenzoate Chemical compound C=12C=CC(=[N+](C)C)C=C2OC2=CC(N(C)C)=CC=C2C=1C1=CC(N=C=S)=CC=C1C([O-])=O OBYNJKLOYWCXEP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 description 2
- 238000012604 3D cell culture Methods 0.000 description 2
- 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 2
- 102000004379 Adrenomedullin Human genes 0.000 description 2
- 101800004616 Adrenomedullin Proteins 0.000 description 2
- 239000012103 Alexa Fluor 488 Substances 0.000 description 2
- 239000012099 Alexa Fluor family Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 2
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 2
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 2
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 2
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 2
- 230000005653 Brownian motion process Effects 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 102100035882 Catalase Human genes 0.000 description 2
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 2
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 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
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 2
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920002683 Glycosaminoglycan Polymers 0.000 description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 229920002971 Heparan sulfate Polymers 0.000 description 2
- 101000595923 Homo sapiens Placenta growth factor Proteins 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 102000014429 Insulin-like growth factor Human genes 0.000 description 2
- 239000013283 Janus particle Substances 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- 108010056852 Myostatin Proteins 0.000 description 2
- 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 2
- ZRKWMRDKSOPRRS-UHFFFAOYSA-N N-Methyl-N-nitrosourea Chemical compound O=NN(C)C(N)=O ZRKWMRDKSOPRRS-UHFFFAOYSA-N 0.000 description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 102000015336 Nerve Growth Factor Human genes 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
- 102100035194 Placenta growth factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 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
- 108010067787 Proteoglycans Proteins 0.000 description 2
- 102000016611 Proteoglycans Human genes 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 206010043276 Teratoma Diseases 0.000 description 2
- 102000036693 Thrombopoietin Human genes 0.000 description 2
- 108010041111 Thrombopoietin Proteins 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 2
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 2
- 108010046516 Wheat Germ Agglutinins Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 2
- 229960004176 aclarubicin Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- ULCUCJFASIJEOE-NPECTJMMSA-N adrenomedullin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H]1C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CSSC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)[C@@H](C)O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ULCUCJFASIJEOE-NPECTJMMSA-N 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000003275 alpha amino acid group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 238000003277 amino acid sequence analysis Methods 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940112869 bone morphogenetic protein Drugs 0.000 description 2
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 2
- 238000005537 brownian motion Methods 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
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- JQXXHWHPUNPDRT-BQVAUQFYSA-N chembl1523493 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2C=NN1CCN(C)CC1 JQXXHWHPUNPDRT-BQVAUQFYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 238000004624 confocal microscopy Methods 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 229960001484 edetic acid Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000003979 granulating agent Substances 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 238000003365 immunocytochemistry Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011572 manganese Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000008204 material by function Substances 0.000 description 2
- 108020004084 membrane receptors Proteins 0.000 description 2
- 102000006240 membrane receptors Human genes 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 239000002082 metal nanoparticle Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- 239000010955 niobium Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000013110 organic ligand Substances 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229920000575 polymersome Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 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
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- 229960002957 praziquantel Drugs 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 229940095574 propionic acid Drugs 0.000 description 2
- 230000001141 propulsive effect Effects 0.000 description 2
- 238000000746 purification Methods 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
- 230000004044 response Effects 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- 229960001225 rifampicin Drugs 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 230000009291 secondary effect Effects 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 235000011008 sodium phosphates Nutrition 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
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- FPZLLRFZJZRHSY-HJYUBDRYSA-N tigecycline Chemical class C([C@H]1C2)C3=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O FPZLLRFZJZRHSY-HJYUBDRYSA-N 0.000 description 2
- 229960004089 tigecycline Drugs 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 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
- 229910052905 tridymite Inorganic materials 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
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- 229960002555 zidovudine Drugs 0.000 description 2
- YKSVGLFNJPQDJE-YDMQLZBCSA-N (19E,21E,23E,25E,27E,29E,31E)-33-[(2R,3S,4R,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-17-[7-(4-aminophenyl)-5-hydroxy-4-methyl-7-oxoheptan-2-yl]-1,3,5,7,37-pentahydroxy-18-methyl-9,13,15-trioxo-16,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid Chemical compound CC(CC(C)C1OC(=O)CC(=O)CCCC(=O)CC(O)CC(O)CC(O)CC2(O)CC(O)C(C(CC(O[C@@H]3O[C@H](C)[C@@H](O)[C@@H](N)[C@@H]3O)\C=C\C=C\C=C\C=C\C=C\C=C\C=C\C1C)O2)C(O)=O)C(O)CC(=O)C1=CC=C(N)C=C1 YKSVGLFNJPQDJE-YDMQLZBCSA-N 0.000 description 1
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 1
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 description 1
- 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 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products 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 1
- MPIPASJGOJYODL-SFHVURJKSA-N (R)-isoconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@@H](OCC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 MPIPASJGOJYODL-SFHVURJKSA-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
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- AYDAHOIUHVUJHQ-UHFFFAOYSA-N 1-(3',6'-dihydroxy-3-oxospiro[2-benzofuran-1,9'-xanthene]-5-yl)pyrrole-2,5-dione Chemical compound C=1C(O)=CC=C2C=1OC1=CC(O)=CC=C1C2(C1=CC=2)OC(=O)C1=CC=2N1C(=O)C=CC1=O AYDAHOIUHVUJHQ-UHFFFAOYSA-N 0.000 description 1
- AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2r)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 description 1
- ZCJYUTQZBAIHBS-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C=CC(SC=2C=CC=CC=2)=CC=1)CN1C=NC=C1 ZCJYUTQZBAIHBS-UHFFFAOYSA-N 0.000 description 1
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-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
- 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 1
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 1
- QXHHHPZILQDDPS-UHFFFAOYSA-N 1-{2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound S1C=CC(COC(CN2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1Cl QXHHHPZILQDDPS-UHFFFAOYSA-N 0.000 description 1
- JLGKQTAYUIMGRK-UHFFFAOYSA-N 1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 JLGKQTAYUIMGRK-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- MBRHNTMUYWQHMR-UHFFFAOYSA-N 2-aminoethanol;6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one Chemical compound NCCO.ON1C(=O)C=C(C)C=C1C1CCCCC1 MBRHNTMUYWQHMR-UHFFFAOYSA-N 0.000 description 1
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- UBLAMKHIFZBBSS-UHFFFAOYSA-N 3-Methylbutyl pentanoate Chemical compound CCCCC(=O)OCCC(C)C UBLAMKHIFZBBSS-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 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
- 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
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 102100022987 Angiogenin Human genes 0.000 description 1
- 108010064760 Anidulafungin Proteins 0.000 description 1
