CN105664160B - A kind of preparation method and applications of the mesoporous door-control type copper sulfide pharmaceutical composition of near infrared light remote control and regulation - Google Patents
A kind of preparation method and applications of the mesoporous door-control type copper sulfide pharmaceutical composition of near infrared light remote control and regulation Download PDFInfo
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- CN105664160B CN105664160B CN201610116240.7A CN201610116240A CN105664160B CN 105664160 B CN105664160 B CN 105664160B CN 201610116240 A CN201610116240 A CN 201610116240A CN 105664160 B CN105664160 B CN 105664160B
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- OMZSGWSJDCOLKM-UHFFFAOYSA-N copper(II) sulfide Chemical compound [S-2].[Cu+2] OMZSGWSJDCOLKM-UHFFFAOYSA-N 0.000 title claims abstract description 77
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 54
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 50
- 229960000304 folic acid Drugs 0.000 claims abstract description 50
- 235000019152 folic acid Nutrition 0.000 claims abstract description 50
- 239000011724 folic acid Substances 0.000 claims abstract description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000004073 vulcanization Methods 0.000 claims abstract description 34
- 150000004699 copper complex Chemical class 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 30
- 239000002244 precipitate Substances 0.000 claims abstract description 29
- 230000001376 precipitating effect Effects 0.000 claims abstract description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 26
- 229940079593 drug Drugs 0.000 claims abstract description 25
- 238000005576 amination reaction Methods 0.000 claims abstract description 24
- 238000005119 centrifugation Methods 0.000 claims abstract description 14
- -1 centrifugation Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- WUIABRMSWOKTOF-OYALTWQYSA-O 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS(O)(=O)=O.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 WUIABRMSWOKTOF-OYALTWQYSA-O 0.000 claims abstract description 10
- 238000004108 freeze drying Methods 0.000 claims abstract description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims abstract description 9
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims abstract description 9
- 235000011130 ammonium sulphate Nutrition 0.000 claims abstract description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 9
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 6
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 42
- 125000003929 folic acid group Chemical group 0.000 claims description 32
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 29
- 239000012498 ultrapure water Substances 0.000 claims description 29
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 22
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 22
- 239000002245 particle Substances 0.000 claims description 22
- 239000006185 dispersion Substances 0.000 claims description 14
- 239000012782 phase change material Substances 0.000 claims description 14
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 11
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- 229940041616 menthol Drugs 0.000 claims description 11
- 230000004913 activation Effects 0.000 claims description 9
- 239000012190 activator Substances 0.000 claims description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 230000036961 partial effect Effects 0.000 claims description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 238000003384 imaging method Methods 0.000 claims description 4
- 239000013049 sediment Substances 0.000 claims description 4
- 235000007164 Oryza sativa Nutrition 0.000 claims description 3
- 235000013339 cereals Nutrition 0.000 claims description 3
- 238000007626 photothermal therapy Methods 0.000 claims description 3
- 235000009566 rice Nutrition 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- 240000007594 Oryza sativa Species 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229940044683 chemotherapy drug Drugs 0.000 claims 1
- 238000007710 freezing Methods 0.000 claims 1
- 230000008014 freezing Effects 0.000 claims 1
- 230000036571 hydration Effects 0.000 claims 1
- 238000006703 hydration reaction Methods 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 26
- 238000002512 chemotherapy Methods 0.000 abstract description 9
- 230000008685 targeting Effects 0.000 abstract description 5
- 201000011510 cancer Diseases 0.000 abstract description 4
- 238000013270 controlled release Methods 0.000 abstract description 4
- 238000003745 diagnosis Methods 0.000 abstract description 4
- 230000010354 integration Effects 0.000 abstract description 3
- 239000008188 pellet Substances 0.000 abstract 2
- 229910052927 chalcanthite Inorganic materials 0.000 abstract 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 51
- 108010006654 Bleomycin Proteins 0.000 description 23
- 229960001561 bleomycin Drugs 0.000 description 23
- 229910052760 oxygen Inorganic materials 0.000 description 14
