CN115590958A - 一种近红外光/酶程序性激活超分子前药系统及制备方法 - Google Patents
一种近红外光/酶程序性激活超分子前药系统及制备方法 Download PDFInfo
- Publication number
- CN115590958A CN115590958A CN202211178740.5A CN202211178740A CN115590958A CN 115590958 A CN115590958 A CN 115590958A CN 202211178740 A CN202211178740 A CN 202211178740A CN 115590958 A CN115590958 A CN 115590958A
- Authority
- CN
- China
- Prior art keywords
- ada
- gflg
- gef
- bpy
- supramolecular
- 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
- 229940002612 prodrug Drugs 0.000 title claims abstract description 51
- 239000000651 prodrug Substances 0.000 title claims abstract description 51
- 102000004190 Enzymes Human genes 0.000 title claims abstract description 26
- 108090000790 Enzymes Proteins 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 230000004913 activation Effects 0.000 title claims description 27
- 239000002105 nanoparticle Substances 0.000 claims abstract description 15
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 11
- -1 thioketone modified beta-cyclodextrin Chemical class 0.000 claims abstract description 9
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims description 26
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 24
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 24
- 229960002584 gefitinib Drugs 0.000 claims description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- 238000003786 synthesis reaction Methods 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000000502 dialysis Methods 0.000 claims description 13
- 239000011261 inert gas Substances 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 229920000642 polymer Polymers 0.000 claims description 6
- AXKGIPZJYUNAIW-UHFFFAOYSA-N (4-aminophenyl)methanol Chemical compound NC1=CC=C(CO)C=C1 AXKGIPZJYUNAIW-UHFFFAOYSA-N 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- CCMKPCBRNXKTKV-UHFFFAOYSA-N 1-hydroxy-5-sulfanylidenepyrrolidin-2-one Chemical compound ON1C(=O)CCC1=S CCMKPCBRNXKTKV-UHFFFAOYSA-N 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 5
- 150000004985 diamines Chemical class 0.000 claims description 5
- 229920002521 macromolecule Polymers 0.000 claims description 5
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 claims description 5
- 229920001184 polypeptide Polymers 0.000 claims description 5
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 5
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 5
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 5
- 239000012498 ultrapure water Substances 0.000 claims description 5
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 claims description 4
- ICCBZGUDUOMNOF-UHFFFAOYSA-N azidoamine Chemical compound NN=[N+]=[N-] ICCBZGUDUOMNOF-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 29
- 229940079593 drug Drugs 0.000 abstract description 22
- 230000003993 interaction Effects 0.000 abstract description 5
- 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 abstract description 4
- 229920002674 hyaluronan Polymers 0.000 abstract description 4