- 239000004261 Ascorbyl stearate Substances 0.000 description 1
- LITUBCVUXPBCGA-WMZHIEFXSA-N Ascorbyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O LITUBCVUXPBCGA-WMZHIEFXSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 102100036597 Basement membrane-specific heparan sulfate proteoglycan core protein Human genes 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108010073361 BioXtra Proteins 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- 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 1
- XMWRBQBLMFGWIX-UHFFFAOYSA-N C60 fullerene Chemical class C12=C3C(C4=C56)=C7C8=C5C5=C9C%10=C6C6=C4C1=C1C4=C6C6=C%10C%10=C9C9=C%11C5=C8C5=C8C7=C3C3=C7C2=C1C1=C2C4=C6C4=C%10C6=C9C9=C%11C5=C5C8=C3C3=C7C1=C1C2=C4C6=C2C9=C5C3=C12 XMWRBQBLMFGWIX-UHFFFAOYSA-N 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- 102000000905 Cadherin Human genes 0.000 description 1
- 108050007957 Cadherin Proteins 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
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000220451 Canavalia Species 0.000 description 1
- 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 1
- 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 1
- 241000283707 Capra Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 108010020326 Caspofungin Proteins 0.000 description 1
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 1
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 description 1
- 108010051109 Cell-Penetrating Peptides Proteins 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
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 241000206575 Chondrus crispus Species 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 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
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010042086 Collagen Type IV Proteins 0.000 description 1
- 102000004266 Collagen Type IV Human genes 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 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
- 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
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 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
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- IMQLKJBTEOYOSI-UHFFFAOYSA-N Diphosphoinositol tetrakisphosphate Chemical compound 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
- 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
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 108010049047 Echinocandins Proteins 0.000 description 1
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 description 1
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
- 229930183931 Filipin Natural products 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- 102000004858 Growth differentiation factor-9 Human genes 0.000 description 1
- 108090001086 Growth differentiation factor-9 Proteins 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 102100031000 Hepatoma-derived growth factor Human genes 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
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001076407 Homo sapiens Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 101001001487 Homo sapiens Phosphatidylinositol-glycan biosynthesis class F protein Proteins 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 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 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
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108010061833 Integrases Proteins 0.000 description 1
- 229940119178 Interleukin 1 receptor antagonist Drugs 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 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
- 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 1
- 108010085895 Laminin Proteins 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 206010024612 Lipoma Diseases 0.000 description 1
- 108010028921 Lipopeptides Proteins 0.000 description 1
- 229930184725 Lipoxin Natural products 0.000 description 1
- 102000004317 Lyases Human genes 0.000 description 1
- 108090000856 Lyases Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 108010021062 Micafungin Proteins 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- 239000012901 Milli-Q water Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 101100334745 Mus musculus Fgfr4 gene Proteins 0.000 description 1
- 201000004458 Myoma Diseases 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 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 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 208000007256 Nevus Diseases 0.000 description 1
- YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 208000025174 PANDAS Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000021155 Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 240000000220 Panda oleosa Species 0.000 description 1
- 235000016496 Panda oleosa Nutrition 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 108010040201 Polymyxins Proteins 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
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- AQXXZDYPVDOQEE-MXDQRGINSA-N Pyrantel pamoate Chemical compound CN1CCCN=C1\C=C\C1=CC=CS1.C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 AQXXZDYPVDOQEE-MXDQRGINSA-N 0.000 description 1
- ZVGNESXIJDCBKN-WUIGKKEISA-N R-Tiacumicin B Natural products O([C@@H]1[C@@H](C)O[C@H]([C@H]([C@H]1O)OC)OCC1=CC=CC[C@H](O)C(C)=C[C@@H]([C@H](C(C)=CC(C)=CC[C@H](OC1=O)[C@@H](C)O)O[C@H]1[C@H]([C@@H](O)[C@H](OC(=O)C(C)C)C(C)(C)O1)O)CC)C(=O)C1=C(O)C(Cl)=C(O)C(Cl)=C1CC ZVGNESXIJDCBKN-WUIGKKEISA-N 0.000 description 1
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 1
- 229930189077 Rifamycin Natural products 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 102000003800 Selectins Human genes 0.000 description 1
- 108090000184 Selectins Proteins 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QTENRWWVYAAPBI-YZTFXSNBSA-N Streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.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](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O.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](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O QTENRWWVYAAPBI-YZTFXSNBSA-N 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 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
- 229940123237 Taxane Drugs 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- 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 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- JPBAVLUULZJFFO-JENHRLMUSA-N [(2s)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O JPBAVLUULZJFFO-JENHRLMUSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- TYBHXIFFPVFXQW-UHFFFAOYSA-N abafungin Chemical compound CC1=CC(C)=CC=C1OC1=CC=CC=C1C1=CSC(NC=2NCCCN=2)=N1 TYBHXIFFPVFXQW-UHFFFAOYSA-N 0.000 description 1
- 229950006373 abafungin Drugs 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229950006816 albaconazole Drugs 0.000 description 1
- UHIXWHUVLCAJQL-MPBGBICISA-N albaconazole Chemical compound C([C@@](O)([C@H](N1C(C2=CC=C(Cl)C=C2N=C1)=O)C)C=1C(=CC(F)=CC=1)F)N1C=NC=N1 UHIXWHUVLCAJQL-MPBGBICISA-N 0.000 description 1
- 229960002669 albendazole Drugs 0.000 description 1
- HXHWSAZORRCQMX-UHFFFAOYSA-N albendazole Chemical compound CCCSC1=CC=C2NC(NC(=O)OC)=NC2=C1 HXHWSAZORRCQMX-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229960001040 ammonium chloride Drugs 0.000 description 1
- 229960003204 amorolfine Drugs 0.000 description 1
- 108010072788 angiogenin Proteins 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229960003348 anidulafungin Drugs 0.000 description 1
- JHVAMHSQVVQIOT-MFAJLEFUSA-N anidulafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@@H](C)O)[C@H](O)[C@@H](O)C=2C=CC(O)=CC=2)[C@@H](C)O)=O)C=C1 JHVAMHSQVVQIOT-MFAJLEFUSA-N 0.000 description 1
- 239000000420 anogeissus latifolia wall. gum Substances 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000003302 anti-idiotype Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940044684 anti-microtubule agent Drugs 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 235000019276 ascorbyl stearate Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 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 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 238000002869 basic local alignment search tool Methods 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960002206 bifonazole Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960002962 butenafine Drugs 0.000 description 1
- ABJKWBDEJIDSJZ-UHFFFAOYSA-N butenafine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)CC1=CC=C(C(C)(C)C)C=C1 ABJKWBDEJIDSJZ-UHFFFAOYSA-N 0.000 description 1
- 229960005074 butoconazole Drugs 0.000 description 1
- SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229940043253 butylated hydroxyanisole 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
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 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