- 239000001301 oxygen Substances 0.000 description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 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 class 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 12
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 12
- 229920002674 hyaluronan Polymers 0.000 description 12
- 229960003160 hyaluronic acid Drugs 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 230000000536 complexating effect Effects 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 229910001431 copper ion Inorganic materials 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 208000019065 cervical carcinoma Diseases 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
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- 239000012071 phase Substances 0.000 description 3
- 238000006479 redox reaction Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-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
- 241000209094 Oryza Species 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002428 photodynamic therapy Methods 0.000 description 2
- 238000001126 phototherapy Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000000015 thermotherapy Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- BWFPGXWASODCHM-UHFFFAOYSA-N copper monosulfide Chemical compound [Cu]=S BWFPGXWASODCHM-UHFFFAOYSA-N 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 239000013335 mesoporous material Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
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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
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/34—Copper; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
-
- 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
- A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/221—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by the targeting agent or modifying agent linked to the acoustically-active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/228—Host-guest complexes, clathrates, chelates
Abstract
It the present invention relates to the preparation method and applications of the mesoporous door-control type copper sulfide pharmaceutical composition of near infrared light remote control and regulation, can effectively solve the problems, such as that there is targeting, controlled release, chemotherapy combined chemotherapy medication simultaneously, realize cancer diagnosis and treatment integration, method is, by CuSO4·5H2O is soluble in water, and polyvinylpyrrolidone, sodium hydroxide, hydrazine hydrate, ammonium sulfate is added, and centrifugation precipitates water-dispersible, addition mercaptoethylmaine, is centrifuged, and freeze-drying obtains the hollow mesoporous vulcanization copper complex of amination；Folic acid is added in n,N-Dimethylformamide, 1- ethyl-(3- dimethylaminopropyl) carbodiimide, HOSu NHS, the hollow mesoporous vulcanization copper complex of amination is added, centrifugation, pellet frozen is dry, and precipitating is scattered in methanol, Bleomycin Sulphate is instilled, oil bath volatilizes methanol, adds water, centrifugation, pellet frozen is dry, preparation process of the present invention is simple, method is reliable and stable, and producing cost is low.
Description
Technical field
The present invention relates to biomedicine field, the mesoporous door-control type copper sulfide medicine of especially a kind of near infrared light remote control and regulation
The preparation method and applications of compositions.
Background technique
Broad-spectrum anti-cancer drug bleomycin is a kind of metal dependent form drug, and a part of group can be with DNA in structure
Chimeric, a part of group can be with complexing of metal ion, wherein the affinity highest with copper ion, Cu after complexing2+It can be intracorporal
Reducing substances (ascorbic acid, glutathione, cysteamine etc.) are reduced to Cu+, Cu+Redox reaction then occurs with water-soluble oxygen
It generates active oxygen and in turn results in DNA damage performance antitumor action.But since bleomycin easily causes serious pulmonary fibrosis, it is
Its toxic side effect in vivo is reduced, carrying out load to bleomycin using targeted nanometer carrier is a selection well.
Nano material should have partial size small as a kind of safe and efficient pharmaceutical carrier, and toxicity is low, good biocompatibility,
The features such as performance is stablized.Wherein the hollow mesoporous copper sulfide nano grain of rice has unique cage structure, and Drug loading capacity is prominent.Close red
Under outer illumination, the good photothermal conversion characteristic of copper sulfide and its copper ion discharged may participate in redox reaction and generate activity
The properties such as oxygen become a kind of emerging photosensitizer, are widely used in tumor thermal therapy and photodynamic therapy.Separately
Outside, copper sulphide nano particles are under the irradiation of near-infrared, inside can vibrate, can be used for photoacoustic imaging, to tumour portion
Position carries out diagnoses and treatment.