- 229960003160 hyaluronic acid Drugs 0.000 abstract description 4
- QPNKJVQPJFVKBC-BKQBYRTQSA-N 2-aminoacetic acid (2S)-2-amino-4-methylpentanoic acid (2S)-2-amino-3-phenylpropanoic acid Chemical compound NCC(O)=O.NCC(O)=O.CC(C)C[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 QPNKJVQPJFVKBC-BKQBYRTQSA-N 0.000 abstract description 2
- 230000003213 activating effect Effects 0.000 abstract description 2
- YOKBFUOPNPIXQC-UHFFFAOYSA-N anti-tetramantane Chemical compound C1C(CC2C3C45)CC6C2CC52CC5CC7C2C6C13CC7C4C5 YOKBFUOPNPIXQC-UHFFFAOYSA-N 0.000 abstract description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 29
- 229940088598 enzyme Drugs 0.000 description 16
- 206010028980 Neoplasm Diseases 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 11
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 102000001301 EGF receptor Human genes 0.000 description 10
- 108060006698 EGF receptor Proteins 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 108090000712 Cathepsin B Proteins 0.000 description 8
- 102000004225 Cathepsin B Human genes 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 8
- 239000008055 phosphate buffer solution Substances 0.000 description 7
- 238000002428 photodynamic therapy Methods 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000003642 reactive oxygen metabolite Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 6
- 229920000858 Cyclodextrin Polymers 0.000 description 5
- 206010059866 Drug resistance Diseases 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 238000012377 drug delivery Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 108010087230 Sincalide Proteins 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229910000365 copper sulfate Inorganic materials 0.000 description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000263 cytotoxicity test Toxicity 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- WEZDRVHTDXTVLT-GJZGRUSLSA-N 2-[[(2s)-2-[[(2s)-2-[(2-aminoacetyl)amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 WEZDRVHTDXTVLT-GJZGRUSLSA-N 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
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 2
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 108010009504 Gly-Phe-Leu-Gly Proteins 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 238000011481 absorbance measurement Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 230000004700 cellular uptake Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000002784 cytotoxicity assay Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000002932 luster Substances 0.000 description 2
- 229940125645 monoclonal antibody drug Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 235000010378 sodium ascorbate Nutrition 0.000 description 2
- 229960005055 sodium ascorbate Drugs 0.000 description 2
- 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 2