- 229960002283 calcium glubionate Drugs 0.000 description 1
- YPCRNBPOUVJVMU-LCGAVOCYSA-L calcium glubionate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.[O-]C(=O)[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 YPCRNBPOUVJVMU-LCGAVOCYSA-L 0.000 description 1
- 229960002562 calcium glucoheptonate Drugs 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- 229960004494 calcium gluconate 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
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 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
- ISTDKKXGLPXJHF-UHFFFAOYSA-N calcium oxygen(2-) phosphoric acid Chemical compound [O--].[Ca++].OP(O)(O)=O ISTDKKXGLPXJHF-UHFFFAOYSA-N 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 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
- 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 1
- YZLMERHFSCVBKZ-UHFFFAOYSA-L calcium;pentanoate Chemical compound [Ca+2].CCCCC([O-])=O.CCCCC([O-])=O YZLMERHFSCVBKZ-UHFFFAOYSA-L 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229960004348 candicidin Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 description 1
- 229960003034 caspofungin Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 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
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 229960004375 ciclopirox olamine Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000003246 corticosteroid 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
- 239000006071 cream Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000005549 deoxyribonucleoside Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229960003974 diethylcarbamazine Drugs 0.000 description 1
- RCKMWOKWVGPNJF-UHFFFAOYSA-N diethylcarbamazine Chemical compound CCN(CC)C(=O)N1CCN(C)CC1 RCKMWOKWVGPNJF-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 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
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 229960003913 econazole Drugs 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 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 1
- 229960005420 etoposide Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 229960001274 fenticonazole Drugs 0.000 description 1
- 229950000152 filipin Drugs 0.000 description 1
- IMQSIXYSKPIGPD-NKYUYKLDSA-N filipin Chemical compound CCCCC[C@H](O)[C@@H]1[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@H](O)\C(C)=C\C=C\C=C\C=C\C=C\[C@H](O)[C@@H](C)OC1=O IMQSIXYSKPIGPD-NKYUYKLDSA-N 0.000 description 1
- IMQSIXYSKPIGPD-UHFFFAOYSA-N filipin III Natural products CCCCCC(O)C1C(O)CC(O)CC(O)CC(O)CC(O)CC(O)CC(O)C(C)=CC=CC=CC=CC=CC(O)C(C)OC1=O IMQSIXYSKPIGPD-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- 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 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 150000005699 fluoropyrimidines Chemical class 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- XCWFZHPEARLXJI-UHFFFAOYSA-N fomivirsen Chemical compound C1C(N2C3=C(C(NC(N)=N3)=O)N=C2)OC(CO)C1OP(O)(=S)OCC1OC(N(C)C(=O)\N=C(\N)C=C)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(N=C(N)C=C2)=O)CC1OP(O)(=S)OCC(C(C1)OP(S)(=O)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)OC1N1C=C(C)C(=O)NC1=O XCWFZHPEARLXJI-UHFFFAOYSA-N 0.000 description 1
- 229960001447 fomivirsen Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- 229910003472 fullerene Inorganic materials 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052733 gallium Inorganic materials 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 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 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 229910021389 graphene Inorganic materials 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 235000019314 gum ghatti Nutrition 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 108010052188 hepatoma-derived growth factor Proteins 0.000 description 1
- WHWDWIHXSPCOKZ-UHFFFAOYSA-N hexahydrofarnesyl acetone Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)=O WHWDWIHXSPCOKZ-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 1
- 229960000908 idarubicin Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 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
- 230000010354 integration Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 239000003407 interleukin 1 receptor blocking agent Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960004849 isoconazole Drugs 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- 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 1
- 238000012933 kinetic analysis Methods 0.000 description 1
- 239000000832 lactitol Substances 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
- 235000010448 lactitol Nutrition 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 235000005772 leucine Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229940041028 lincosamides Drugs 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 150000002639 lipoxins Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229960000816 magnesium hydroxide Drugs 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 201000000271 mature teratoma Diseases 0.000 description 1
- 229960003439 mebendazole Drugs 0.000 description 1
- BAXLBXFAUKGCDY-UHFFFAOYSA-N mebendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CC=C1 BAXLBXFAUKGCDY-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960002159 micafungin Drugs 0.000 description 1
- PIEUQSKUWLMALL-YABMTYFHSA-N micafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS(O)(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 PIEUQSKUWLMALL-YABMTYFHSA-N 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- FXWHFKOXMBTCMP-WMEDONTMSA-N milbemycin Natural products COC1C2OCC3=C/C=C/C(C)CC(=CCC4CC(CC5(O4)OC(C)C(C)C(OC(=O)C(C)CC(C)C)C5O)OC(=O)C(C=C1C)C23O)C FXWHFKOXMBTCMP-WMEDONTMSA-N 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- QXYYYPFGTSJXNS-UHFFFAOYSA-N mitozolomide Chemical compound N1=NN(CCCl)C(=O)N2C1=C(C(=O)N)N=C2 QXYYYPFGTSJXNS-UHFFFAOYSA-N 0.000 description 1
- 229950005967 mitozolomide Drugs 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- UFVHVURXVBHPDA-UHFFFAOYSA-N n-(dichloromethyl)-n-ethylethanamine Chemical compound CCN(CC)C(Cl)Cl UFVHVURXVBHPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004313 naftifine Drugs 0.000 description 1
- OZGNYLLQHRPOBR-DHZHZOJOSA-N naftifine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OZGNYLLQHRPOBR-DHZHZOJOSA-N 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 239000002071 nanotube Substances 0.000 description 1
- 239000002070 nanowire Substances 0.000 description 1
- 229960003940 naproxen sodium Drugs 0.000 description 1
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 1
- 229960003255 natamycin Drugs 0.000 description 1
- 235000010298 natamycin Nutrition 0.000 description 1
- 239000004311 natamycin Substances 0.000 description 1
- NCXMLFZGDNKEPB-FFPOYIOWSA-N natamycin Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C[C@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 229960000801 nelarabine Drugs 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
- 230000000926 neurological effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229960001920 niclosamide Drugs 0.000 description 1
- RJMUSRYZPJIFPJ-UHFFFAOYSA-N niclosamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC=C([N+]([O-])=O)C=C1Cl RJMUSRYZPJIFPJ-UHFFFAOYSA-N 0.000 description 1
- 108010008217 nidogen Proteins 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical compound [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 229960002950 novobiocin Drugs 0.000 description 1
- YJQPYGGHQPGBLI-KGSXXDOSSA-N novobiocin Chemical compound O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960004031 omoconazole Drugs 0.000 description 1
- JMFOSJNGKJCTMJ-ZHZULCJRSA-N omoconazole Chemical compound C1=CN=CN1C(/C)=C(C=1C(=CC(Cl)=CC=1)Cl)\OCCOC1=CC=C(Cl)C=C1 JMFOSJNGKJCTMJ-ZHZULCJRSA-N 0.000 description 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- 208000008798 osteoma Diseases 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 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 1
- 229960003483 oxiconazole Drugs 0.000 description 1
- QRJJEGAJXVEBNE-MOHJPFBDSA-N oxiconazole Chemical compound ClC1=CC(Cl)=CC=C1CO\N=C(C=1C(=CC(Cl)=CC=1)Cl)\CN1C=NC=C1 QRJJEGAJXVEBNE-MOHJPFBDSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical compound [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 208000003154 papilloma Diseases 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 230000007903 penetration ability Effects 0.000 description 1
- 108010049224 perlecan Proteins 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229960004838 phosphoric acid Drugs 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
- 229960001221 pirarubicin Drugs 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000003361 porogen Substances 0.000 description 1
- 229960001589 posaconazole Drugs 0.000 description 1