For the carrier of hollow mesoporous material, solve the problems, such as that its " zero leakage " during drug delivery has become in recent years
The research hotspot come.Wherein phase-change material can be used as " gate " molecular Control drug release as a kind of temperature response type material.
Drug and phase-change material are loaded altogether in hollow mesoporous copper sulfide, phase-change material is that solid-state can prevent below the phase transition temperature
Bleomycin release, and the system is under near infrared light photograph, using the photothermal conversion characteristic of copper sulfide, phase-change material is being higher than it
Liquid is converted under the conditions of phase transition temperature, then bleomycin can be discharged from duct.Due to also can promote vulcanization under near infrared light
The release of Cu2+ in copper, and then can reach Cu2+With Cu2+Dependent form drug bleomycin discharges simultaneously in same site, plays swollen
Tumor synergistic therapeutic action reduces the effect to the toxic side effect of its hetero-organization.Therefore, a kind of near infrared light remote control and regulation is studied
Mesoporous door-control type copper sulfide pharmaceutical composition is of great importance and is worth in medicine controlled releasing and cancer diagnosis and treatment.
Summary of the invention
For above situation, for the defect for overcoming the prior art, it is remote that the purpose of the present invention is just to provide a kind of near infrared light
The preparation method and applications of the mesoporous door-control type copper sulfide pharmaceutical composition of journey regulation, can effectively solve to have simultaneously targeting,
The problem of controlled release, chemotherapy combined chemotherapy medication, realizes cancer diagnosis and treatment integration.
The technical solution that the present invention solves is the folic acid in hollow mesoporous copper sulfide nano grain of rice surface modification, hollow mesoporous
Drug bleomycin and phase-change material are loaded inside copper sulfide, are specifically realized by following steps:
(1) hollow mesoporous nano copper sulfate particle is prepared: by the CuSO of 0.3-0.4g4·5H2O is dissolved in 90-110ml water
In, under stirring, 2.75-3.25g polyvinylpyrrolidone is added, reacts at room temperature 10-20min, adds 0.50-0.75g hydrogen-oxygen
Change sodium, stir evenly, 5-7ml hydrazine hydrate is added dropwise, stir 5-10min, 0.55-0.65ml ammonium sulfate is added, stir 1h, use is ultrapure
Water is centrifuged 5-10min in 15000rpm, must precipitate, and precipitating is washed with water to neutrality, is freeze-dried 22-26h, obtains hollow mesoporous vulcanization
Copper nano particles；
(2) it prepares the hollow mesoporous vulcanization copper complex of amination: being added to hollow mesoporous nano copper sulfate particle 45-55mg
45-55ml ultrapure water, ultrasonic disperse 10-30min, then 90-110mg mercaptoethylmaine is added under stiring, it stirs for 24 hours,
15000rpm centrifugation 5-10min must be precipitated, and precipitating is redissolved with ultrapure water, then 15000rpm is centrifuged 5-10min, must precipitate, and precipitates
It is redissolved again with ultrapure water, until neutral, freeze-drying obtains the hollow mesoporous vulcanization copper complex of amination；
(3) it prepares the hollow mesoporous copper sulfide of hyaluronic acid modified with folic acid: N, N- dimethyl methyl is added in 50-60mg folic acid
In amide 4-5ml, 130-150mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide and 80-90mg is added in stirring and dissolving
HOSu NHS is activator, and 30min is stirred at room temperature, and is obtained in the folic acid n,N-Dimethylformamide dispersion liquid of activation,
Under ice bath instill step (2) preparation the hollow mesoporous vulcanization copper complex of amination, be warmed to room temperature, react 3h, 15000rpm from
Heart 5-10min must be precipitated, and precipitating plus water dispersion, dialyse 2d in water, be freeze-dried to get the hollow of hyaluronic acid modified with folic acid
Mesoporous copper sulfide；
(4) it prepares copper sulfide pharmaceutical composition: dispersing the hollow mesoporous copper sulfide of 3-5mg hyaluronic acid modified with folic acid in
In 3-5ml methanol, instilled at 50-55 DEG C dissolved in the 3-5ml phase-change material of 3-5mg Bleomycin Sulphate, it is oily at 50-55 DEG C
Bath stirring 4h, volatilizes methanol, and 70-80 DEG C of water 3-5ml is added, then 15000rpm is centrifuged 5-10min, must precipitate, and is freeze-dried,
Near infrared light remote control and regulation mesoporous door-control type copper sulfide pharmaceutical composition；
The phase-change material is one kind of menthol, 1- tetradecyl alchohol or 7- tetradecyl alchohol, and solid-liquid phase change temperature is higher than just
Chang Tiwen 1-10 DEG C.