- 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 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- ULUNQYODBKLBOE-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)-1h-pyrrole Chemical compound C1=CNC(C=2NC=CC=2)=C1 ULUNQYODBKLBOE-UHFFFAOYSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- 241001330002 Bambuseae Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 150000004924 Gefitinib derivatives Chemical class 0.000 description 1
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 description 1
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- MIBQYWIOHFTKHD-UHFFFAOYSA-N adamantane-1-carbonyl chloride Chemical compound C1C(C2)CC3CC2CC1(C(=O)Cl)C3 MIBQYWIOHFTKHD-UHFFFAOYSA-N 0.000 description 1
- UPWLURAENVJIJL-UHFFFAOYSA-N adamantane;hydrochloride Chemical compound Cl.C1C(C2)CC3CC1CC2C3 UPWLURAENVJIJL-UHFFFAOYSA-N 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- QTQUJRIHTSIVOF-UHFFFAOYSA-N amino(phenyl)methanol Chemical compound NC(O)C1=CC=CC=C1 QTQUJRIHTSIVOF-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- VTJUKNSKBAOEHE-UHFFFAOYSA-N calixarene Chemical compound COC(=O)COC1=C(CC=2C(=C(CC=3C(=C(C4)C=C(C=3)C(C)(C)C)OCC(=O)OC)C=C(C=2)C(C)(C)C)OCC(=O)OC)C=C(C(C)(C)C)C=C1CC1=C(OCC(=O)OC)C4=CC(C(C)(C)C)=C1 VTJUKNSKBAOEHE-UHFFFAOYSA-N 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- MSBXTPRURXJCPF-DQWIULQBSA-N cucurbit[6]uril Chemical compound N1([C@@H]2[C@@H]3N(C1=O)CN1[C@@H]4[C@@H]5N(C1=O)CN1[C@@H]6[C@@H]7N(C1=O)CN1[C@@H]8[C@@H]9N(C1=O)CN([C@H]1N(C%10=O)CN9C(=O)N8CN7C(=O)N6CN5C(=O)N4CN3C(=O)N2C2)C3=O)CN4C(=O)N5[C@@H]6[C@H]4N2C(=O)N6CN%10[C@H]1N3C5 MSBXTPRURXJCPF-DQWIULQBSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- LVXJQMNHJWSHET-AATRIKPKSA-N dacomitinib Chemical compound C=12C=C(NC(=O)\C=C\CN3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 LVXJQMNHJWSHET-AATRIKPKSA-N 0.000 description 1
- 229950002205 dacomitinib Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- 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
- A61K47/6949—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 inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,具体涉及一种近红外光/酶程序性激活超分子前药系统及制备方法。本发明以由亲水透明质酸(HA)和缩硫酮修饰的β‑环糊精(TK‑CD)合成的HA‑CD作为主体分子,以金刚烷和GFLG(四肽甘氨酸‑苯丙氨酸‑亮氨酸‑甘氨酸(GFLG)修饰的GEF前药Ada‑GFLG‑GEF以及四金刚烷修饰的氮杂氟硼二咯(4ADA‑BPY二吡啶)光敏剂作为客体分子,通过主客体相互作用和亲疏水作用形成纳米粒子HA‑BPY‑GEF‑PNs,所制得的超分子前药系统具有载体安全性高,生物相容性好,肿瘤细胞摄取能力强,药物释放精准可控等优点,能够实现更高的治疗精准度,减少毒副作用。
Description
技术领域
本发明属于医药技术领域,具体涉及一种近红外光/酶程序性激活超分子前药系统及制备方法。
背景技术
恶性肿瘤一直以来严重威胁着人类的健康,据全球最新癌症数据统计显示,2020年全球新发癌症1929万例,癌症死亡病例996万例。其中,肺癌的发生率及死亡率极高,而非小细胞肺癌(NSCLC)的占比约为85%。因此,对NSCLC进行有效的治疗具有重大的意义。
表皮生长因子受体(EGFR)突变是非小细胞肺癌最常见的突变。目前,酪氨酸激酶抑制剂(TKIs)能给EGFR突变的非小细胞肺癌(NSCLC)患者带来显著的临床治疗效果,并改变了EGFR突变肺癌的治疗格局,但用药一段时间后,容易出现耐药性。2003年5月,吉非替尼(GEF)成为首个被FDA批准的靶向药,开启了TKIs用于治疗EGFR突变NSCLC患者的新时代。目前临床上广泛使用的EGFR TKI主要有三代,其中一代TKI是EGFR可逆抑制剂,包括吉非替尼、厄洛替尼,埃克替尼;二代TKI是泛HER抑制剂,包括阿法替尼,达克替尼;三代TKI,包括奥希替尼,阿美替尼等等。然而,TKIs在用药9-12个月之后,不可避免出现耐药现象,进而严重降低了临床治疗效果。因此,TKIs的耐药问题成为临床上亟待解决的问题。而GEF的耐药机制一般可以分为靶内机制和靶外机制,后者又叫EGFR非依赖途径,主要包括EGFR信号传导路径的变化以及EGFR的旁路激活效应。为此,研究者们致力于开发新的小分子抑制剂或者单抗药物,以降低NSCLC患者的耐药性。然而,开发新的小分子抑制剂或者单抗药物不仅耗时耗力,还面临适用性较窄的问题。因此,如何科学设计载药体系和药物协同作用抑制旁路激活对临床治疗NSCLC具有重大意义。