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 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
- 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
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 229940043349 potassium metabisulfite Drugs 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 229960000996 pyrantel pamoate Drugs 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 0.000 description 1
- 229950004154 ravuconazole Drugs 0.000 description 1
- 238000005067 remediation Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229960003292 rifamycin Drugs 0.000 description 1
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052706 scandium Inorganic materials 0.000 description 1
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 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
- 229910052711 selenium Inorganic materials 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- FVLVBPDQNARYJU-UHFFFAOYSA-N semustine Chemical compound CC1CCC(NC(=O)N(CCCl)N=O)CC1 FVLVBPDQNARYJU-UHFFFAOYSA-N 0.000 description 1
- 229960005429 sertaconazole Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 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
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 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
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 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
- 238000003980 solgel method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000002336 sorption--desorption measurement Methods 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000037959 spinal tumor Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960002607 sulconazole Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 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 1
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical compound [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
- 229960000580 terconazole Drugs 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 150000004905 tetrazines Chemical class 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 239000004308 thiabendazole Substances 0.000 description 1
- 229960004546 thiabendazole Drugs 0.000 description 1
- 235000010296 thiabendazole Nutrition 0.000 description 1
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- 229960004214 tioconazole Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000000954 titration curve Methods 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 1
- 229960004880 tolnaftate Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 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 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- ZSDSQXJSNMTJDA-UHFFFAOYSA-N trifluralin Chemical compound CCCN(CCC)C1=C([N+]([O-])=O)C=C(C(F)(F)F)C=C1[N+]([O-])=O ZSDSQXJSNMTJDA-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
- B82B1/00—Nanostructures formed by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
- B82B1/008—Nanostructures not provided for in groups B82B1/001 - B82B1/007
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
- C12N9/80—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
-
- 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
- A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- 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
- A61K47/6861—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 the tumour determinant being from kidney or bladder cancer 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
- A61K47/6921—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y35/00—Methods or apparatus for measurement or analysis of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/03—Particle morphology depicted by an image obtained by SEM
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/50—Agglomerated particles
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/60—Particles characterised by their size
- C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y305/00—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5)
- C12Y305/01—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5) in linear amides (3.5.1)
- C12Y305/01005—Urease (3.5.1.5)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Nanotechnology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Urology & Nephrology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- Gastroenterology & Hepatology (AREA)
- Cell Biology (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Food Science & Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
本发明提供了一种酶驱动的纳米马达,其包括具有表面的颗粒、酶和异源分子;其特征在于,所述酶和所述异源分子不连续地附着在所述颗粒的整个表面之上。本发明还提供了所述纳米马达,其用于治疗、诊断和预后,具体地用于治疗癌症。另外,本发明提供了纳米马达的用途,其用于检测分离的样品中的分析物。
Description
本申请要求于2018年12月5日提交的欧洲专利申请EP18382896的权益。
技术领域
本发明属于纳米技术领域。具体地,本发明涉及外部官能化的酶驱动的纳米马达。本发明的纳米马达对于治疗和生物传感特别有用。
背景技术
催化微泳器是一种人工系统,由于将化学能转化为机械力,最终转化为主动运动,因此能够实现自推进。
尽管化学驱动的微型和纳米马达在许多领域,如环境修复、货物运输和递送、组织和细胞渗透以及活性药物在体内向胃部的递送中都显示出有前景的适用性,但其在生物医学中的实施经常受到燃料固有的毒性或在生物体内的有限可用性的限制。
近来,酶催化的使用已成为替代常用的有毒燃料的有吸引力的替代方法,因为其具有独特的特征,包含生物相容性、多功能性和燃料生物利用度。在这方面,尿素酶、过氧化氢酶和葡萄糖氧化酶的使用已显示出在酶底物的生理相关浓度下增加了纳米大小的颗粒的扩散。
另外,当使用尿素酶为中空二氧化硅Janus颗粒提供动力时——即,具有两个半球的颗粒,其中仅一个与酶偶联,可以实现定向推进。可以通过添加酶抑制盐来开启和关闭其运动,并且可以通过施加磁场按需修改轨迹,从而实现高度可控性(Xing MA等人,“尿素驱动的生物相容性中空微胶囊的运动控制(Motion Control of Urea-PoweredBiocompatible Hollow Microcapsules)”,《ACS纳米(ACS Nano.)》,2016,第10(3)卷,第3597-605页)。
还已经描述了使用酶推进的纳米马达来提高体外阿霉素到癌细胞的递送效率(Ana C.等人,“酶驱动的纳米机器人增强抗癌药物递送(Enzyme-Powered NanobotsEnhance Anticancer Drug Delivery)”,《先进功能材料(Advanced FunctionalMaterials)》,2017,第28(25)卷)。
然而,球形Janus颗粒的生产涉及昂贵且费时的技术,这可能会损害其可扩展性并因此损害其适用性。
最近,并且尽管事实上传统上一直声称催化剂的不对称结构和分布对于产生主动运动是必不可少的,但结果表明,非Janus球形马达的自推进是由定位在整个颗粒表面的酶催化驱动的(Patino T.等人,“酶数量和分布对非Janus尿素酶驱动的微型马达的自推进的影响(Influence of Enzyme Quantity and Distribution on the Self-Propulsion ofNon-Janus Urease-Powered Micromotors)”,《美国化学学会期刊(J.Am.Chem.Soc.)》,2018,第140(25)卷,第7896-7903页)。然而,此类型的纳米马达的移动显示出对酶覆盖率极为敏感。实际上,已经发现每个纳米马达大量的酶分子对于实现期望的移动是必需的。由于其对外部官能化的限制性,这严重阻碍了这些纳米马达的使用和适用性。
因此,尽管到目前为止已经做出了努力,但是仍然需要易于生产并适应各种应用同时维持高移动能力的酶驱动的纳米马达。
发明内容
本发明人已经开发了在多种生物医学、化学和环境应用中有用的新颖的酶推进的官能化纳米马达。
令人惊讶地,发明人发现,通过将分子外部附着到酶驱动的非Janus纳米马达,所述纳米马达可以维持或者甚至增加颗粒的速度和移动模式(参见图2D和图7B)。
这是非常出乎意料的,因为先前已经证明了其中推进酶附着在颗粒的整个表面之上的纳米马达的移动高度依赖于酶覆盖率。因此,当酶数量降到给定阈值以下时,表明完全消除了颗粒的移动(T.等人,同上)。因此,显而易见的是,预期在这些颗粒的表面上进行的必定减少用于酶附着的可用表面的任何修饰会降低纳米马达移动能力,并因此降低其适用性。
如以下实例所示,发明人发现不同类型的大分子的外部附着,如抗体或DNA结构,不仅不影响纳米马达的移动,而且还增加了所述纳米马达的细胞穿透能力、稳定性并避免了所述纳米马达聚集。图4表明尽管没有任何细胞穿透肽,但用抗体官能化的纳米马达具有更高的穿透肿瘤细胞的能力。
另外,发明人惊奇地发现,本文提供的官能化酶驱动的纳米马达表现出如此强的活性,使得即使所述纳米马达没有装载任何细胞毒性药物,其也能够增加癌细胞的死亡(参见图4D)。这构成了很大的优势,因为其允许开发特异性更高且继发效应更低的抗癌治疗药物。
本发明的纳米马达的重要优点在于其多功能性-所述纳米马达可以用不同的酶工程化以使其仅在存在底物的位置中才具有活性。这进一步提供了允许开发具有高特异性和低继发效应的治疗的优点。
鉴于上述情况,本发明的纳米马达提供了用于如疾病治疗和生物传感等多种领域的非常有价值的工具。
因此,在第一方面中,本发明提供了一种酶驱动的纳米马达,其包括具有表面的颗粒;酶;以及异源分子;其特征在于,所述酶和所述异源分子不连续地附着在所述颗粒的整个表面之上。本发明还提供了一种酶驱动的纳米马达,其包括具有表面的颗粒;酶;以及异源分子;其中所述酶和所述异源分子不连续地附着在所述颗粒的整个表面之上。
在第二方面中,本发明提供了一种药物组合物,其包括治疗有效量的根据第一方面所述的纳米马达,以及药学上可接受的赋形剂和/或载体。
在第三方面中,本发明提供了根据第一方面所述的纳米马达或根据第二方面所述的药物组合物,其用于治疗、诊断或预后。
在第四方面中,本发明提供了一种成套试剂盒,其包括根据第一方面所述的纳米马达,或根据第二方面所述的药物组合物,以及任选地其使用说明书。本发明还提供了一种成套试剂盒,其包括根据第一方面所述的纳米马达,或根据第二方面所述的药物组合物,以及其使用说明书。本发明的试剂盒可以进一步包括适于稀释本发明的纳米马达的缓冲液,或重悬本发明的干燥或冻干的纳米马达的缓冲液。
在第五方面中,本发明提供了一种检测分离的样品中的分析物的体外方法,所述体外方法包括使根据第一方面所述的纳米马达与样品接触。
在第六方面中,本发明提供了根据第一方面所述的纳米马达在体外方法中的用途,所述纳米马达用于检测分离的样品中的分析物。
附图说明
与实例1有关的图1示出了尿素酶/PEG纳米马达(MSNP-Ur/PEG)和抗体修饰的尿素酶纳米马达(MSNP-Ur/PEG-Ab)的制备和表征。A)方案展示了逐步制造过程以获得纳米马达。
与实例1有关的图2示出了MSNP-Ur/PEG和MSNP-Ur/PEG-Ab的运动分析。A)MSNP-Ur/PEG纳米马达和B)MSNP-Ur/PEG-Ab纳米马达在0mM、50mM和100mM尿素下的代表性跟踪轨迹以及C)两种类型的纳米马达在0mM、50mM和100mM下的代表性均方位移(MSD)。D)通过MSD分析在不同尿素浓度下获得的有效扩散系数(N=20,误差线表示SE,p<0.001)。
与实例1有关的图3示出了在存在不同尿素浓度的情况下,具有以及不具有抗体的纳米马达对球体的活力的影响。在不同尿素浓度(N=3,误差线表示SE)下,在用MSNP-Ur/PEG(最初为蓝色)和MSNP-Ur/PEG-Ab(最初为红色)温育4小时后,对球体的活力进行定量。
与实例1有关的图4示出了抗体修饰的纳米马达靶向和渗透到膀胱癌球体中的能力。在温育4小时后,在存在尿素(40mM)和不存在尿素的情况下,对抗体修饰的纳米马达内化到膀胱癌球体进行定量,并在48小时静置时间段之后测量后,在存在尿素(40mM)和不存在尿素的情况下,对与MSNP-Ur/PEG和MSNP-Ur/PEG-Ab温育4小时的球体的增殖进行定量。
与实例2有关的图5示出了DNA微型马达的制造方法和表征。A)微型马达制造的示意性图示,其中通过添加APTES和TEOS二氧化硅前体使二氧化硅层生长在商用聚苯乙烯模板上生长。然后通过DMF去除聚苯乙烯芯,并通过使用戊二醛(GA)接头将微胶囊用尿素酶和DNA支架进行官能化。B)pH响应性DNA纳米开关与共价连接在微型马达上的互补DNA支架杂交。通过尿素转化为氨和二氧化碳来实现通过尿素酶介导的自推进。C)单分子DNA纳米开关的pH依赖性三链体到双链体转变导致FRET效率发生变化。D)SiO2微胶囊的扫描电子显微照片。插图示出了放大的所选区域。比例尺=2μm。E)通过透射电子显微镜获得的地形图像。校准条指示以μm为单位的高度。F)沿官能化过程的微粒表面的Z电位测量结果(NH2=通过合成产生的胺涂层颗粒;GA=在与戊二醛温育后的微粒,UR=尿素酶-官能化的微粒;UR+DNAss=用尿素酶和DNA支架两者官能化的微粒;开关=在与DNA开关杂交持续30分钟之后尿素酶和DNA支架官能化的微粒)。
与实例2有关的图6示出,基于三链体的pH响应性DNA纳米开关能够检测溶液中的pH变化并与微型马达结构缀合。A)三链体DNA纳米开关通过形成pH不敏感的沃森-克里克相互作用(Watson-Crick interactions)(虚线)和pH敏感的胡格斯丁(Hoogsteen)相互作用(点)来形成分子内双发夹结构。含有CGC和TAT三联体的三链体纳米开关通过增加溶液的pH值而展开成双链体构象。比率计FRET发射(左)示出了DNA纳米开关的三链体到双链体转变随溶液中pH变化。B)DNA纳米开关官能化微粒的FRET效应的CSLM分析,从右到左示出了Cy3通道、FRET通道和FRET/Cy3比值,在校准栏中指示。比例尺=2μm。白色箭头指示官能化微粒(对于Cy3通道,最初为红色,对于FRET通道为绿色,对于Cy3/FRET合并为黄色)。通过DNA官能化微型马达针对pH敏感(C)和非pH特异(D)的定量pH测量,示出为平均FRET/Cy3发射值,示出为平均值±平均值的标准误差。
与实例2有关的图7。A)DNA开关微型马达的MSD。结果示出为平均值±平均值的标准误差。B)根据MSD计算的速度。结果示出为平均值±平均值的标准误差。
具体实施方式
除非另有说明,否则本申请中本文使用的所有术语应以本领域已知的普通含义来理解。在本申请中使用的某些术语的其它更具体的定义如下文所述,并且旨在贯穿整个说明书和权利要求书中统一地应用,除非另外明确陈述的定义提供了更宽泛的定义。
如本文中所使用的,不定冠词“一个和一种(a/an)”与“至少一个”或“一个或多个”同义。除非另有说明,否则本文中使用的定冠词,例如“所述”也包含名词的复数形式。