The mesoporous door-control type copper sulfide pharmaceutical composition of the near infrared light remote control and regulation is in the preparation of antitumor drugs
Application.
The mesoporous door-control type copper sulfide pharmaceutical composition of the near infrared light remote control and regulation is preparing photo-thermal therapy joint
Application in chemotherapeutics.
The mesoporous door-control type copper sulfide pharmaceutical composition of the near infrared light remote control and regulation is to prepare near infrared light long-range
Application in regulation drug release drug.
The mesoporous door-control type copper sulfide pharmaceutical composition of the near infrared light remote control and regulation is preparing photoacoustic imaging drug
In application.
The mesoporous door-control type copper sulfide and its pharmaceutical composition partial size of the near infrared light remote control and regulation are 100-
150nm。
The drugloading rate of the bleomycin is 25%~35%.
Preparation process of the present invention is simple, and method is reliable and stable, and producing cost is low, and the copper sulfide pharmaceutical composition of preparation is being made
The effects of targeting, controlled release, chemotherapy combined phototherapy, diagnosing tumor can be played in terms of standby anti-tumor drug, enhances the anti-swollen of drug
Tumor effect, is the innovation in tumor therapeutic agent, and economic and social benefit is huge.
Specific embodiment
It elaborates with reference to embodiments with concrete condition to a specific embodiment of the invention.
The present invention can be provided in specific implementation by following embodiment
Embodiment 1
The preparation method of the mesoporous door-control type copper sulfide pharmaceutical composition of near infrared light remote control and regulation of the present invention, by following step
It is rapid to realize:
(1) hollow mesoporous nano copper sulfate particle is prepared: by the CuSO45H of 0.35g2O is dissolved in 100ml water, is stirred
It mixes down, 3.00g polyvinylpyrrolidone is added, react at room temperature 10min, 0.60g sodium hydroxide is added, stirs evenly, 6ml is added dropwise
Hydrazine hydrate stirs 8min, adds 0.60ml ammonium sulfate, stirs 1h, is centrifuged 8min in 15000rpm with ultrapure water, must precipitate,
Precipitating is washed with water to neutrality, is freeze-dried 22-26h, obtains hollow mesoporous nano copper sulfate particle；
(2) it prepares the hollow mesoporous vulcanization copper complex of amination: being added to hollow mesoporous nano copper sulfate particle 50mg
50ml ultrapure water, ultrasonic disperse 10min, then 100mg mercaptoethylmaine is added under stiring, for 24 hours, 15000rpm is centrifuged 8min for stirring
It must precipitate, precipitating is redissolved with ultrapure water, then 15000rpm is centrifuged 8min, must precipitate, and precipitating is redissolved with ultrapure water again, until in
Property, freeze-drying obtains the hollow mesoporous vulcanization copper complex of amination；
(3) it prepares the hollow mesoporous copper sulfide of hyaluronic acid modified with folic acid: N, N- dimethyl formyl is added in 55mg folic acid
In amine 4.5ml, 140mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide and 85mg hydroxysuccinimidyl is added in stirring and dissolving
Acid imide is activator, and 30min is stirred at room temperature, and obtains the folic acid n,N-Dimethylformamide dispersion liquid of activation, instills under ice bath
The hollow mesoporous vulcanization copper complex of amination of step (2) preparation, is warmed to room temperature, and reacts 3h, and 15000rpm centrifugation 8min must sink
It forms sediment, precipitating plus water dispersion, dialyse 2d in water, is freeze-dried the hollow mesoporous copper sulfide to get hyaluronic acid modified with folic acid；
(4) it prepares copper sulfide pharmaceutical composition: dispersing the hollow mesoporous copper sulfide of 4mg hyaluronic acid modified with folic acid in
It in 4ml methanol, is instilled at 52 DEG C dissolved in the 4ml menthol of 4mg Bleomycin Sulphate, 4h is stirred in oil bath at 52 DEG C, is volatilized
75 DEG C of water 4ml is added in methanol, then 15000rpm is centrifuged 8min, must precipitate, and is freeze-dried to get near infrared light remote control and regulation
Mesoporous door-control type copper sulfide pharmaceutical composition.