光疗已经有3000多年的悠久历史,而光动力疗法(PDT)作为一种重要的癌症治疗手段近年来备受青睐。当肿瘤部位的光敏剂(PS)受到外源性光辐射时,可以吸收照射光的能量并将其传递给组织中的氧气,进而转化为活性氧(ROS),ROS可与生物大分子发生作用,破坏细胞器的结构与功能,从而对肿瘤细胞产生杀伤力,达到治疗肿瘤的目的。目前PDT已经被科学家们广泛研究并且应用于临床治疗。众所周知,ROS也是一种重要的气体分子,研究发现肿瘤细胞内的ROS浓度提高可以显著抑制IGF1R旁路信号通路,增加耐药肿瘤对吉非替尼的敏感性。因此,可以利用PDT去解决使用吉非替尼过程中出现的耐药问题。然而,光敏剂水溶性差、肿瘤靶向能力不足等问题限制了PDT的治疗效果,所以开发一种高效的载体来递送光敏剂用于PDT以及PDT介导的旁路信号通路抑制,从而克服GEF的耐药性,具有重要的科学价值。
前药(Prodrug)是指药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物。肿瘤微环境具有高还原性、偏酸性等特点,也过表达组织蛋白酶B(Cathepsin B),而四肽Gly–Phe–Leu–Gly(GFLG)在生理环境下比较稳定,但是在溶酶体中可以被组织蛋白酶B降解,因此GFLG多肽被广泛用于酶响应性前药设计。同时,基于EPR效应(enhanced permeability and retentioneffect,增强渗透滞留效应),纳米药物体现出了优越的肿瘤靶向能力,可以提高药物的治疗效果,同时减少全身毒性。但是,药物精准可控靶向释药仍然是临床面临的一大挑战,所以开发时空以及剂量可控的按需释药体系迫在眉睫。基于底层逻辑,结合内源性和外源性因素,科学设计多重响应性纳米载体,对实现肿瘤的精准治疗具有极大的现实意义。
相比于化学合成载体,超分子具有合成较少,分离纯化容易等优点。因为超分子主要是通过具有可逆性的非共价相互作用形成,这一特性使其可以被加工和再循环,并且能够实现对内外源性刺激的响应。近年来,各种环状超分子化合物如雨后春笋般出现,例如环糊精、葫芦脲、冠醚、杯芳烃等,其中,环糊精由于具有低免疫原性、低毒性和刺激响应性等多种优点而在生物医学方面具有极高的潜力,值得深入研究。环糊精(CDs)是一种由α-1,4糖苷键连接而成的大环寡糖族,主要分为α、β、γ环糊精三种,各自由6、7、8个葡萄糖单元组成,具有锥形空腔的环状结构,内部空腔疏水无极性,外部亲水而具有高极性,因此可以包合各种各样的客体分子形成包合物,这一性质已被大量应用于药物制造领域,从而提高药物的溶解性、增强药物稳定性、增加药物吸收、降低药物毒性、改善药物跨越生物屏障的能力。
综上可见,开发一种生物相容性好、药物释放精准可控、能够靶向肿瘤的药物递送体系来解决非小细胞肺癌治疗过程中容易产生的耐药问题是非常有必要的。
发明内容
为了克服上述现有技术的不足,本发明提供了一种近红外光/酶程序性激活超分子前药系统的制备方法,所制得的超分子前药系统具有载体安全性高,生物相容性好,肿瘤细胞摄取能力强,药物释放精准可控等优点,能够实现更高的治疗精准度,减少毒副作用。
为实现上述目的,本发明是通过以下技术方案来实现的:
本发明提供了一种近红外光/酶程序性激活超分子前药系统的制备方法,所述制备方法包括以下步骤:
S1、主体高分子HA-CD的合成:
S11、将TOS-CD和缩硫酮二胺在惰性气体氛围下于有机溶剂中经反应后制备得到TK-CD;
S12、将透明质酸钠、N-羟基硫代琥珀酰亚胺、1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐和TK-CD于PBS中经搅拌反应和透析后制备得到HA-CD;
S2、客体分子近红外光敏剂4Ada-BPY的合成:
S21、通过氨基叠氮、4-二甲氨基吡啶和金刚烷酰氯于有机溶剂中制成Ada-N3;
S22、将四炔基BPY和NBS溶于有机溶剂中,经反应后制得溴代BPY,然后将Ada-N3和溴代BPY溶于有机溶剂中,惰性气体氛围下经反应后制得4Ada-BPY;
S3、客体分子吉非替尼前药Ada-GFLG-GEF的合成:
S31、先将N,N'-二甲基乙二胺和二碳酸二叔丁酯于有机溶剂中经搅拌反应制成DTA-Boc;再将吉非替尼和4-二甲氨基吡啶溶于有机溶剂中,加入三光气反应后再加入DTA-Boc,经室温反应后制得GEF-DTA;
S32、先以EEDQ作为缩合剂,将Ada-GFLG与对氨基苄醇进行酰胺缩合制得修饰有对氨基苄醇的GFLG多肽Ada-GFLG-AB;再将Ada-GFLG-AB溶于有机溶剂中,在惰性气体保护及冰浴下加入4-硝基苯基氯甲酯和N,N-二异丙基乙胺,室温搅拌反应后制得Ada-GFLG-AB-NC;
S33、将GEF-DTA溶于有机溶剂中,在惰性气体保护及冰浴下加入N,N-二异丙基乙胺和Ada-GFLG-AB-NC,经反应后制得Ada-GFLG-GEF;
S4、纳米粒制备:
将HA-CD溶于水中制成高分子溶液,另将两种客体分子Ada-GFLG-GEF和4Ada-BPY分别溶于有机溶剂中制成溶液,然后先将Ada-GFLG-GEF加入高分子溶液中制成胶体溶液,再讲4Ada-BPY溶液加入到胶体溶液中,经透析后制得纳米粒,得到近红外光/酶程序性激活超分子前药系统HA-BPY-GEF-PNs。
本发明以由亲水透明质酸(HA)和缩硫酮修饰的β-环糊精(TK-CD)合成的HA-CD作为主体分子,以金刚烷和GFLG(四肽甘氨酸-苯丙氨酸-亮氨酸-甘氨酸(Gly-Phe-Leu-Gly,GFLG)修饰的GEF前药Ada-GFLG-GEF以及四金刚烷修饰的氮杂氟硼二咯(4ADA-BPY二吡啶)光敏剂作为客体分子,通过主客体相互作用和亲疏水作用形成纳米粒子HA-BPY-GEF-PNs。该体系的特点是,只有当交联层被光照破坏时,组织蛋白酶B才可以切断GFLG多肽释放药物GEF。这种由环糊精和光敏剂构成的超分子交联层,一方面作为最里层的门控结构,使得药物激活更加精准更加可控,另一方面提供了光动力治疗和发挥抑制旁路激活的作用。可见,本发明设计的纳米粒子HA-BPY-GEF-PNs属于近红外光/酶程序性激活的超分子前药系统,基于“与”逻辑门的释药逻辑使得药物激活更加精准可控,为非小细胞肺癌治疗产生的耐药问题提供了一个新的解决思路,同时对于生物医用高分子材料的开发、肿瘤诊断等领域也具有重要的科学价值。
优选地,步骤S11中,所述TOS-CD和缩硫酮二胺的质量比为1:10-1:50;所述反应的温度为70-90℃、时间为12-36小时。
优选地,步骤S11中,所述有机溶剂包括但不限于DMF。
优选地,步骤S12中,所述透明质酸钠、N-羟基硫代琥珀酰亚胺、1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐和TK-CD的质量比为60:(100-120):(100-120):(160:200)。
优选地,步骤S12中,所述透析为用8000~14000MW的透析袋超纯水透析5天。
优选地,步骤S21具体为:将氨基叠氮和4-二甲氨基吡啶溶于有机溶剂制成溶液1,另将金刚烷酰氯溶于有机溶剂制成溶液2,溶液1和溶液2混合后经放置、萃取、洗涤,干燥和纯化制得Ada-N3;