术语“酶推进的纳米马达”或“酶驱动的纳米马达”是指在微米或纳米级的分子装置,其能够通过定位在装置的表面上的酶的作用将化学能转化为移动。换句话说,纳米马达是用酶外部官能化的纳米颗粒或微粒。不受理论的束缚,酶通过催化反应中涉及的产物的不对称释放而产生移动,从而产生取决于渗透梯度、电荷或其它特性的界面力。术语“纳米马达”和“微型马达”在本申请中可互换使用。
如本文所使用的,“异源分子”是指与一种或多种酶不同的任何分子,所述一种或多种酶负责纳米马达的推进,并且不连续地附着在颗粒的整个表面之上。实施例由此使基本上可以与颗粒连接的任何类型的分子通过其与颗粒的直接或间接连接而被固定在表面上。
下文提供的异源分子的列表仅应被视为可以用于本发明的纳米马达的分子的说明性且非限制性的列表。然而,实施例不限于此,并且涵盖可以与实施例的纳米马达直接或间接连接的任何异源分子。
所关注的异源分子可以选自标志物,如荧光标志物,即荧光团,例如,异硫氰酸荧光素(FITC)、异硫氰酸四甲基罗丹明(TRITC)和其它异硫氰酸酯;N-羟基琥珀酰亚胺(NHS)荧光素和其它琥珀酰亚胺酯;荧光素-5-马来酰亚胺和其它马来酰亚胺活化的荧光团;花菁荧光团;荧光素荧光团;罗丹明荧光团;ATTO染料;DyLight Fluor染料;Alexa Fluor染料;和硼-二吡咯亚甲基(BODIPY)染料。另外的实例包含同位素标记或标志物、化学发光标志物、不透射线标志物等。在这种情况下,可以将纳米马达用作测试分子以能够使用标志物在表面上检测纳米马达。
异源分子的另外的实例包含细胞粘附和细胞附着分子,如细胞粘附分子(CAM),包含免疫球蛋白(Ig)超家族、整联蛋白、钙粘蛋白和选择蛋白。
异源分子的另外的实例是细胞外基质(ECM)分子,包含例如蛋白聚糖(PG)、糖胺聚糖(GAG)、硫酸乙酰肝素(HS)、硫酸软骨素、硫酸角蛋白、胶原蛋白、弹性蛋白等。
所关注的分子的相关类型是基底层分子,其包含基底层的分子,所述基底层是上皮细胞分泌的一层ECM。此类基底层分子的非限制性实例包含层粘连蛋白、IV型胶原蛋白、巢蛋白和基底膜聚糖。
所关注的异源分子的又另一个实例是抗炎分子,如皮质类固醇;糖皮质激素;非甾体类抗炎药(NSAID),如乙酰水杨酸、异-丁基-丙酸-酚酸和萘普生钠(INN);脂氧素;白介素-1受体拮抗剂(IL-1RA);等等。
抗生素也可以用作所关注的异源分子,以抑制细菌生长或杀伤细菌。抗生素的非限制性实例包含青霉素;头孢菌素;多粘菌素;利福霉素;闰年霉素;喹诺酮类;磺酰胺;大环内酯类;林可酰胺类;四环素;杀菌性氨基糖苷类;环状脂肽,如达托霉素;甘氨酰环素,如替加环素;噁唑烷酮,如利奈唑胺;和闰年霉素,如非达霉素。
以类似方式,靶向其它类型微生物的分子,如抗真菌分子,例如,多烯抗真菌剂,如两性霉素B、杀念菌素、菲律宾菌素、哈霉素、游霉素、制霉菌素和龟裂霉素;唑类抗真菌剂,如咪唑类,例如,联苯苄唑、布康唑、克霉唑、益康唑、芬替康唑、异康唑、咪康唑、奥莫康唑、奥昔康唑、舍他康唑、硫康唑和噻康唑;三唑,例如,阿尔巴康唑、氟康唑、艾沙康唑、伊曲康唑、泊沙康唑、雷夫康唑、特康唑和伏立康唑;和噻唑类,例如,阿巴芬净;烯丙胺类,如阿莫罗芬、布替萘芬、萘替芬和特比萘芬;棘白菌素类,如阿尼芬净、卡泊芬净和米卡芬净;苯甲酸;环吡酮胺;氟胞嘧啶;灰黄霉素;托萘酯和十一碳烯酸。还有抗病毒分子,例如,病毒相关蛋白(VAP)抗独特型抗体;金刚烷胺;金刚乙胺;普拉康纳利;阿昔洛韦;齐多夫定(AZT);拉米夫定;整合酶;福米韦森;利福平;扎那米韦和奥司他韦,以及抗寄生虫分子,如甲苯咪唑;双羟萘酸噻嘧啶;噻苯咪唑;乙胺嗪;伊维菌素;氯硝柳胺;吡喹酮;阿苯达唑;吡喹酮;利福平;两性霉素B;美拉胂醇;依氟鸟氨酸;甲硝哒唑;替硝唑和米替福新可以用作所关注的异源分子。
异源分子的另外的实例包含生长因子,如肾上腺髓质素(AM)、血管生成素(Ang)、自分泌运动因子、骨形态发生蛋白(BMP)、脑源性神经营养因子(BDNF)、表皮生长因子(EGF)、促红细胞生成素(EPO)、成纤维细胞生长因子(FGF)、神经胶质细胞系源性神经营养因子(GDNF)、粒细胞集落刺激因子(G-CSF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、生长分化因子-9(GDF9)、肝细胞生长因子(HGF)、肝癌衍生生长因子(HDGF)、胰岛素样生长因子(IGF)、肌生长抑制素(GDF-8)、神经生长因子(NGF)、血小板衍生生长因子(PDGF)、促血小板生成素(TPO)、转化生长因子α(TGF-α)、转化生长因子β(TGF-β)、肿瘤坏死因子α(TNF-α)、血管内皮生长因子(VEGF)、胎盘生长因子(PIGF)等。具有与表面结合肽连接的生长因子的纳米马达可以用于提供具有例如刺激细胞生长、增殖和/或细胞分化能力的表面。
所关注的异源分子的另外的实例包含细胞生长抑制剂和化学治疗剂。当包含在纳米马达中时,这种类型的异源分子将提供局部细胞生长抑制作用。此类所关注的异源分子的非限制性实例包含法呢基转移酶抑制剂;烷基化剂,如氮芥,例如,二氯甲基二乙胺、环磷酰胺、美法仑、苯丁酸氮芥、异环磷酰胺和白消安;亚硝基脲,例如,N-亚硝基-N-甲基脲(MNU)、卡莫斯汀(BCNU)、洛莫司汀(CCNU)、司莫司汀(MeCCNU)、福莫司汀和链尿素佐菌素;四嗪,例如,达卡巴嗪、米托唑胺和替莫唑胺和氮丙啶类,例如,噻替派、丝裂霉素、亚丝醌(AZQ);和顺铂,例如,顺铂、卡铂和奥沙利铂;抗代谢物,如抗叶酸,例如,甲氨蝶呤和培美曲塞;氟嘧啶,例如,氟尿嘧啶和卡培他滨;脱氧核苷类类似物,如阿糖胞苷、吉西他滨、地西他滨、维达扎、氟达拉滨、奈拉拉滨、克拉屈滨、氯法拉滨和喷司他汀;和硫嘌呤,例如,硫鸟嘌呤和巯嘌呤;抗微管剂,如长春花生物碱,例如,长春新碱、长春花碱、长春瑞滨、长春地辛和长春氟宁;和紫杉烷,例如,紫杉醇和多西他赛;和鬼臼毒素;拓扑异构酶抑制剂,如伊立替康、拓扑替康、喜树碱、依托泊苷、阿霉素、米托蒽醌、替尼泊苷、新生霉素、美巴龙和阿柔比星;细胞毒性抗生素,如蒽环类,例如,阿霉素、道诺霉素、表柔比星、伊达比星、吡柔比星、阿柔比星、米托蒽醌、放线菌素、博来霉素、普卡霉素和丝裂霉素。
所关注的其它异源分子组包含多核苷酸,如DNA或RNA分子。异源分子也可以是纳米传感器或分子门。
“不连续地附着在整个表面之上”是指不限于颗粒的单个面或半球体的离散分布,即,其是指非极性分布。然而,这并不意味着分子以均匀的方式覆盖了颗粒的整个表面。本发明的颗粒可以呈现外部附着的分子,从而在颗粒的整个表面之上形成离散的斑块,或者相同的,呈现出其中没有附着分子的间隙。
如本文所用,“靶向分子”是指对特定细胞、组织或器官具有特异性的分子。靶向分子的优选实例包含但不限于抗体、生长因子和多糖。
如本文所使用的,“纳米传感器”是指任何纳米或微米级感测装置。本发明的纳米传感器能够检测并响应其所处环境的变化。具体地,本发明的纳米传感器可以是纳米开关,其是能够在两种不同形式之间切换的纳米传感器。DNA纳米开关含有具有构象的单链DNA分子,所述构象响应于例如pH变化等环境变化而变化。DNA分子可以与允许检测构象变化的荧光分子偶联。
如本文所使用的,“标记分子”是指可以与纳米马达化学结合并发出可检测的信号以使纳米马达能够被检测到的分子。标记分子的特别优选的实例包含但不限于化学发光分子、荧光分子和同位素。
如本文所使用的,“分子门”或“纳米阀”是指纳米或微米级的分子系统,其响应于如光、温度、磁场和pH等所选触发而在第一闭合形式与第二打开形式之间切换。闭合形式的设计阻断释放分子门附着的颗粒中含有的货物。在施加触发之后,门将变成打开形式,从而可以释放货物。
“抗癌抗体”是指具有阻止或消除癌细胞的能力的抗体。
如上所述,本发明在第一方面中提供了用异源分子外部官能化的酶驱动的纳米马达。
在第一方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,颗粒是纳米颗粒或微粒。本文所使用的术语“纳米颗粒”是指在纳米级上具有至少两个维度,具体地在纳米级上具有所有三个维度的颗粒。为了类比,本文所使用的术语“微粒”是指在微米级上具有至少两个维度,具体地在微米级上具有所有三个维度的颗粒。在特定的实施例中,颗粒为1nm到100μm。具体地,30nm到2μm。更具体地,100nm到1μm。甚至更具体地,400nm到600nm。
关于本文描述的纳米颗粒或微粒的形状,包含球体、多面体和棒状。具体地,当纳米颗粒或微粒是具有基本上圆形横截面的如纳米线或纳米管、微线或微管等基本上棒状时,“纳米颗粒”或“微粒”是指在纳米级或微米级上具有至少两个维度的颗粒,这两个维度是纳米颗粒或微粒的横截面。
在第一方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,颗粒是球形的。
如本文所使用的,术语“大小”是指特征物理尺寸。例如,在纳米颗粒/微粒基本上为球形的情况下,纳米颗粒/微粒的大小对应于纳米颗粒/微粒的直径。当将一组纳米颗粒/微粒称为特定大小时,可设想到所述一组纳米颗粒/微粒可以具有围绕指定大小的大小分布。因此,如本文所使用的,一组纳米颗粒/微粒的大小可以指大小分布的模式,如大小分布的峰大小。另外,当不是完全球形时,直径是包含物体的球体的当量直径。此直径通常被称为“流体动力学直径”,其可以使用与Atlas细胞增压系统耦接的Wyatt Mobius或Malvern进行测量。透射电子显微镜(TEM)或扫描电子显微镜(SEM)图像也确实提供了关于直径的信息。
技术人员可用多种颗粒材料,并且其将理解,所选择的材料将取决于纳米马达的预期应用,例如,用于治疗用途的纳米马达应由生物相容性颗粒制成。
因此,在第一方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,颗粒由选自由以下组成的组的材料制成:金属、金属氧化物、聚合物、脂质、蛋白质、细胞膜、细胞体、碳质材料和其混合物。在特定实施例中,金属是铝(Al)、铂(Pt)、钯(Pd)或镁(Mg)。在特定实施例中,金属氧化物选自二氧化硅(SiO2)、氧化锰(MnO2)和氧化钛(TiO2)。在特定实施例中,聚合物是聚苯乙烯或金属有机框架。在特定实施例中,碳质材料选自碳、石墨烯和富勒烯。在颗粒实施例中,颗粒的材料是聚合物囊泡。在颗粒实施例中,颗粒是基于蛋白质的颗粒(蛋白质体)。在特定实施例中,细胞体是血小板或红细胞(RBC)。
术语“金属有机框架”或“MOF”是指包括与有机配体配位的金属离子或簇的化合物。中心金属元素可以是选自由以下组成的组的至少一个:锌(Zn)、钴(Co)、镉(Cd)、镍(Ni)、锰(Mn)、铬(Cr)、铜(Cu)、镧(La)、铁(Fe)、铂(Pt)、钯(Pd)、银(Ag)、金(Au)、铑(Rh)、铱(Ir)、钌(Ru)、铅(Pb)、锡(Sn)、铝(Al)、钛(Ti)、钼(Mo)、钨(W)、钒(V)、铌(Nb)、钽(Ta)、钪(Sc)、钇(Y)、镓(Ga)、锗(Ge)、铟(In)、铋(Bi)、硒(Se)和锑(Sb)。有机配体可以包含可连接到至少两个金属离子的官能团。
“细胞膜”是指在细胞周围形成连续屏障的脂质双层。本发明的颗粒可以由原核或真核细胞膜形成。
如本文所使用的,“细胞体”是指含有被细胞质和质膜包围的遗传材料的细胞部分。
术语“聚合物囊泡”是指由两亲性合成嵌段共聚物制成的人工囊泡。
术语“蛋白体”是指由自组装蛋白质或蛋白-聚合物缀合物构成的颗粒。
在特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,颗粒由介孔二氧化硅制成。如本文所使用的,“介孔二氧化硅”是指具有规则布置的中等大小的孔的多孔二氧化硅,具体地,所述孔为2nm到50nm,并且更具体地,为4nm到约40nm。
在第一方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,酶选自由以下组成的组:氧化还原酶、水解酶和裂解酶。在更特定的实施例中,酶选自由以下组成的组:葡萄糖氧化酶、尿素酶、过氧化氢酶、谷氨酸氧化酶、黄嘌呤氧化酶、过氧化物酶、胆红素氧化酶、脂肪酶、蛋白酶和其组合。在更特定的实施例中,酶是尿素酶。术语尿素酶(EC 3.5.1.5)是指使尿素催化水解为二氧化碳和氨的一组酶。在本发明的特定实施例中,尿素酶来自洋刀豆(Canavalia ensiformis)(CAS编号9002-13-5)。在更特定的实施例中,其是来自洋刀豆(CAS编号9002-13-5)的IX型尿素酶。酶的序列可以在各种数据库中找到,如Uniprot(P07374 UREA_CANEN,1994年01月02日更新)。
在第一方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,异源分子选自由以下组成的组:靶向分子、标记分子、纳米传感器和分子门。
在第一方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,异源分子是抗体。在更特定的实施例中,抗体是抗癌抗体。在更特定的实施例中,抗癌抗体结合膜受体。在更特定的实施例中,膜受体是选自由FGFR1、FGFR2、FGFR3和FGFR4组成的组的FGFR(成纤维细胞生长因子受体)。在更特定的实施例中,FGFR是FGFR3。
在第一方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,异源分子是纳米传感器。本领域技术人员可用许多纳米传感器(Campuzano S.等人,“使用电化学推进的纳米马达进行运动驱动的感测和生物感测(Motion-driven sensingand biosensing using electrochemically propelled nanomotors)”,《分析家(Analyst.)》2011,第36(22)卷,第4621-30页)。在特定实施例中,纳米传感器是DNA纳米开关。DNA纳米开关是包括与荧光团-淬灭剂对偶联的单链DNA分子的分子络合物。在特定实施例中,DNA纳米开关的DNA分子的序列与SEQ ID NO:1具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的序列同一性。
在特定实施例中,纳米传感器是纳米颗粒。在更特定的实施例中,纳米传感器是金属纳米颗粒。更具体地,金属纳米颗粒是金(Au)纳米颗粒。本领域技术人员将理解,形成纳米传感器的纳米颗粒必须小于形成纳米马达的纳米颗粒或微粒。
在本发明中,术语“同一性”是指当序列最佳比对时在两个序列中相同的残基的百分比。如果在最佳比对中,第一序列中的位置被与在第二序列中的对应位置相同的氨基酸残基占据,则序列相对于所述位置表现出同一性。两个序列之间的同一性水平(或“序列同一性百分比”)被测量为序列共有的相同位置的数量相对于序列大小的比率(即,序列同一性百分比=(相同位置的数量)/位置总数)×100)。
用于快速获得最佳比对和计算两个或更多个序列之间的同一性的多种数学算法是已知的,并且被并入到多个可用的软件程序中。此类程序的实例包含用于氨基酸序列分析的MATCH-BOX、MULTAIN、GCG、FASTA和ROBUST程序以及其它程序。优选的软件分析程序包含ALIGN、CLUSTAL W和BLAST程序(例如,BLAST 2.1、BL2SEQ及其更高版本)。
对于氨基酸序列分析,在确定同一性时使用权重矩阵,如BLOSUM矩阵(例如,BLOSUM45、BLOSUM50、BLOSUM62和BLOSUM80矩阵)、Gonnet矩阵或PAM矩阵(例如,PAM30、PAM70、PAM120、PAM160、PAM250和PAM350矩阵)。
BLAST程序通过将所选序列相对于数据库(例如,GenSeq)中的多个序列进行比对,或者通过在两个所选序列之间用BL2SEQ进行比对,来提供对至少两个氨基酸序列的分析。优选地,通过如DUST或SEG程序等低复杂度过滤程序来修改BLAST程序,所述低复杂度过滤程序优选地被集成到BLAST程序操作中。如果使用空位存在罚分(或空位评分),则空位存在罚分优选地设置介于约-5与-15之间。类似的空位参数可以适当地与其它程序一起使用。BLAST程序和作为其基础的原理进一步描述于例如Altschul等人,“基本局部比对搜索工具(Basic local alignment search tool)”,1990,《分子生物学杂志(J.Mol.Biol)》,第215卷,第403-410页中。
对于多序列分析,可以使用CLUSTAL W程序。期望使用“动态”(对“快速”)设置运行CLUSTAL W程序。根据序列之间的同一性水平,使用一组可变的BLOSUM矩阵评估氨基酸序列。CLUSTAL W程序和基本操作原理进一步描述于例如Higgins等人,“CLUSTAL V:用于多序列比对的改进软件(CLUSTAL V:improved software for multiple sequencealignment)”,1992,CABIOS,8(2),第189-191页中。
在第一方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,纳米马达进一步包括货物。在特定实施例中,货物选自由药物组成的列表,其中药物选自由以下组成的组:小分子、核酸、治疗性酶、肽、蛋白质或激素。对于“货物”,应理解为在纳米马达内运输的要递送到期望的靶标处的任何分子。取决于颗粒的表面材料和孔隙度,货物可以位于颗粒内部或吸附到其表面。
在特定实施例中,药物是细胞毒性药物。更具体地,其是抗癌药。
在第一方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,酶和异源分子直接或通过接头附着到颗粒表面。在更具体的实施例中,接头选自由以下组成的组:酸酐、醇、酸、胺、环氧树脂、异氰酸酯、硅烷、卤代基团和可聚合基团,优选地3-氨基丙基三乙氧基硅烷(APTES)。在甚至更特定的实施例中,接头是戊二醛。
在此方面,接头的一部分与颗粒的表面结合,并且接头的另一部分与酶或异源分子结合,由此在酶或异源分子与表面之间形成共价键。接头与所述表面与所述酶或异源分子之间的键受到接头与酶或异源分子之间发生的化学反应的影响,由此确保表面与所述酶或异源分子之间的共价键。在一个实施例中,在对颗粒的所述表面进行化学预处理之后,将酶和/或异源分子附着到颗粒的表面。
如上所述,在第二方面中,本发明提供了一种药物组合物,其包括治疗有效量的第一方面的纳米马达,以及药学上可接受的赋形剂和/或载体。
本文所使用的表达“治疗有效量”是指纳米马达在施用时足以预防所解决的疾病或病症的症状中的一种或多种症状的发展或在某种程度上对其进行减轻的量。当然,根据本发明施用的试剂的具体剂量将由围绕病例的具体情况确定,包含施用的纳米马达、施用途径、所治疗的具体病状以及类似的考虑因素。
表达“药物组合物”涵盖旨在用于人以及用于非人动物(即,兽医用组合物)的两种组合物。
术语“药学上可接受的载体或赋形剂”是指药学上可接受的材料、组合物或媒剂。在与药物组合物的其它成分相容的意义上,每种组分必须是药学上可接受的。它还必须适用于以合理的受益/风险比与人和非人动物的组织或器官相接触,而不产生过度的毒性、刺激、过敏反应、免疫原性或其它问题或并发症。
合适的药学上可接受的赋形剂的实例是溶剂、分散介质、稀释剂或其它液体媒剂、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。除非任何常规的赋形剂介质与某种物质或其衍生物不相容,如通过产生任何不期望的生物学作用或以其它有害的方式与药物组合物的任何其它一种或多种组分进行相互作用,否则设想其将在本发明的范围内使用。
本发明的药物组合物中的纳米马达、药学上可接受的赋形剂和/或任何另外的成分的相对量将根据所治疗的受试者的同一性、大小和/或病状,以及进一步地根据组合物所施用的途径而变化。
在药物组合物的制造中使用的药学上可接受的赋形剂包含但不限于惰性稀释剂、分散和/或造粒剂、表面活性剂和/或乳化剂、崩解剂、结合剂、防腐剂、缓冲剂、润滑剂和/或油。根据调配者的判断,组合物中可以存在赋形剂,如着色剂、包衣剂、甜味剂和调味剂。
含有本发明的纳米马达的药物组合物可以以任何剂型存在,例如,固体或液体,并且可以通过任何合适的途径施用,例如,口服、肠胃外、直肠、局部、鼻内或舌下途径,因为所述药物组合物将包含调配物的期望的剂型所必需的药学上可接受的赋形剂,例如,局部调配物(软膏、乳膏、脂凝胶、水凝胶等)、滴眼剂、气雾剂、可注射溶液、渗透泵等。
示例性稀释剂包含但不限于碳酸钙、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、甘露醇、山梨醇、肌醇、氯化钠、干淀粉、玉米淀粉、糖粉和其组合。
示例性制粒剂和/或分散剂包含但不限于马铃薯淀粉、玉米淀粉、木薯淀粉、羟基乙酸淀粉钠、粘土、海藻酸、瓜尔胶、柑橘渣、琼脂、膨润土、纤维素和木材产物、天然海绵、阳离子交换树脂、碳酸钙、硅酸盐、碳酸钠、交联聚乙烯吡咯烷酮(交聚维酮)、羧甲基淀粉钠(羧甲淀粉钠)、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(维格姆(Veegum))、月桂基硫酸钠、季铵化合物和其组合。
示例性结合剂包含但不限于淀粉(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);天然和合成树胶(例如,阿拉伯胶、海藻酸钠、爱尔兰苔藓提取物、潘瓦尔胶、加蒂胶、伊萨波尔豆壳的粘液、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、聚乙烯吡咯烷酮、硅酸铝镁(维格姆)和落叶松阿拉伯半乳聚糖);海藻酸盐;聚氧化乙烯;聚乙二醇;无机钙盐;硅酸;聚甲基丙烯酸酯;蜡;水;醇;以及其组合。
示例性防腐剂可以包含抗氧化剂、螯合剂、抗微生物防腐剂、抗真菌防腐剂、醇防腐剂、酸性防腐剂和其它防腐剂。示例性抗氧化剂包含但不限于α生育酚、抗坏血酸、抗坏血酸棕榈酸酯、抗坏血酸硬脂酸酯、抗坏血酸油酸酯、丁基化羟基茴香醚、丁基化羟基甲苯、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、焦亚硫酸钠以及亚硫酸钠。示例性螯合剂包含乙二胺四乙酸(EDTA)、柠檬酸一水合物、依地酸二钠、依地酸二钾、依地酸、富马酸、苹果酸、磷酸、依地酸钠、酒石酸和依地酸三钠。
示例性缓冲剂包含但不限于柠檬酸盐缓冲溶液、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、葡萄糖酸钙、D-葡萄糖酸、甘油磷酸钙、乳酸钙、丙酸、戊酮酸钙、戊酸、磷酸氢钙、磷酸、磷酸三钙、磷酸氢氧化钙、乙酸钾、氯化钾、葡萄糖酸钾、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、氢氧化镁、氢氧化铝、海藻酸、无热原水、等渗盐水、林格氏溶液、乙醇和其组合。
示例性润滑剂包含但不限于硬脂酸镁、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、月桂基硫酸钠和其组合。
如前所述,本发明在第三方面还提供了本发明的纳米马达或药物组合物,其用于治疗、诊断或预后。
尿素酶推进的纳米马达不仅能够在液体介质(如尿液)中移动,而且能够在粘性介质(如透明质酸)中移动。此外,其还活跃于粘液分泌物中。因此,本发明的纳米马达可以用于液体和粘性组织两者中,如在眼睛的房水中。
在第三方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,第一方面的纳米马达或第二方面的药物组合物用于治疗癌症。
此实施例也可以调配成第一方面的纳米马达或第二方面的药物组合物的用途,其用于制造用于治疗和/或预防癌症的药物。此方面也可以调配成一种用于治疗和/或预防癌症的方法,方法包括向有需要的受试者施用治疗有效量的第一方面的纳米马达或第二方面的药物组合物。
可以用本发明的纳米马达或药物组合物治疗的癌症的说明性非限制性实例包含尽管不限于乳头状瘤、腺瘤、脂肪瘤、骨瘤、肌瘤、血管瘤、痣、成熟畸胎瘤、癌、肉瘤、未成熟畸胎瘤、黑色素瘤、骨髓瘤、白血病、霍奇金氏淋巴瘤、基底细胞癌、脊柱瘤、乳腺癌、卵巢癌、宫颈癌、膀胱癌、肺癌、支气管癌、前列腺癌、结肠癌、胰腺癌、肾癌、食道癌、肝癌、头颈癌等。在第三方面的特定实施例中,癌症是膀胱癌。
根据本文提供的数据,本领域技术人员将理解,本发明的纳米马达和药物组合物还可以用于治疗其它疾病,如代谢性疾病、神经性疾病和炎性疾病。
如上所述,在第五方面中,本发明提供了一种检测分离的样品中的分析物的体外方法,所述体外方法包括使根据第一方面所述的纳米马达与样品接触。本领域技术人员将理解,本发明的纳米马达可以通过用所述分析物的传感器进行官能化而适于检测不同的分析物。
在第五方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,样品是生物分离的样品。更具体地,生物分离的样品是血液、血浆或血清。
如上所述,在第六方面中,本发明提供了根据第一方面所述的纳米马达在体外方法中的用途,所述纳米马达用于检测分离的样品中的分析物。
在第五或第六方面的特定实施例中,任选地与上文或下文提供的实施例中的任何实施例组合,样品是液体样品。如前所述,发明人的纳米马达能够在具有各种粘度的液体中移动。例如,其可以在尿液中移动,所述尿液的运动粘度为:在20℃下为1.0700cSt(通过Inman等人,“温度和尿液成分对尿液粘度的影响及其与膀胱高热治疗的相关性(Theimpact of temperature and urinary constituents on urine viscosity and itsrelevance to bladder hyperthermia treatment)”,《国际高热杂志(Int JHyperthermia)》,2013,第29(3)卷,第206-10页进行测量)以及在滑膜液中存在的浓度下的透明质酸中移动(1mg/ml,针对1到10Hz的剪切速率范围,为10-2Pa*s左右,在流变仪中进行测量)。
本发明的纳米马达对于检测多种分析物(如污染物或生物标志物)特别有用。
在整个说明书和权利要求书中,词语“包括”和词语的变体并不旨在排除其它技术特征、添加剂、组分或步骤。此外,词语“包括”涵盖“由……组成”的情况。通过阅读说明书,本发明的另外的目的、优点和特征对于本领域技术人员来说将变得显而易见,或者可以通过本发明的实践来学习。通过说明的方式提供以下实例和附图,并且它们并非旨在限制本发明。与附图相关的附图标记和位于权利要求中的括号中的附图标记仅用于试图提高权利要求的理解性,并且不应被解释为限制权利要求的范围。此外,本发明涵盖本文所述的具体和优选实施例的所有可能组合。
实例
1.用尿素酶驱动的纳米马达靶向3D膀胱癌球体
1.1.方法
材料
乙醇(EtOH,99%)、甲醇(MeOH,99%)、盐酸(37%于水中)、氢氧化铵(25%于水中)、正硅酸四乙酯(TEOS,99%)、三乙醇胺(TEOA,99%)、十六烷基三甲基溴化铵(CTAB,99%)、3-氨基丙基三乙氧基硅烷(APTES,99%)、戊二醛(GA,25%于水中)、尿素酶(来自洋刀豆,IX型,粉末,50 000-100 000单位/克的固体)、尿素酶活性测定试剂盒(西格玛奥德里奇公司(Sigma-Aldrich))、尿素(99.9%)、甘油(99%)、硼氢化钠粉末(NaBH4,98.0%)、甲醛溶液(37%于水中)、牛血清白蛋白(冻干粉末)、4-硝基苯酚溶液(10mM)、氯化钠特纯(NaCl)、无水氯化钾(KCl)、磷酸二氢钠(NaH2PO4)、碳酸氢钠BioXtra(99.5-100.5%,NaHCO3)、二甲基亚砜(DMSO,99.9%)和HS-PEG5K-NH2(HCl盐)从西格玛奥德里奇公司购买。PierceTMBCA蛋白质测定试剂盒、小麦胚芽凝集素(WGA AlexaFluorTM647缀合物)、山羊抗小鼠IgG(H+L)Alexa FluorTM 488缀合物、3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)和磷酸盐缓冲盐水(PBS)从赛默飞世尔科技公司(Thermo Fisher Scientific)购买。MatrigelTM基底基质从康宁公司(Corning)购买。抗FGFR3抗体(ab89660)从艾博抗公司(Abcam)购买。Hoechst 33342从生命科技公司(Life Sciences)购买。标准RC预处理透析管(3.5kD)从仕必纯公司(Spectrum)购买。花菁3NHS酯从Lumiprobe公司购买。McCoy的5A(经改良的)培养基、青霉素链霉素溶液、胎牛血清(FBS)和胰蛋白酶0.5%EDTA从Gibco公司购买。LIVE/DEADTM活力/细胞毒性试剂盒从英杰公司(Invitrogen)购买。人膀胱移行细胞乳头状瘤RT4细胞从ATCC(马萨诸塞州罗克维尔(Rockville,MA))获得。
仪器
使用JEOL JEM-2100显微镜捕获透射电子显微镜(TEM)图像。使用FEI NOVANanoSEM230在10kV下捕获扫描电子显微镜(SEM)图像。使用与Atlas细胞增压系统耦接的Wyatt进行流体动力学半径和电泳迁移率测量。使用Micromeritics Tristar IIPlus自动分析仪进行Brunauer-Emmett-Teller(BET)分析。使用配备有63×水物镜、振镜台的倒置光学显微镜(Leica DMi8)和针对FITC、罗丹明、DAPI和CY5的过滤管,进行光学视频和细胞培养物成像。使用Infinite M200 PRO多模式微孔板读取器进行蛋白质定量和酶活性测定。共聚焦显微镜分析是使用配备有63×油物镜的LSM 800-蔡司进行的。
介孔二氧化硅纳米颗粒(MSNP)的合成:使用溶胶-凝胶法制备MSNP。简而言之,将含有CTAB(570mg)、TEOA(35g)和水(20mL)的溶液在硅油浴中加热到95℃。将此混合物搅拌30分钟,并且然后逐滴添加TEOS(1.5mL)。将混合物在95℃下进一步搅拌2小时。通过离心收集产生的颗粒,并用乙醇洗涤(3次,1350g,10分钟)。然后,将颗粒悬浮于MeOH:HCl混合物(30mL,10:0.6)中,并且在80℃下回流24小时,以从MSNP的孔中去除CTAB。最后,通过离心收集颗粒,并在乙醇中洗涤(3次,1350g,10分钟),每次离心之间超声处理20分钟。收集等分试样(0.5mL),离心并风干以测定MSNP悬浮液的浓度。
MSNP(MSNP-NH2)的胺官能化:将先前合成的MSNP悬浮于EtOH(2mg/mL)中。然后,将APTES添加到悬浮液(10μL/mg MSNP)中,并使用端对端旋转振荡器在室温下摇动24小时。最后,通过离心收集颗粒,并在乙醇中洗涤(3次,1350g,10分钟),并在水中洗涤(3次,1928g,10分钟),每次离心之间超声处理20分钟。收集等分试样(0.5mL),离心并风干以测定MSNP悬浮液的浓度。用尿素酶和异双官能H2N-PEG-SH(MSNP-Ur/PEG)对MSNP-NH2进行官能化:将MSNP-NH2以1340g离心10分钟,将其悬浮于900μL PBS(2mg/mL)中,并超声处理20分钟。此后,添加100μL的戊二醛,并将混合物涡旋30秒以获得良好的分散体。将混合物在室温下在端对端旋转振荡器上放置2.5小时。然后收集纳米颗粒,并用PBS洗涤三次(1340g,10分钟),并且在每次洗涤之间超声处理20分钟。接下来,将GA活化的纳米颗粒悬浮于含尿素酶(3mg/mL)和H2N-PEG-SH(1μg/mg MSNP-NH2)的PBS溶液中。然后将混合物在室温下在端对端旋转振荡器上放置过夜。通过离心(1340g,10分钟)用PBS将所得纳米马达洗涤三次,并在超声处理3分钟时嵌入洗涤中。
用抗FGFR3抗体(MSNP-Ur/PEG-Ab)对聚乙二醇化尿素酶纳米马达进行官能化:将纳米马达悬浮于PBS(2mg/mL)中,并添加抗FGFR3抗体(每毫克纳米马达30μg抗体)。然后将混合物在室温下在旋转振荡器中温育过夜。最后,通过离心(1340g,10分钟)收集抗体修饰的纳米马达,并用PBS洗涤三次,并在超声处理3分钟时嵌入洗涤。流体动力学半径和表面电荷分析:与ATLAS增压器耦接的Wyatt Mobius DLS用于表征MSNP、MSNP-NH2、MSNP-Ur/PEG和MSNP-Ur/PEG-Ab的大小分布和表面电荷。设备使用532nm波长的激光和163.5°的检测器角度。将分析的样品稀释到0.3mg/mL的浓度,并同时分析光散射和电泳迁移率,其中采集时间为5秒,每次测量进行3轮。总共进行了9次测量以获得统计相关数据。
MSNP上尿素酶和抗体量的定量:根据制造商的说明,使用来自赛默飞世尔科技公司的BCA蛋白质测定试剂盒测量存在于MSNP-Ur/PEG上的尿素酶的浓度。此试剂盒使蛋白质的数量与通过肽键减少的铜相关。针对MSNP-Ur/PEG-Ab重复相同的程序,以定量与纳米马达结合的抗体的量。
尿素酶活性测定:使用商业试剂盒评估了尿素酶与MSNP结合时的酶促活性,所述试剂盒测定了通过Berthelot方法产生的氨的浓度(Patton,C.J.等人,“用于测定氨的Berthelot反应的分光光度和动力学研究(Spectrophotometric and KineticsInvestigation of the Berthelot Reaction for the Determination of Ammonia)”,《分析化学(Anal.Chem.)》,1977,第49卷,第464-469页)。纳米马达的浓度为0.5mg/mL,并根据制造商的说明进行了实验。
将用Cy3:尿素酶(22mg)标记的尿素酶溶解于1mL碳酸氢钠缓冲液(100mM)中。接着,将7μL Cy 3于DMSO中的溶液(5mM)添加到尿素酶溶液中,并将混合物在室温下温育4小时,并在黑暗中振荡。然后将标记的尿素酶溶液透析(3.5kD孔膜)24小时,以消除未反应的Cy3分子。
对由MSNP-Ur/PEG产生的氨进行定量:使用滴定法对由纳米马达产生的氨进行定量。为此,将纳米马达以不同的尿素浓度(12.5、25、50、100、200和300mM)进行温育,并在不同的时间点(5分钟、15分钟、60分钟、120分钟、240分钟和24小时)对样品进行分析。在每个时间点,将纳米马达的悬浮液离心,并使用对硝基苯酚作为指示剂,使用HCl(10mM)滴定上清液。
纳米马达的光学视频记录和MSD分析:使用配备有63×水物镜的倒置显微镜观察和记录纳米马达移动的视频。将含有纳米马达的模拟尿液的水溶液样品放置在载玻片中,并在一定范围的尿素浓度(12.5、25、50、100、200和300mM)下与模拟尿液充分混合。然后将样品用载玻片覆盖,以避免由漂移引起的伪像,并记录30秒的视频。这些视频是使用Hamamatsu相机以50fps的帧速率在亮场中获取的。每种情况下至少分析20个纳米马达。使用基于python的代码对视频进行了分析,以获得纳米马达的轨迹,并计算均方位移(MSD),如下:
MSD(Δt)=〈(x_i(t+Δt)-x_i(t))^2〉对于2D分析,i=2。
此后,通过将MSD数据拟合为等式2来获得扩散系数(De),所述等式在短时间间隔内对于小颗粒有效,其中旋转扩散较低。3D细胞培养:在37℃下和5%CO2气氛中,将人膀胱移行细胞乳头状瘤RT4细胞在补充有FBS(10%)和青霉素-链霉素溶液(1%)的McCoy的5A(改良)培养基中培养。每4天以1:2的比率分裂细胞。为了获得3D RT4细胞培养物,在8孔ibidi培养皿中预涂覆23μL MatrigelTM(5mg/mL),并在37℃下温育30分钟,以形成凝胶。接下来,将30μL RT4细胞悬浮液以5×106细胞/mL的密度均匀地遍布在每个孔中,并将培养皿在37℃下温育30分钟。最后,添加150μL含10%MatrigelTM的RT4 McCoy培养基。在实验前使培养物生长7天,每2天更换一次培养基。
FGFR3跨膜蛋白在3D RT4细胞培养物中的免疫染色:将上述3D培养物用PBS 1x洗涤3次。然后,用移液管尖端轻轻刮擦孔的表面,并将培养物悬浮于试管中的McCoy培养基中。将试管短暂旋转并去除上清液。接下来,将细胞悬浮于甲醛(3.7%)中,放置于8孔培养皿中,并在室温下温育15分钟。随后,将培养物用PBS 1x洗涤,添加PBS-BSA溶液(5%),并将培养皿在室温下温育40分钟。然后,将抗FGFR3以1:50的比例添加到培养物中,并将培养皿在37℃下,5%CO2气氛中温育24小时。之后,将培养物用PBS 1x洗涤3次,以1:500的比例添加次级抗体(用AlexaFluor 488标记),并将培养皿在室温下在黑暗中温育40分钟。最后,将培养物用PBS 1x洗涤3次,用Hoescht标记细胞核,并添加甘油于PBS中的溶液(70%)。使用共聚焦显微镜观察培养物。
细胞毒性测定:使用阿尔玛蓝测定(Alamar blue assay)对RT4 3D培养物的活力进行了定量,并按照制造商的说明使用活/死活力试剂盒进行了可视化。为此,如上所述培养RT4细胞,并将其在以下每种处理的情况下的第7天进行温育-氨(1mM、1.5mM、3mM、5mM、10mM和20mM,持续24小时)、尿素(25mM、30mM、40mM和50mM,持续24小时)、MSNP-Ur/PEG(12.5μg/mL,在尿素浓度范围为25mM、30mM、40mM和50mM的情况下,分别持续1小时、2小时和4小时)。之后,将培养物用培养基洗涤,静置24小时,并根据制造商的说明对活力进行了研究。
此外,还在48小时的时间点评估了活力。
RT4 3D培养物和纳米马达的成像:在第7天,将3D细胞培养物在每种处理的情况下(MSNP-Ur/PEG或MSNP-Ur/PEG-Ab,12.5μg/mL)温育4小时。在每个时间点,将培养物洗涤并在37℃下和5%CO2的气氛中静置24小时。然后,将培养物标记为WGA 647(膜),并使用配备有63×物镜和振镜台的倒置荧光显微镜以及针对罗丹明、FITC、DAPI和Cy5的过滤管进行成像。
1.2.结果和讨论
使用溶胶-凝胶化学法制备了全介孔二氧化硅纳米颗粒(MSNP),其中十六烷基三甲基溴化铵(CTAB)用作致孔剂,并且三乙醇胺(TEOA)用作碱催化剂。经制备的MSNP通过扫描电子显微镜(SEM)表征。SEM分析揭示样品具有良好的单分散性(多分散性指数=0.114),并且平均直径为481±2nm(N=150,平均大小±平均值的标准误差(SE))。此外,通过透射电子显微镜评估了MSNP的多孔结构。TEM证实了明显的径向孔隙度。通过快速傅立叶变换进一步证实了此晶体构型,其表明了多孔图案的周期性。通过使用Brunauer-Emmett-Teller分析(BET)方法进行氮吸附/解吸研究了纳米颗粒的表面积。MSNP显示出IV型等温线,典型的是介孔二氧化硅结构,并且BET比表面积为1184.8m2/g,平均孔径为2nm。
然后通过使用氨基丙基三乙氧基硅烷(APTES)将产生的颗粒用胺基官能化。MSNP的表面上的胺基稍后被戊二醛(GA)活化,所述戊二醛充当颗粒与尿素酶和异双官能聚乙二醇(PEG)分子之间的接头(图1A)。使PEG的末端硫醇基与靶向部分,抗成纤维细胞生长因子3(anti-FGFR3)偶联。
官能化步骤之后是动态光散射(DLS)和电泳迁移率分析,以分别获得流体动力学半径和表面电荷。合成后的MSNP的DLS分析显示出宽峰,从而表明悬浮液中存在聚集体。MSNP的电泳迁移率分析表明表面电荷为-26.81±0.35mV(N=9,平均值±SE),通常用于二氧化硅纳米颗粒。表面电荷显著变化为强正值(33.6±1.0mM,N=9,平均值±SE),证明了胺的成功官能化,这表征了表面上存在游离胺基。胺官能化MSNP(MSNP-NH2)的流体动力学半径指示了较尖锐的峰,这可能是由于颗粒通过表面电荷和表面化学两者而稳定所产生的。
随后的官能化步骤涉及尿素酶和酶两者与异双官能PEG的偶联。通常,PEG用作间隔子或通过在颗粒之间提供空间位阻来防止悬浮液中的聚集的方式。通过DLS分析证实了对MSNP-Ur/PEG的胶体稳定性的此影响,其中观察到了尖锐的单个群峰。此外,通过将PEG外端处的游离巯基与抗体的半胱氨酸残基连接,PEG分子允许抗体与纳米颗粒缀合。由于存在于重链恒定区上的半胱氨酸残基含量高,所以此方法对IgG抗体的结合提供了更高的特异性(图1A)。还通过DLS分析了MSNP-Ur/PEG与抗FGFR3抗体(MSNP-Ur/PEG-Ab)的缀合,并且观察到的单峰表明抗体的存在不影响溶液中颗粒的稳定性。已经使用基于蛋白质的肽键对铜的还原作用来定量蛋白质的试剂盒证实了MSNP的表面上的尿素酶以及抗体的存在,并评估在与纳米马达结合后的尿素酶的酶活性。
遵循以下等式,MSNP-Ur/PEG和MSNP-Ur/PEG-Ab的表面上存在的尿素酶使尿素生物催化转化为氨和二氧化碳:
(NH2)2CO+H2O→CO2+2NH3
通常,在微米/纳米结构(例如,Janus颗粒)上引起几何不对称,以产生不对称力,这是在低雷诺数下产生运动的重要的要求。然而,最近,据报道对于通过生物催化转化、酶的分子不平衡分布推进的马达足以产生要产生净运动所需的不对称性。然而,据报道先前的研究是针对微米级马达的。这项工作中报道的MSNP-Ur/PEG和MSNP-Ur/PEG-Ab纳米马达依靠这种固有的不对称性来实现纳米级马达的自推进。在存在一定范围的尿素浓度(0mM、12.5mM、25mM、50mM、100mM、200mM和300mM)的情况下,评估MSNP-Ur/PEG和MSNP-Ur/PEG-Ab在模拟尿液中的运动曲线。其使用光学跟踪技术获得纳米马达的跟踪轨迹(图2A和B),然后用于计算均方位移(MSD)。图2C显示了模拟尿液中尿素酶/PEG纳米马达和抗体修饰的纳米马达的典型MSD。观察到,MSD随时间呈线性增长,这是扩散运动的特性,并且通过将MSD拟合为以下等式,获得了每个给定条件下的有效扩散系数:
MSD(Δt)=4DeΔt,
其中De表示有效扩散系数,并且Δt表示时间间隔。
图2D示出了MSNP-Ur/PEG和MSNP-Ur/PEG-Ab两者的经计算的有效扩散系数,证明在50mM尿素浓度下扩散显著增加(p<0.001)。扩散系数随模拟尿液中尿素浓度的增加而进一步增加,达到平台期。随着尿素浓度的增加,扩散的增加可以与尿素酶Michaelis-Menten动力学有关,其遵循以下等式:
其中Vmax表示最大反应速率,S表示底物浓度,并且Km表示Michaelis-Menten常数。如图2D所显示的,在MSNP-Ur/PEG与MSNP-Ur/PEG-Ab的运动曲线之间未发现显著差异,表明此靶向部分的存在并不阻碍纳米马达的运动能力。
通过使用人膀胱移行细胞乳头状瘤RT4细胞的3D培养物(球体)研究了纳米马达的运动所需的底物(尿素)的体外生物相容性和生物催化的副产物(氨)。通过将RT4细胞接种在涂覆有MatrigelTM的培养皿中来获得球体,所述培养皿类似于细胞外基质,并为细胞生长提供3D环境。然后,使培养物增殖7天,并每天监测球体的生长。然后在每种情况下通过将球体温育持续24小时来研究一定范围的尿素浓度(0mM、25mM、50mM和100mM)和氨浓度(0mM、20mM、30mM、40mM和50mM)的影响。在这之后,用培养基洗涤培养物,并使用阿尔玛蓝测定评估细胞活力和增殖。此测定基于通过代谢活性细胞将刃天青还原为荧光化合物试卤灵。
尿素表现出良好的生物相容性,即使在研究的最高浓度下也不会影响球体活力,而氨则随浓度的增加而显示出增加的细胞毒性趋势。然而,在测试的所有氨浓度下,球体仍保持活力(>70%的活力)。
进一步研究了在一定范围的尿素浓度和不同的温育时间段中,当暴露于纳米马达(MSNP-Ur/PEG)时的球体的活力。将球体与12.5μg/mL裸露的纳米马达或抗体修饰的纳米马达在0mM、25mM、30mM和40mM尿素下一起温育1小时、2小时和4小时。接下来,将培养物用培养基彻底洗涤以去除纳米马达和未催化的尿素,并在分析前静置24小时。使用活力试剂盒可以使纳米马达对膀胱癌球体的活力的影响可视化,并使用阿尔玛蓝测定对其进行量化(图3)。观察到在不存在尿素的情况下,纳米马达没有毒性,这表明纳米马达的底盘(介孔二氧化硅,MCM-41型)以及PEG和酶具有良好的生物相容性。随着尿素浓度的增加,两种纳米马达均表现出细胞毒性作用,在抗体修饰的纳米马达上更为明显(图3)。裸露的纳米马达观察到的毒性是由于尿素的生物催化转化产生氨而引起的。然而,携带抗体的纳米马达被验证的更高的细胞毒性作用可以来自球体膜上存在的抗FGFR3与抗原之间的相互作用。据报道,这些部分之间的相互作用阻断FGF信号传导途径,这与细胞生长和增殖有关。
为了更好地理解氨对在球体上观察到的细胞毒性作用的贡献,研究了在不同的尿素浓度下,纳米马达在定义的时间段内产生的氨的有效浓度。将12.5μg/mL纳米马达与一定范围的尿素浓度(0mM、12.5mM、25mM、50mM、100mM、200mM和300mM)一起温育,并使用对硝基苯酚作为pH的指示剂。由于纳米马达将尿素转化为氨和二氧化碳会导致pH急剧上升,因此,由于对硝基苯酚的存在,含有纳米马达的溶液会变成黄色,并根据以下等式,可以用HCl滴定以量化存在的氨含量:
NH3+HCl→NH4Cl
发现在此浓度的纳米马达下,达到的最大氨输出为17mM,发现所述氨与膀胱癌球体具有生物相容性(对于20mM氨,其活力>70%)。然而,与纳米马达和尿素一起温育后,观察到的细胞毒性作用比游离氨更强。此结果可能是由于球体附近的纳米马达在局部产生更高浓度的氨而产生的,从而导致更高的细胞毒性。
考虑到纳米马达增强的扩散能力和生物相容性,随后研究了其靶向和渗透到膀胱癌球体中的潜力(图4)。首先,通过免疫细胞化学验证了靶向抗原(FGFR3)在膀胱癌球体的表面上的表达,技术用于通过荧光标记的抗体视觉上检测特异性蛋白质在样品上的位置。膀胱癌球体的免疫细胞化学在细胞膜上显示出绿色荧光,从而证实了存在跨膜蛋白FGFR3,并且蓝色表示用Hoechst标记的细胞核。
然后研究了纳米马达穿透膀胱癌球体的能力,以及靶向部分的存在对内化效率的影响。此外,在存在40mM尿素的情况下通过将球体与裸露的纳米马达或抗体修饰的纳米马达一起温育,评估了主动运动对内化效率的影响。为此,在其官能化到MSNP-NH2之前,用荧光标志物花菁3(Cy3)标记尿素酶,以使用荧光显微镜精确定位纳米马达。然后,用纯尿素酶和经标记的尿素酶(5%)两者对纳米马达进行官能化,并验证了尽管存在经标记的酶,运动能力仍得以保留。接下来,在不存在和存在尿素(40mM)的情况下,将3D培养物与12.5μg/mL的MSNP-Ur/PEG-Ab或MSNP-Ur/PEG温育4小时,后者作为阴性对照物以进行靶向。之后,洗涤培养物,用小麦胚芽凝集素(WGA)标记细胞膜。球体(直径为50-100pm)内Cy3的荧光强度的量化揭示,与不存在尿素的情况相比,主动马达呈现出的内化效率要高三倍,这可能是由于主动运动产生的推进力所致。此外,在存在尿素的情况下,抗体修饰的纳米马达呈现出的内化效率比没有抗体的纳米马达的内化效率高四倍(图4)。这可能是因为,与发生仅布朗扩散(Brownian diffusion)时相比,当纳米马达主动移动时,抗体与靶抗原进行相互作用的可能性更高。在病例中,通过MSD证明了以40mM尿素推进的纳米马达在一秒内比仅经历布朗扩散的纳米马达多覆盖53%的面积,这增加了抗体与抗原接触并渗透到球体中的机会。
考虑到所使用的抗体在与抗原结合时会阻断细胞的FGF信号传导途径,因此通过分析细胞增殖进一步研究了抗体修饰的纳米马达的潜在治疗效果(插图4)。为此,使用无抗体的纳米马达作为对照物,将膀胱癌球体与MSNP-Ur/PEG-Ab在有以及没有尿素的情况下温育4小时。之后,洗涤球体以去除未催化的尿素和未内化的纳米马达,并在48小时静置时间段之后使用阿尔玛蓝测定测量增殖。观察到,用裸露的纳米马达(无抗体)温育的球体维持了在24小时观察到的活力水平,而用抗体修饰的纳米马达温育的球体的活力降低了,表明细胞增殖被阻止。这些结果指向携带抗FGFR3抗体的纳米马达作为靶向膀胱癌治疗工具的适用性。
1.3.结论
开发了由尿素酶驱动的包括PEG的纳米马达,其中PEG既是防止聚集的位阻,又是在纳米马达表面连接特异性膀胱癌抗体(抗FGFR3)的接头。具有以及不具有抗体的纳米马达在膀胱中存在的一定范围的尿素浓度下,在模拟尿液中呈现出扩散增强,这可以使其用于此器官的生物医学应用。已经证明,与传统的2D培养物相比,使用人膀胱癌细胞衍生的球体(3D培养物),这些酶促纳米马达的底物依赖性诱导的毒性被认为更好地模拟了肿瘤环境。在类似于膀胱排尿间隔的时间段内监测内化现象,并观察到主动运动使纳米马达的穿透力增强了3倍。此外,活性抗体修饰的纳米马达表现出的内化效率比没有抗体的活性纳米马达的内化效率高4倍,从而反映了自推进的影响,并靶向活性颗粒穿透球体的能力。对球体的细胞增殖研究表明,与裸露的纳米马达(不含抗体)相比,靶向的纳米马达诱导更高的活力丧失,表明抗FGFR3的治疗效果可能来自细胞增殖的抑制和较高的纳米马达内化率两者。这些结果指向这种抗体修饰的纳米马达作为靶向膀胱癌治疗工具的潜力,因为通过主动运动增强了颗粒的靶向能力,从而提高了抗FGFR3抗体的治疗效果。
2.用DNA纳米开关修饰的酶驱动的微型马达用于局部pH监测
2.1.材料和方法
化学品
未经修饰且荧光团标记的DNA寡核苷酸通过IBA GmBH(德国哥廷根(Gottingen,Germany))合成和纯化(HPLC纯化),并且无需进一步纯化即可使用。DNA构建体的序列报告如下。
DNA序列
pH响应性DNA纳米开关
氨基修饰的DNA支架
5'-GACAGACAGACAGACAAGGA-NH2-3'
对照开关
对于以上所有序列,粗体的碱基表示双链体部分的环,并且带下划线的碱基表示平行三链体区域的环。pH响应性DNA纳米开关和对照开关两者都具有与氨基修饰的DNA支架完全互补(20个碱基)的部分(此处为斜体)。
缓冲条件
将所有DNA低聚物(100μM)储存在1x PBS中。
荧光测量
在Cary Eclipse荧光计(瓦里安公司(Varian))上进行荧光测量,将激发波长设置为λex=530nm(狭缝ex=5nm),并使用体积减小(100μL)的石英比色皿在540与700nm(狭缝em=5nm)之间进行采集。所有测量均在T=25℃下在10mM HEPES中进行。首先在10mM的HEPES中以1μM的浓度稀释开关。然后将此储备溶液在相同的缓冲液中稀释到20nM,其pH值调节到期望值(pH介于5.0到9.0之间)。
荧光数据分析
比率计FRET计算如下:
其中FCy5是Cy5的最大荧光发射(λem=670nm),并且FCy3是Cy3的最大荧光发射(λem=570nm)。pH滴定曲线通过绘制Rat.FRET对水合氢离子浓度,并使用以下朗缪尔型等式(Langmuir-type equation)拟合数据来获得:
其中Rat.FRET三链体和Rat.FRET双链体分别表示处于三链体状态(闭合)和双链体状态(打开)的开关的FRET信号,并且其中[H+]表示氢离子的总浓度,并且KA app是观察到开关的酸常数。
微胶囊制造
通过先前报道的共缩聚方法将基于聚苯乙烯(PS)的商用2μm颗粒(西格玛奥德里奇公司,目录号78452)用于二氧化硅壳(参见Ma Xing《ACS纳米》2016)。简而言之,将250μL聚苯乙烯颗粒(储备溶液,10%固体)与0.5mL的99%乙醇(Panreac Applichem,目录号131086-1214)、0.4mL的Milli-Q水和25ul氢氧化铵(西格玛奥德里奇公司,目录号221228)混合。将混合物在室温(RT)下搅拌5分钟。然后,将2.5μL 3-氨基丙基三乙氧基硅烷(APTES)(西格玛奥德里奇公司,目录号440140)99%添加溶液中,在搅拌和室温下温育6小时。接下来,添加≥99%的7.5μl正硅酸四乙酯(TEOS)(西格玛奥德里奇公司,目录号86578),并使所得混合物在磁力搅拌下在RT下反应过夜。通过将其在3500rpm下离心3.5分钟,将所得的由涂覆有二氧化硅壳的聚苯乙烯组成的微粒在乙醇中洗涤三次。然后,通过以下来去除聚苯乙烯芯:在15分钟期间在≥99.8%二甲基甲酰胺(DMF)(阿克洛斯有机物公司(AcrosOrganics),目录号423640010)中进行4次洗涤来温育颗粒。将所得微胶囊在乙醇中洗涤三次,并在室温下储存直至使用。为了表征微胶囊的大小和形态,进行了扫描电子显微镜(SEM)(FEI NOVA NanoSEM 230)和透射电子显微镜。
尿素酶和DNA纳米开关官能化
将中空二氧化硅微胶囊用尿素酶官能化以使其具有自推进。为此,通过将其在3500rpm下离心3.5分钟用Milli-Q将SiO2微胶囊洗涤三次。之后,在磷酸盐缓冲盐水(PBS,pH=7.4)(赛默飞世尔科技公司,目录号70011-036)中洗涤三次以上。然后将微胶囊悬浮于2.5%(wt)戊二醛于中的PBS溶液(西格玛奥德里奇公司,目录号G6257)中,并使其在RT下端对端混合3小时。将GA官能化的颗粒在PBS 1x中洗涤3次,并悬浮于含有200μg/ml来自洋刀豆(Jack bean)的尿素酶和1μM DNA支架的PBS溶液(西格玛奥德里奇公司,目录号U4002)中。将所得溶液在端对端混合下保持2小时。然后,在PBS中进行三次洗涤,并将官能化的颗粒保持在4℃下直至使用。
运动分析
在配备有63×水浸物镜和hammamatsu相机的倒置光学显微镜(Leica DMi8)下,以25帧每秒的速率记录微型马达20秒。对于每种情况,至少记录了15个颗粒。通过基于Phyton的定制代码分析了微型马达的轨迹,这允许通过应用以下等式来计算马达的MSD和速度:
MSD(Δt)=<(xi(t+Δt)-xi(t))2>(1)
通过将MSD拟合为等式1,可以获得速度。
尿素酶活性测量
按照制造商的说明,使用尿素酶活性试剂盒(西格玛奥德里奇公司)来测量酶促活性,所述试剂盒基于Barthelot方法,即,通过尿素酶活性测量氨产生的比色测定。首先,将微型马达与100mM尿素一起温育。然后,在不同的时间点按照制造商的说明停止酶促反应。随后,为避免颗粒对测量的干扰,将样品在3500rpm下离心3.5分钟。收集来自每个样品的上清液,并在670nm下测量吸光度,以测定尿素酶活性。
2.2.结果和讨论
根据先前报道的共缩合方法合成表面上的具有胺基的中空二氧化硅微胶囊(Ma,X.等人,“尿素驱动的生物相容性中空微胶囊的运动控制”,《ACS纳米》,2016,第10(3)卷,第3597-3605页),这是基于使用3-氨基丙基三乙氧基硅烷(APTES)和正硅酸四乙酯(TEOS)作为二氧化硅前体,将SiO2壳生长到的商用聚苯乙烯微粒上,然后通过二甲基甲酰胺去除聚苯乙烯芯,如图5A所描绘的。
如实例1所描述的,使用戊二醛(GA)作为接头将尿素酶与微型马达表面共价缀合。在此步骤期间,还缀合了氨基修饰的单链DNA(DNAss,20个碱基),充当pH响应性DNA纳米开关的锚定部分(图5B)。图5C示出了基于DNA纳米开关的打开/闭合状态的pH感测策略的示意性图示,其分别导致低或高的FRET效率。通过扫描电子显微镜和透射电子显微镜两者(分别为SEM和TEM)研究所得中空微胶囊。图5D示出了SEM显微照片,其中可以观察到微胶囊具有非常单分散的大小(2.04±0.06μm,平均值±平均值的标准误差)和粗糙的表面。如前所报道的,微胶囊在二氧化硅壳的生长期间可能由于颗粒的接近而在其表面上显示出孔,这提供了结构上的不对称性。图5E示出了通过TEM获得的地形图像,其中不同的伪彩色表示高度(以μm为单位)。
在每个步骤之后,通过测量微粒的ζ电位来表征官能化过程(图5F)。首先,由于胺基的存在,微胶囊显示出带正电的表面,然后由于用GA修饰而变为带负电的表面。在添加尿素酶之后,表面电荷略有减少。用尿素酶和DNAss(UR+DNAss)两者进行的官能化也导致相对于GA的ζ电位降低。
最后,将微粒在含有DNA纳米开关(即,1μM)的磷酸盐缓冲盐水(PBS)中温育。将纳米开关与酶/锚定链缀合的马达一起温育15分钟,足以使带有pH响应性纳米开关的二氧化硅颗粒官能化。值得注意的是,开关在序列的5'端处呈现了20个碱基长的侧翼尾巴,所述序列与共价缀合到二氧化硅微胶囊上的DNAss互补。作为缀合的结果,已经测量到表面电荷进一步减少,并且证实了带有开关的马达的有效官能化。还值得注意的是,此处采用的pH响应性DNA纳米开关是形成三链体的单链DNA,其含有通过沃森-克里克和平行胡格斯丁相互作用两者来稳定的分子内DNA发夹。尽管沃森-克里克(W-C)相互作用对pH有效地不敏感,但胡格斯丁相互作用显示出强烈且可编程的pH依赖性(图6A)。通过用FRET对来标记纳米开关,可以监测pH依赖性三链体向双链体的转变,所述转变可以用来测定微型马达附近溶液的pH值。更具体地,花菁3荧光团(Cy3)内部缀合在发夹双链体DNA的环中,并且花菁5荧光团(Cy5)连接在形成三链体的DNA部分的3'端处。
通过变化荧光微量比色皿中缓冲溶液(100μL溶液)的pH在固定浓度(即,50nM)的DNA开关下进行的荧光测定清楚地显示出FRET效率随pH而变化。如所预期的,在酸性pH值下,分子内三链体结构是有利的,并且观察到高FRET效率(使Cy3和Cy5紧密接近)。随着溶液pH增加,三链体结构不稳定,并且观察到由于三链体到双链体转变(展开)而导致FRET信号逐渐降低(图6A)。注意,此处采用的荧光团对所研究的pH范围内(介于pH 5.0到pH 9.5)的pH值不敏感,以避免信号中的任何干扰。重要的是要注意,此类基于三链体的开关显示出的打开/闭合动力学足够快,以允许实时监测pH变化(平均时间常数约100毫秒)。
为了测试与微型马达缀合后的开关的官能化,通过配备63×油浸物镜的Leica-SP5共聚焦激光扫描显微镜(CSLM)监测FRET效率(图6B)。为此,将微型马达悬浮于pH 5或pH9的PBS中,并放置于8孔玻璃底皿中,以在CSLM下进行分析。使用564nm二极管激光器记录供体(Cy3)的发射。通过激发Cy3荧光团并检测接纳体(Cy5)发射来获得FRET图像。使用定制的ImageJ插件,可以通过计算FRET/Cy3比来实现FRET效率的量化。
这些结果表明,DNA纳米开关修饰的微型马达能够检测其周围环境的pH变化。为了证明pH检测的特异性并消除pH对荧光强度的任何影响,微型马达通过对照开关进行了修饰,其不响应pH变化。图6C和6D示出了来自用pH响应性DNA纳米开关(图6C)或非pH响应性DNA纳米开关(图6D)修饰的微型马达的FRET/Cy3发射的定量。具体地,作为非pH响应性探针,选择单链DNA,其含有通过WC相互作用稳定的相同分子内DNA发夹和不允许三链体折叠的加扰DNA尾巴。如所预期的,当使用非pH响应性纳米开关时,在评估的所有pH下均显示出高FRET效率时,没有发现显著差异。
在不存在或存在100mM尿素作为燃料的情况下,通过光学记录分析了用尿素酶和DNA纳米开关双官能化的中空微型马达的运动动力学。为此,使用了配备有63×水浸物镜和Hamamatsu相机的Leica DMi8倒置荧光显微镜。在20秒期间以每秒25帧(FPS)的速率每种情况下记录至少15个微粒。使用基于Python的代码,跟踪微型马达的轨迹,并根据以下等式从轨迹中计算出MSD:
MSD(Δt) =< (xi(t + Δt) - xi(t))2 > (1)
其中对于2D分析,i=2。在添加尿素底物之后,MSD呈抛物线形状,其对应于活性微粒的推进方案。
然而,在不存在燃料的情况下,观察到仅布朗运动,从而产生线性拟合,表明运动是由微型马达的表面上的催化反应引起的。通过应用以下等式计算得出,发现推进颗粒的速度为6.4±0.6微米/秒(均值±均值的标准误差):
MSD(t)=4Dtt+v2t2,(2)
其中Dt=扩散系数,v=速度,并且t=时间。
令人惊讶地,此速度与之前报道的不对称Janus酶驱动的微胶囊的速度(Ma X.等人,同上)相当,并且略高于非Janus微粒的速度(T.等人,同上)。不受任何理论的束缚,此影响可能是由于通过以随机方式将DNA纳米开关和酶共同固定在颗粒周围所提供的不对称性而引起的。
通过结合光学跟踪和使用CSLM的FRET成像两者,评估了微型马达同时记录在其自推进时产生的局部pH变化的能力,其中以3FPS录制了25秒的视频。在不存在燃料的情况下,观察到的平均FRET/Cy3比为1.8±0.09(均值±均值的标准误差)。当将尿素添加到溶液中时,FRET/Cy3比立即降低到1.5±0.05,表明由于微型马达的活性,pH增加。在记录的25秒期间,未观察到FRET/Cy3比的显著差异。在不存在燃料的情况下,微型马达仅显示布朗运动,并且FRET/Cy3比接近2。相比之下,在微型马达暴露于尿素的情况下,FRET/Cy3比在分析时(0秒)已经降低,表明因为在添加尿素底物后立即发生基于尿素酶的酶促反应,因此pH已发生变化,引起颗粒周围的局部pH变化,所述变化是瞬间检测到的。
这些结果证明了活性的DNA修饰的微型马达感测其周围的微环境,同时产生连续的化学反应以进行自推进的能力。
为了深入了解反应开始时微型马达周围的瞬时pH变化,使用APTES作为涂层剂将微型马达固定在玻璃表面上,以提供正表面电荷并稳定与带负电荷的微型马达的静电相互作用。固定微型马达允许在添加燃料之前和之后对同一微型马达进行可视化,并在较长的时间段(2分钟和10分钟)进行分析,然后才将其排除在所关注的区域之外。
图7A和7B示出了从马达的光学跟踪分别获得的平均MSD和速度。可以清楚地观察到MSD和速度连续下降。感兴趣的是,尽管速度随时间降低,但当发现速度接近于0时,pH持续升高持续10分钟。
这些结果表明,速度的降低并不直接归因于酶活性的降低,并且其它因素,如尿素分解时产生离子产物或酶促反应的不理想的高pH可能影响运动动力学。
DNA开关纳米技术的使用允许在马达的微环境中感测pH,并且当使用诱导pH变化的酶(如尿素酶)时,还可以用于监测其自身的活性。因此,将生物传感工具集成到酶驱动的马达中不仅为其作为传感器的应用提供了新见解,而且还为监测其在微型马达中的固有活动提供了新见解,以了解其运动动力学和机理。另外,DNA和酶的高度多功能性使微型马达的特性得以调整,以用于广泛范围的应用。
2.3.结论
本文提供的数据证明了将DNA技术与生物催化微泳器相组合以产生能够在检测其周围环境时同时进行自推进的主动和智能系统的潜力。通过使用pH敏感的DNA纳米开关和通过共聚焦显微镜进行的FRET成像,可以精确且定量地分析在存在燃料的情况下在微型马达活化后的所述微型马达的表面周围的pH变化。在存在燃料的情况下,在30秒、2分钟和10分钟时,同时分析了微型马达的局部pH变化和运动动力学。pH值不断增加,而速度则呈指数下降,这表明除酶活性以外的其它因素都可能影响微型马达的自推进。
这些结果突显了以精确且定量的方式通过微型马达进行同时感测的相关性,不仅可以监测微环境的变化,而且还可以作为活性指示剂。未来的方向将导致检测细胞内或局部组织的pH变化以及其它分析物。进一步地,此协同技术还将为多官能微型马达打开领域,其中pH变化将触发通过感测作用平台释放货物。
引文列表
Ma,X.等人,“尿素驱动的生物相容性中空微胶囊的运动控制”,《ACS纳米》,2016,第10(3)卷,第3597-3605页。
Patton,C.J.等人,“用于测定氨的Berthelot反应的分光光度和动力学研究”,《分析化学》,1977,第49卷,第464-469页。