优选地,步骤S22具体为:将四炔基BPY和NBS溶于有机溶剂中,经反应后制得溴代BPY,然后将Ada-N3和溴代BPY溶于有机溶剂中,再加入硫酸铜,通入惰性气体氧气后在惰性气体氛围下再加入抗坏血酸钠,经室温反应后制得4Ada-BPY。
优选地,步骤S21、22中,所述有机溶剂包括但不限于二氯甲烷、THF。
优选地,步骤S31中,所述N,N'-二甲基乙二胺与二碳酸二叔丁酯的体积质量比为(3-5):3.0;所述吉非替尼、4-二甲氨基吡啶、三光气和DTA-Boc的质量比为(1300-1500):(1100-1200):(300-500):1300。优选地,步骤S32中,所述Ada-GFLG-AB、4-硝基苯基氯甲酯和N,N-二异丙基乙胺的质量比为300:(300-500):(300-500)
优选地,步骤S33中,GEF-DTA、N,N-二异丙基乙胺和Ada-GFLG-AB-NC的质量比为(200-300):(500-600):200。
优选地,步骤S31、32、33中,所述有机溶剂包括但不限于二氯甲烷、DMF。
优选地,步骤S4中,所述高分子溶液的浓度为(100-200)μM,所述Ada-GFLG-GEF溶液和4Ada-BPY溶液的浓度均为(2-4)mM,所述高分子溶液、Ada-GFLG-GEF溶液和4Ada-BPY溶液的体积比为(90-95):(4-6):(1-4)。
优选地,步骤S4中,所述透析为2000MW的透析袋中透析2-5小时。
优选地,步骤S4中,制备Ada-GFLG-GEF溶液和4Ada-BPY溶液所用的有机溶剂包括但不限于DMSO。
本发明还提供了采用上述的制备方法制备得到的近红外光/酶程序性激活超分子前药系统。
与现有技术相比,本发明的有益效果是:
本发明公开了一种近红外光/酶程序性激活超分子前药系统的制备方法,以由亲水透明质酸(HA)和缩硫酮修饰的β-环糊精(TK-CD)合成的HA-CD作为主体分子,以金刚烷和GFLG(四肽甘氨酸-苯丙氨酸-亮氨酸-甘氨酸(Gly-Phe-Leu-Gly,GFLG)修饰的GEF前药Ada-GFLG-GEF以及四金刚烷修饰的氮杂氟硼二咯(4ADA-BPY二吡啶)光敏剂作为客体分子,通过主客体相互作用和亲疏水作用形成纳米粒子HA-BPY-GEF-PNs,即得超分子前药系统。
本发明开发了基于主客体作用的新型超分子纳米前药递送系统HA-BPY-GEF-PNs,该纳米载药系统具有近红外光照和组织蛋白酶B内外源性程序性激活效应的特点,为响应性纳米载药系统的设计提供了新的思路。同时,本发明开发的新型超分子纳米前药递送系统HA-BPY-GEF-PNs,载体安全性高,生物相容性好,肿瘤细胞摄取能力强,药物释放精准可控,能够实现更高的治疗精准度,减少毒副作用。此外,在本发明的新型超分子纳米前药递送系统HA-BPY-GEF-PNs中,光敏剂的掺入,一方面提供了光动力治疗(PDT)作用,另一方面可以通过提高肿瘤细胞内的ROS来抑制旁路激活信号通路,进而对耐药细胞产生较大毒性,为克服非小细胞肺癌产生的耐药问题提供了新的解决思路。
附图说明
图1为近红外光/酶程序性激活超分子前药系统HA-BPY-GEF-PNs的透射电子显微镜图;
图2为近红外光/酶程序性激活超分子前药系统HA-BPY-GEF-PNs的粒径分布图;
图3为近红外光/酶程序性激活超分子前药系统HA-BPY-GEF-PNs的体外吉非替尼释放曲线;
图4为不同浓度的主体高分子在24小时和48小时时对不同细胞的细胞毒性实验结果。
图5为近红外光/酶程序性激活超分子前药系HA-BPY-GEF-PNs的细胞摄取与时间的关系;
图6为超分子前药系统HA-BPY-GEF-PNs在有无近红外光照的情况下孵育48小时后对PC9细胞的细胞毒性实验结果;
图7为超分子前药系统HA-BPY-GEF-PNs在有无近红外光照的情况下孵育48小时后对PC9GR细胞的细胞毒性实验结果。
具体实施方式
下面对本发明的具体实施方式作进一步说明。在此需要说明的是,对于这些实施方式的说明用于帮助理解本发明,但并不构成对本发明的限定。此外,下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
下述实施例中的实验方法,如无特殊说明,均为常规方法,下述实施例中所用的试验材料,如无特殊说明,均为可通过常规的商业途径购买得到。
实施例1超分子前药系统HA-BPY-GEF-PNs的制备
该方法包括如下步骤:
(1)主体高分子HA-CD的合成
根据下列合成路线,合成过程如下:
1)TK-CD合成:将TOS-CD(合成见参考文献“X.Niu,Y.Liu,X.Li,W.Wang,Z.Yuan,Adv.Funct.Mater.2020,30,2006883”)和缩硫酮二胺以1:20的质量比例加入到干燥DMF中,80℃氮气保护下反应24小时,反应后旋蒸除去DMF,所得粗产物溶解在水中(1-5g/mL),然后将水溶液滴加到大量丙酮中(体积比=1:100-200),沉淀三次得到产物TK-CD。
2)HA-CD合成:将60mg透明质酸钠、113.4mgN-羟基硫代琥珀酰亚胺和100.1mg1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐溶于PBS(0.1M,pH7.2)中,室温搅拌30分钟后,加入186.3mgTK-CD,持续搅拌24小时,然后将溶液转移到8000~14000MW的透析袋中,超纯水透析5天,透析结束后冻干得到产物HA-CD。
(2)客体分子近红外光敏剂4Ada-BPY的合成
根据下列合成路线,合成过程如下:
1)Ada-N3合成:将氨基叠氮(130mg)溶于干燥二氯甲烷(20mL)中,再加入4-二甲氨基吡啶(120mg)制成溶液1;另将金刚烷酰氯(160mg)溶解在干燥二氯甲烷(10mL)中制成溶液2;冰浴下将溶液1滴加到溶液2中,室温放置过夜,乙酸乙酯萃取,盐水洗涤,干燥旋干,过硅胶柱,分离纯化得到产物。
2)4Ada-BPY合成:将四炔基BPY(100mg)溶于二氯甲烷(30mL)中,再加入2.5当量的NBS(N-溴代琥珀酰亚胺),室温反应过夜,柱层析提纯,得到溴代的BPY,产物为金属光泽深蓝色粉末。然后将Ada-N3(80mg)和溴代的BPY(200mg)溶解在THF(20mL)中,并加入2-3滴超纯水,再加入催化量的硫酸铜,通氮气十五分钟除去体系中的氧气后,在氮气保护下加入5倍当量于硫酸铜的抗坏血酸钠,室温反应24小时,旋干过硅胶柱,纯化得到产物,产物为金属光泽蓝黑色粉末。
(3)客体分子吉非替尼前药Ada-GFLG-GEF的合成
根据下列合成路线,合成过程如下:
1)GEF-DTA合成:将N,N'-二甲基乙二胺(4.87mL)溶解在干燥二氯甲烷(50mL)中制成溶液1,另将二碳酸二叔丁酯(3.0g)溶解在干燥二氯甲烷中制成溶液2,冰浴下将溶液1滴加到溶液2中,所得混合物升至室温,搅拌反应24小时,旋蒸除去溶剂,然后乙酸乙酯(30mL)萃取,NaHCO3溶液洗涤两次,所得有机相用Na2SO4干燥,旋干得到油状产物DTA-Boc。
将吉非替尼(1340.7mg)和4-二甲氨基吡啶(1136.2mg)溶于干燥二氯甲烷(20mL)中,再加入三光气(311.6mg),反应0.5小时,反应后再加入DTA-Boc(1299.1mg),室温反应24小时,旋干过硅胶柱,纯化得到白色固体产物。将上述产物(240mg)溶于二氯甲烷(20mL)中,再加入三氟乙酸(二氯甲烷和三氟乙酸的体积比为1:1),室温反应2小时,旋蒸除去溶剂,得产物,即GEF-DTA。
2)Ada-GFLG-GEF合成
①Ada-GFLG-AB-NC合成:Ada-GFLG(450mg),2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉EEDQ(600mg),对氨基苄醇(400mg)溶解于干燥二氯甲烷中(20mL),氮气保护下室温反应24-36小时。乙酸乙酯萃取,盐水洗涤,Na2SO4干燥,旋干过硅胶柱,分离纯化得到对氨基苄醇修饰的GFLG多肽(Ada-GFLG-AB)。
将Ada-GFLG-AB(300mg)溶于无水二氯甲烷(20mL)中,再加入两滴DMF,在氮气保护及冰浴下加入4-硝基苯基氯甲酯(274mg)和N,N-二异丙基乙胺(206.7mg),所得混合物升至室温,搅拌反应24-36小时,反应后将反应混合液旋干,KHSO4洗涤两次,Na2SO4干燥,粗产物旋干,过硅胶柱纯化后得到产物,产物为白色固体Ada-GFLG-AB-NC。
②Ada-GFLG-GEF合成:将GEF-DTA(204.2mg)溶于无水DMF(10mL)中,在氮气保护及冰浴下加入N,N-二异丙基乙胺(564.5mg)和Ada-GFLG-AB-NC(200mg),反应24小时,反应后旋蒸除去DMF,将产物重新溶于乙酸乙酯,KHSO4萃取洗涤,Na2SO4干燥后,旋干过硅胶柱,纯化得白色固体产物Ada-GFLG-GEF。
(4)纳米粒制备
根据下列合成路线,合成过程如下:
将3.5mgHA-CD溶于1mL超纯水中,得到高分子溶液,以β-CD标定为1mM,将高分子溶液稀10倍成100μM。另将两种客体分子Ada-GFLG-GEF和4Ada-BPY分别溶于DMSO(1mL)中,标定为2mM,先将客体分子Ada-GFLG-GEF溶液(40μL)在5分钟内缓慢注射进高分子溶液中(950μL)中得到胶体溶液,然后再将客体分子4Ada-BPY溶液(10μL)在5分钟内缓慢注射进上述高分子溶液中,得到胶体溶液,最后用2000MW的透析袋中透析2小时,去除溶液中的微量DMSO,所得溶液的保存条件为4℃,制备得到HA-BPY-GEF-PNs超分子前药系统。
HA-BPY-GEF-PNs的透射电子显微镜结果及粒径分布情况分别如图1、2所示,可以看出本实施例成功制备得到球状纳米粒,粒径主要分布在80-90nm。
实验例1性能测试
(1)HA-BPY-GEF-PNs体外释放吉非替尼的能力
采用岛津公司的LC-20AT分析仪及半制备液相测试超分子前药系统HA-BPY-GEF-PNs在模拟人体37℃环境中体外释放吉非替尼的情况。测试过程如下:
药物释放动力学通过高效液相测定,检测波长为254nm,流动相条件(甲醇:水=80:20)。首先,在PBS buffer(pH 7.4)中制备HA-BPY-GEF-PNs纳米粒子溶液,浓度为100μM,然后单独加入组织蛋白酶B(10μg),或者单独施加660nm波长的近红外光照射,或者同时,加入组织蛋白酶B并施加660nm波长的近红外光照射,最后不同时间点取出100μL溶液甲醇稀释到浓度为50μM,并通过HPLC测定药物释放量。
由图3可以看出,在pH 7.4的环境中,单独加入木瓜蛋白酶或者单独施加660nm近红外光激活条件都无法激活前药,即“或”门释放条件的底层逻辑无法实现前药的可控激活。然而,先经过660nm近红外光照射,再在组织蛋白酶B存在的条件下前药可被激活并释放出GEF,即必须满足符合先后顺序的“与”门底层逻辑的前药激活条件下,前药的精确可控激活才可实现。可见,所制备得到的超分子前药系统HA-BPY-GEF-PNs属于近红外光/酶程序性激活超分子前药系统。
此外,图3也可以看出,pH 5.4的肿瘤环境可以促进HA-BPY-GEF-PNs纳米系统中药物的释放。
(2)高分子载体安全性测定
通过CCK-8法来研究高分子载体HA-CD的细胞毒性。具体实验如下:
分别将PC9和PC9GR两种人肺腺癌细胞系接种在96孔板中培养24小时,当细胞生长至80%时,将不同浓度梯度(0、1.95、3.9、7.81、15.63、31.25、62.5、125、250)的载体材料和细胞共孵育,并继续培养24小时和48小时。移除旧培养基(DMEM培养基),加入含有10%CCK8的新鲜培养基并继续培养1-2个小时,加入CCK-8试剂经过1-2小时显色后,通过酶标仪(型号Victor Nivo,Perkin Elmer公司)于450nm处进行吸光度测定。
由图4可以看出,超分子前药系统中采用的高分子载体对PC9和PC9GR都具有高度的生物相容性。
(3)细胞摄取评价
采用Zeiss公司的LSN880型激光共聚焦显微镜观察细胞对HA-BPY-GEF-PNs纳米粒的摄取效果。具体实验过程为:
首先,在含有10%(体积比)牛血清蛋白(FBS)和1%(体积比)盘尼西林和链霉素的DMEM培养基中,将吉非替尼敏感的PC9细胞系在5%CO2气体和37℃条件的培养箱中培养。当细胞增殖至能够覆盖培养皿底表面约80%面积时加入1mL 0.25%胰酶消化细胞,轻轻吹打,待细胞能够成片脱落时终止消化。1000rpm离心3分钟后弃去上清液,细胞沉淀重新加入培养基轻轻吹打均匀后,移入共聚焦皿内,控制每皿的细胞浓度约为1.0×105/mL,在细胞培养箱中37℃培养。培养24小时后,将纳米粒加入培养基中,并使其最终浓度为2μM。当细胞经过药物不同时间孵育后,将培养基去除,用PBS缓冲液洗涤3次,并使用4%的甲醛溶液在室温下固定15分钟,再用PBS缓冲液洗涤3次,常温DAPI染色5分钟,用PBS缓冲液洗涤3次后,通过激光共聚焦显微镜观察细胞对纳米粒的摄取情况。
由图5的实验结果可以看出,PC9细胞对超分子前药系统HA-BPY-GEF-PNs具有较好的摄取效果。
(4)细胞毒性测定
通过CCK-8法来研究HA-GEF-PNs、HA-BPY-GEF-PNs-L、GEF、HA-BPY-PNs+L、HA-BPY-GEF-PNs+L的细胞毒性(+L和-L分别代表有无施加光照)。分别将PC9和PC9GR两种细胞(吉非替尼敏感的PC9细胞系和耐药的PC9GR细胞系)接种在96孔板中培养24小时,当细胞生长至80%时,将不同药物或纳米粒子以相同的浓度梯度(0、0.01、0.1、0.25、0.5、1、2.5、5、10、20μM)和细胞共孵育,并继续培养48小时,期间使用660nm近红外光照射光毒性细胞组(照射10min)。去除旧培养基,并加入含有10%CCK8的新鲜培养基并继续培养1-2个小时,之后加入CCK-8试剂,经过1-2小时显色后,通过酶标仪(型号Victor Nivo,Perkin Elmer公司)于450nm处进行吸光度测定。
由图6和图7可以看出,近红外光/酶程序性激活超分子前药系统对PC9和PC9GR都具有最佳的肿瘤细胞杀伤力。