Campuzano S.等人,“使用电化学推进的纳米马达进行运动驱动的感测和生物感测”,《分析家》2011,第36(22)卷,第4621-30页。
Altschul等人,“基础局部比对搜索工具”,1990,《分子生物学杂志》,第215卷,第403-410页。
Higgins等人,“CLUSTAL V:用于多序列比对的改进软件”,1992,CABIOS,8(2),第189-191页。
Inman等人,“温度和尿液成分对尿液粘度的影响及其与膀胱高热治疗的相关性”,《国际高热杂志》,2013,第29(3)卷,第206-10页。
Xing MA等人,“尿素驱动的生物相容性中空微胶囊的运动控制”,《ACS纳米》,2016,第10(3)卷,第3597-605页。
Ana C.等人,“酶驱动的纳米机器人增强抗癌药物递送”,《先进功能材料》,2017,第28(25)卷。
序列表
<110> 加泰罗尼亚生物工程基础研究所
加泰罗尼亚高级研究所
<120> 官能化酶驱动的纳米马达
<130> P4851PC00
<150> EP18382896
<151> 2018-12-05
<160> 3
<170> PatentIn版本3.5
<210> 1
<211> 65
<212> DNA
<213> 人工(Artificial)
<220>
<221>
<222>
<223> 纳米开关
<400> 1
tccttgtctg tctgtctgtc ttttttgaag aaggaattta ttccttcttc gtttgcttct 60
tcctt 65
<210> 2
<211> 20
<212> DNA
<213> 人工(Artificial)
<220>
<221>
<222>
<223> 支架
<220>
<221> modified_base
<222> (20)..(20)
<223> 酰胺化(AMIDATION)
<400> 2
gacagacaga cagacaagga 20
<210> 3
<211> 36
<212> DNA
<213> 人工(Artificial)
<220>
<221>
<222>
<223> 对照开关(Control switch)
<400> 3
tccttgtctg tctgtctgtc tgaacgtttt tcgttc 36
Claims (16)
1.一种酶驱动的纳米马达,其包括:
-具有表面的颗粒;
-酶;以及
-异源分子;
其特征在于,所述酶和所述异源分子不连续地附着在所述颗粒的整个表面之上。
2.根据权利要求1所述的纳米马达,其中所述颗粒是纳米颗粒或微粒。
3.根据权利要求1到2中任一项所述的纳米马达,其中所述颗粒由选自由以下组成的组的材料制成:金属、金属氧化物、聚合物、脂质、蛋白质、细胞膜、细胞体、碳质材料和其混合物。
4.根据权利要求1到3中任一项所述的纳米马达,其中所述颗粒由介孔二氧化硅制成。
5.根据权利要求1到4中任一项所述的纳米马达,其中所述酶选自由以下组成的组:葡萄糖氧化酶、尿素酶、过氧化氢酶、谷氨酸氧化酶、黄嘌呤氧化酶、过氧化物酶、胆红素氧化酶、脂肪酶、蛋白酶、己糖激酶、乙酰胆碱酯酶和胰蛋白酶。
6.根据权利要求5所述的纳米马达,其中所述酶是尿素酶。
7.根据权利要求1到6中任一项所述的纳米马达,其中所述异源分子选自由以下组成的组:靶向分子、标记分子、纳米传感器和分子门。
8.根据权利要求7所述的纳米马达,其中所述靶向分子是抗体。
9.根据权利要求7所述的纳米马达,其中所述纳米传感器是DNA纳米开关。
10.根据权利要求1到9中任一项所述的纳米马达,其进一步包括货物。
11.一种药物组合物,其包括治疗有效量的根据权利要求1到10中任一项所述的纳米马达以及药学上可接受的赋形剂和/或载体。
12.根据权利要求1到10中任一项所述的纳米马达或根据权利要求11所述的药物组合物,其用于治疗、诊断或预后。
13.根据权利要求12所述的供使用的纳米马达或药物组合物,其用于治疗癌症。
14.根据权利要求13所述的供使用的纳米马达或药物组合物,其中所述癌症是膀胱癌。
15.一种成套试剂盒,其包括:
-根据权利要求1到10中任一项所述的纳米马达或根据权利要求11所述的药物组合物以及
-其使用说明书。
16.一种检测分离的样品中的分析物的体外方法,所述体外方法包括使根据权利要求1到10中任一项所述的纳米马达与所述样品接触。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP18382896.1A EP3663257A1 (en) | 2018-12-05 | 2018-12-05 | Functionalized enzyme-powered nanomotors |
EP18382896.1 | 2018-12-05 | ||
PCT/EP2019/083662 WO2020115124A1 (en) | 2018-12-05 | 2019-12-04 | Functionalized enzyme-powered nanomotors |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113840798A true CN113840798A (zh) | 2021-12-24 |
CN113840798B CN113840798B (zh) | 2024-07-05 |
Family
ID=
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113999835A (zh) * | 2021-11-01 | 2022-02-01 | 西南交通大学 | 一种口形红细胞结构的载酶胶体囊微马达的制备方法 |
CN114404611A (zh) * | 2022-01-05 | 2022-04-29 | 南方医科大学 | 一种酶动力蛋白马达的制备方法及应用 |
WO2023130537A1 (zh) * | 2022-01-04 | 2023-07-13 | 雷艳丽 | 一种自主驱动的生物分子马达和生物分子马达毛丝 |
CN117653747A (zh) * | 2023-12-27 | 2024-03-08 | 中南大学 | 一种纳米马达复合材料及其制备方法和应用 |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050266416A1 (en) * | 2002-09-18 | 2005-12-01 | Purdue Research Foundation | Molecular nanomotor |
US20080187764A1 (en) * | 2007-02-05 | 2008-08-07 | Samsung Electronics Co., Ltd. | Nano- or micro-scale organic-inorganic composite device and method for producing the same |
CN102431966A (zh) * | 2011-12-27 | 2012-05-02 | 复旦大学 | 一种管状多孔微米马达及其制备方法和应用 |
US20120211467A1 (en) * | 2009-08-25 | 2012-08-23 | The Regents Of The University Of California | Nanomotor-based patterning of surface microstructures |
CN107098384A (zh) * | 2017-04-06 | 2017-08-29 | 武汉理工大学 | 一种基于TiO2双晶相微米粒子的光控微米马达及其制备和控制 |
US20180134549A1 (en) * | 2016-11-15 | 2018-05-17 | The Govenors Of The University Of Alberta | Microrna initiated dnazyme motor operating in living cells |
CN108524941A (zh) * | 2018-04-08 | 2018-09-14 | 哈尔滨工业大学 | 一种酶驱动瓶状纳米马达及其制备方法 |
CN108773831A (zh) * | 2018-06-11 | 2018-11-09 | 南京师范大学 | L-精氨酸纳米粒子和一氧化氮为动力源的可降解型纳米马达及其制备方法 |
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050266416A1 (en) * | 2002-09-18 | 2005-12-01 | Purdue Research Foundation | Molecular nanomotor |
US20080187764A1 (en) * | 2007-02-05 | 2008-08-07 | Samsung Electronics Co., Ltd. | Nano- or micro-scale organic-inorganic composite device and method for producing the same |
US20120211467A1 (en) * | 2009-08-25 | 2012-08-23 | The Regents Of The University Of California | Nanomotor-based patterning of surface microstructures |
CN102431966A (zh) * | 2011-12-27 | 2012-05-02 | 复旦大学 | 一种管状多孔微米马达及其制备方法和应用 |
US20180134549A1 (en) * | 2016-11-15 | 2018-05-17 | The Govenors Of The University Of Alberta | Microrna initiated dnazyme motor operating in living cells |
CN107098384A (zh) * | 2017-04-06 | 2017-08-29 | 武汉理工大学 | 一种基于TiO2双晶相微米粒子的光控微米马达及其制备和控制 |
CN108524941A (zh) * | 2018-04-08 | 2018-09-14 | 哈尔滨工业大学 | 一种酶驱动瓶状纳米马达及其制备方法 |
CN108773831A (zh) * | 2018-06-11 | 2018-11-09 | 南京师范大学 | L-精氨酸纳米粒子和一氧化氮为动力源的可降解型纳米马达及其制备方法 |
Non-Patent Citations (2)
Title |
---|
ANA C. HORTELAO等: "Enzyme-powered nanobots enhance anticancer drug delivery", vol. 28, no. 28, pages 1705086 * |
TANIA PATINO等: "Fundamental aspects of enzyme-powered micro- and nanoswimmers", vol. 51, pages 2662 - 2671 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113999835A (zh) * | 2021-11-01 | 2022-02-01 | 西南交通大学 | 一种口形红细胞结构的载酶胶体囊微马达的制备方法 |
WO2023130537A1 (zh) * | 2022-01-04 | 2023-07-13 | 雷艳丽 | 一种自主驱动的生物分子马达和生物分子马达毛丝 |
CN114404611A (zh) * | 2022-01-05 | 2022-04-29 | 南方医科大学 | 一种酶动力蛋白马达的制备方法及应用 |
CN114404611B (zh) * | 2022-01-05 | 2023-11-07 | 南方医科大学 | 一种酶动力蛋白马达的制备方法及应用 |
CN117653747A (zh) * | 2023-12-27 | 2024-03-08 | 中南大学 | 一种纳米马达复合材料及其制备方法和应用 |
CN117653747B (zh) * | 2023-12-27 | 2024-06-04 | 中南大学 | 一种纳米马达复合材料及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
EP3891094C0 (en) | 2023-09-27 |
JP2022512131A (ja) | 2022-02-02 |
BR112021010861A2 (pt) | 2021-08-31 |
EP3891094B1 (en) | 2023-09-27 |
ES2967598T3 (es) | 2024-05-03 |
US20220016223A1 (en) | 2022-01-20 |
WO2020115124A1 (en) | 2020-06-11 |
EP3663257A1 (en) | 2020-06-10 |
CA3120178A1 (en) | 2020-06-11 |
MX2021006510A (es) | 2021-10-13 |
EP3891094A1 (en) | 2021-10-13 |
AU2019394017A1 (en) | 2021-06-03 |
PL3891094T3 (pl) | 2024-04-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3891094B1 (en) | Functionalized enzyme-powered nanomotors | |
Sun et al. | Metal–organic framework nanocarriers for drug delivery in biomedical applications | |
Llopis-Lorente et al. | Enzyme-powered gated mesoporous silica nanomotors for on-command intracellular payload delivery | |
Seaberg et al. | Hybrid nanosystems for biomedical applications | |
Bernardos et al. | Enzyme-responsive intracellular controlled release using nanometric silica mesoporous supports capped with “saccharides” | |
Jia et al. | Molecular assembly of Schiff base interactions: construction and application | |
Lynge et al. | Recent developments in poly (dopamine)-based coatings for biomedical applications | |
Yorulmaz Avsar et al. | Biomolecules turn self-assembling amphiphilic block co-polymer platforms into biomimetic interfaces | |
Godoy-Gallardo et al. | Multicompartment artificial organelles conducting enzymatic cascade reactions inside cells | |
Passeri et al. | Biomedical applications of nanodiamonds: an overview | |
Zhang et al. | In situ monitoring of intracellular controlled drug release from mesoporous silica nanoparticles coated with pH-responsive charge-reversal polymer | |
Deng et al. | Water-solubilizing hydrophobic ZnAgInSe/ZnS QDs with tumor-targeted cRGD-sulfobetaine-PIMA-histamine ligands via a self-assembly strategy for bioimaging | |
Li et al. | Tadpole-like unimolecular nanomotor with sub-100 nm size swims in a tumor microenvironment model | |
Zhu et al. | Cell microenvironment stimuli-responsive controlled-release delivery systems based on mesoporous silica nanoparticles | |
Li et al. | One-pot synthesis of diphenylalanine-based hybrid nanospheres for controllable pH-and GSH-responsive delivery of drugs | |
Li et al. | Surface functionalization of nanomaterials by aryl diazonium salts for biomedical sciences | |
Diez et al. | Neoglycoenzyme-gated mesoporous silica nanoparticles: toward the design of nanodevices for pulsatile programmed sequential delivery | |
Roy et al. | Biodegradable alginate polyelectrolyte capsules as plausible biocompatible delivery carriers | |
Yang et al. | Enzyme-driven micro/nanomotors: Recent advances and biomedical applications | |
Wang et al. | Charge and coordination directed liposome fusion onto SiO2 and TiO2 nanoparticles | |
Rastmanesh et al. | Bioinspired micro/nanomotors towards a self-propelled noninvasive diagnosis and treatment of cancer | |
Shivalkar et al. | Nanoengineering of biohybrid micro/nanobots for programmed biomedical applications | |
Delpiano et al. | Assembly of multicomponent nano-bioconjugates composed of mesoporous silica nanoparticles, proteins, and gold nanoparticles | |
Baig et al. | The integrin facilitated internalization of fibronectin-functionalized camptothecin-loaded DNA-nanofibers for high-efficiency anticancer effects | |
Massaro et al. | Supramolecular association of halochromic switches and halloysite nanotubes in fluorescent nanoprobes for tumor detection |
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 | ||
GR01 | Patent grant |