综上可见,本发明开发的新型超分子纳米前药递送系统HA-BPY-GEF-PNs属于近红外光/酶程序性激活超分子前药系统,具有载体安全性高,生物相容性好,肿瘤细胞摄取能力强,药物释放精准可控等优点,能够实现更高的治疗精准度,减少毒副作用。
以上对本发明的实施方式作了详细说明,但本发明不限于所描述的实施方式。对于本领域的技术人员而言,在不脱离本发明原理和精神的情况下,对这些实施方式进行多种变化、修改、替换和变型,仍落入本发明的保护范围内。
Claims (10)
1.一种近红外光/酶程序性激活超分子前药系统的制备方法,其特征在于,所述制备方法包括以下步骤:
S1、主体高分子HA-CD的合成:
S11、将TOS-CD和缩硫酮二胺在惰性气体氛围下于有机溶剂中经反应后制备得到TK-CD;
S12、将透明质酸钠、N-羟基硫代琥珀酰亚胺、1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐和TK-CD于PBS中经搅拌反应和透析后制备得到HA-CD;
S2、客体分子近红外光敏剂4Ada-BPY的合成:
S21、通过氨基叠氮、4-二甲氨基吡啶和金刚烷酰氯于有机溶剂中制成Ada-N3;
S22、将四炔基BPY和NBS溶于有机溶剂中,经反应后制得溴代BPY,然后将Ada-N3和溴代BPY溶于有机溶剂中,惰性气体氛围下经反应后制得4Ada-BPY;
S3、客体分子吉非替尼前药Ada-GFLG-GEF的合成:
S31、先将N,N'-二甲基乙二胺和二碳酸二叔丁酯于有机溶剂中经搅拌反应制成DTA-Boc;再将吉非替尼和4-二甲氨基吡啶溶于有机溶剂中,加入三光气反应后再加入DTA-Boc,经室温反应后制得GEF-DTA;
S32、先以EEDQ作为缩合剂,将Ada-GFLG与对氨基苄醇进行酰胺缩合制得修饰有对氨基苄醇的GFLG多肽Ada-GFLG-AB;再将Ada-GFLG-AB溶于有机溶剂中,在惰性气体保护及冰浴下加入4-硝基苯基氯甲酯和N,N-二异丙基乙胺,室温搅拌反应后制得Ada-GFLG-AB-NC;
S33、将GEF-DTA溶于有机溶剂中,在惰性气体保护及冰浴下加入N,N-二异丙基乙胺和Ada-GFLG-AB-NC,经反应后制得Ada-GFLG-GEF;
S4、纳米粒制备:
将HA-CD溶于水中制成高分子溶液,另将两种客体分子Ada-GFLG-GEF和4Ada-BPY分别溶于有机溶剂中制成溶液,然后先将Ada-GFLG-GEF加入高分子溶液中制成胶体溶液,再将4Ada-BPY溶液加入到胶体溶液中,经透析后制得纳米粒,得到近红外光/酶程序性激活超分子前药系统HA-BPY-GEF-PNs。
2.根据权利要求1所述的一种近红外光/酶程序性激活超分子前药系统的制备方法,其特征在于,步骤S11中,所述TOS-CD和缩硫酮二胺的质量比为1:10-1:50;所述反应的温度为70-90℃、时间为12-36小时。
3.根据权利要求1所述的一种近红外光/酶程序性激活超分子前药系统的制备方法,其特征在于,步骤S12中,所述透明质酸钠、N-羟基硫代琥珀酰亚胺、1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐和TK-CD的质量比为60:(100-120):(100-120):(160:200)。
4.根据权利要求1所述的一种近红外光/酶程序性激活超分子前药系统的制备方法,其特征在于,步骤S12中,所述透析为用8000~14000MW的透析袋超纯水透析5天。
5.根据权利要求1所述的一种近红外光/酶程序性激活超分子前药系统的制备方法,其特征在于,步骤S31中,所述N,N'-二甲基乙二胺与二碳酸二叔丁酯的体积质量比为(3-5):3.0;所述吉非替尼、4-二甲氨基吡啶、三光气和DTA-Boc的质量比为(1300-1500):(1100-1200):(300-500):1300。
6.根据权利要求1所述的一种近红外光/酶程序性激活超分子前药系统的制备方法,其特征在于,步骤S32中,所述Ada-GFLG-AB、4-硝基苯基氯甲酯和N,N-二异丙基乙胺的质量比为300:(300-500):(300-500)。
7.根据权利要求1所述的一种近红外光/酶程序性激活超分子前药系统的制备方法,其特征在于,步骤S33中,GEF-DTA、N,N-二异丙基乙胺和Ada-GFLG-AB-NC的质量比为(200-300):(500-600):200。
8.根据权利要求1所述的一种近红外光/酶程序性激活超分子前药系统的制备方法,其特征在于,步骤S4中,所述高分子溶液的浓度为(100-200)μM,所述Ada-GFLG-GEF溶液和4Ada-BPY溶液的浓度均为(2-4)mM,所述高分子溶液、Ada-GFLG-GEF溶液和4Ada-BPY溶液的体积比为(90-95):(4-6):(1-4)。
9.根据权利要求1所述的一种近红外光/酶程序性激活超分子前药系统的制备方法,其特征在于,步骤S4中,所述透析为2000MW的透析袋中透析2-5小时。
10.采用权利要求1-9任一项所述的制备方法制备得到的近红外光/酶程序性激活超分子前药系统。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211178740.5A CN115590958B (zh) | 2022-09-27 | 2022-09-27 | 一种近红外光/酶程序性激活超分子前药系统及制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211178740.5A CN115590958B (zh) | 2022-09-27 | 2022-09-27 | 一种近红外光/酶程序性激活超分子前药系统及制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115590958A true CN115590958A (zh) | 2023-01-13 |
CN115590958B CN115590958B (zh) | 2023-12-01 |
Family
ID=84844827
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211178740.5A Active CN115590958B (zh) | 2022-09-27 | 2022-09-27 | 一种近红外光/酶程序性激活超分子前药系统及制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115590958B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107629077A (zh) * | 2017-09-25 | 2018-01-26 | 深圳市声光动力生物医药科技有限公司 | 酸敏感的吉非替尼‑氟硼二吡咯衍生物及其制备方法和在医药上的应用 |
CN107629063A (zh) * | 2017-09-25 | 2018-01-26 | 深圳市声光动力生物医药科技有限公司 | 酸敏感的酞菁锌‑吉非替尼配合物及其制备方法和在医药上的应用 |
CN110732027A (zh) * | 2019-11-06 | 2020-01-31 | 内蒙古农业大学 | 一种刺激响应的靶向聚多糖超分子诊疗组装体及其制备方法 |
-
2022
- 2022-09-27 CN CN202211178740.5A patent/CN115590958B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107629077A (zh) * | 2017-09-25 | 2018-01-26 | 深圳市声光动力生物医药科技有限公司 | 酸敏感的吉非替尼‑氟硼二吡咯衍生物及其制备方法和在医药上的应用 |
CN107629063A (zh) * | 2017-09-25 | 2018-01-26 | 深圳市声光动力生物医药科技有限公司 | 酸敏感的酞菁锌‑吉非替尼配合物及其制备方法和在医药上的应用 |
CN110732027A (zh) * | 2019-11-06 | 2020-01-31 | 内蒙古农业大学 | 一种刺激响应的靶向聚多糖超分子诊疗组装体及其制备方法 |
Non-Patent Citations (1)
Title |
---|
XIAJING GU等: "CuS Nanoparticles as a Photodynamic Nanoswitch for Abrogating Bypass Signaling To Overcome Gefitinib Resistance", 《NANO LETT》, vol. 19, pages 3344 - 3352 * |
Also Published As
Publication number | Publication date |
---|---|
CN115590958B (zh) | 2023-12-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Chen et al. | In vivo near-infrared imaging and phototherapy of tumors using a cathepsin B-activated fluorescent probe | |
CA2101227C (en) | Chlorophyll and bacteriochlorophyll derivatives and pharmaceutical compositions containing them | |
CN105188717B (zh) | 卟啉修饰末端树枝状聚合物 | |
Shen et al. | pH-responsive aerobic nanoparticles for effective photodynamic therapy | |
CN102898542B (zh) | 一种水溶性富勒烯及其应用 | |
Zhou et al. | Ru (II)-modified TiO2 nanoparticles for hypoxia-adaptive photo-immunotherapy of oral squamous cell carcinoma | |
CN108354901A (zh) | 用于肿瘤化疗与光热联合治疗的pH/还原双重敏感多功能纳米胶束及其应用 | |
Kwag et al. | Photodynamic therapy using glycol chitosan grafted fullerenes | |
CN104274834A (zh) | 一种环境敏感的肿瘤靶向聚合物胶束及其制备方法 | |
CN105343878A (zh) | 还原敏感型水溶性分子靶向光敏剂及其制备方法和应用 | |
Liu et al. | Supramolecular organic frameworks improve the safety of clinically used porphyrin photodynamic agents and maintain their antitumor efficacy | |
CN104258391B (zh) | 一种多功能刺激敏感型聚合物-纳米金笼载体及其制备方法 | |
CN104940945A (zh) | 一种透明质酸修饰的中空介孔硫化铜复合物及其制备方法与应用 | |
Zhu et al. | Sonodynamic cancer therapy by novel iridium-gold nanoassemblies | |
Li et al. | Hypoxia/pH dual-responsive nitroimidazole-modified chitosan/rose bengal derivative nanoparticles for enhanced photodynamic anticancer therapy | |
CN105031651B (zh) | 一种酶响应型磁性纳米粒及其制备方法与应用 | |
Li et al. | Targeted methotrexate prodrug conjugated with heptamethine cyanine dye improving chemotherapy and monitoring itself activating by dual-modal imaging | |
CN114748639B (zh) | 一种光敏剂-羟烷基淀粉-多肽偶联的两亲性大分子化合物、纳米载药系统及其制备方法 | |
Zhang et al. | MnO 2-capped silk fibroin (SF) nanoparticles with chlorin e6 (Ce6) encapsulation for augmented photo-driven therapy by modulating the tumor microenvironment | |
US20130315989A1 (en) | Method for treating a patient via photodynamic therapy comprising a macromolecular capsule | |
CN105963703B (zh) | 一种抗肿瘤药物的制备方法 | |
CN108721618B (zh) | Fe3O4@CuO@OxyHb@ZnPc@m-HA五元复合体系及其制备方法和应用 | |
CN115590958B (zh) | 一种近红外光/酶程序性激活超分子前药系统及制备方法 | |
Adriouach et al. | Squalene-PEG: Pyropheophorbide-a nanoconstructs for tumor theranostics | |
CN110200945A (zh) | 一种光敏性多巴胺基纳米药物载体的制备方法 |
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 | ||
GR01 | Patent grant |