Embodiment 2
The preparation method of the mesoporous door-control type copper sulfide pharmaceutical composition of near infrared light remote control and regulation of the present invention, by following step
It is rapid to realize:
(1) hollow mesoporous nano copper sulfate particle is prepared: by the CuSO of 0.3g4·5H2O is dissolved in 90ml water, stirring
Under, 2.75g polyvinylpyrrolidone is added, reacts at room temperature 10min, 0.50g sodium hydroxide is added, stirs evenly, 5ml water is added dropwise
Hydrazine is closed, 5min is stirred, adds 0.55ml ammonium sulfate, stirs 1h, 5min is centrifuged in 15000rpm with ultrapure water, must precipitate, sink
Shallow lake is washed with water to neutrality, is freeze-dried 22h, obtains hollow mesoporous nano copper sulfate particle；
(2) it prepares the hollow mesoporous vulcanization copper complex of amination: being added to hollow mesoporous nano copper sulfate particle 45mg
45ml ultrapure water, ultrasonic disperse 10min, then 90mg mercaptoethylmaine is added under stiring, for 24 hours, 15000rpm is centrifuged 5min for stirring
It must precipitate, precipitating is redissolved with ultrapure water, then 15000rpm is centrifuged 5min, must precipitate, and precipitating is redissolved with ultrapure water again, until in
Property, freeze-drying obtains the hollow mesoporous vulcanization copper complex of amination；
(3) it prepares the hollow mesoporous copper sulfide of hyaluronic acid modified with folic acid: N, N- dimethyl formyl is added in 50mg folic acid
In amine 4ml, it is sub- that 130mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide, 80mg hydroxysuccinimidyl acyl is added in stirring and dissolving
Amine is activator, and 30min is stirred at room temperature, and obtains the folic acid n,N-Dimethylformamide dispersion liquid of activation, instills step under ice bath
(2) the hollow mesoporous vulcanization copper complex of amination is prepared, is warmed to room temperature, 3h is reacted, 15000rpm centrifugation 5min must be precipitated, be precipitated
Add water dispersion, dialyse 2d in water, is freeze-dried the hollow mesoporous copper sulfide to get hyaluronic acid modified with folic acid；
(4) it prepares copper sulfide pharmaceutical composition: dispersing the hollow mesoporous copper sulfide of 3mg hyaluronic acid modified with folic acid in
It in 3ml methanol, is instilled at 50 DEG C dissolved in the 3ml 1- tetradecyl alchohol of 3mg Bleomycin Sulphate, 4h is stirred in oil bath at 50 DEG C, is waved
70 DEG C of water 3ml is added in dry methanol, then 15000rpm is centrifuged 5min, must precipitate, and freeze-drying is remotely adjusted to get near infrared light
The mesoporous door-control type copper sulfide pharmaceutical composition of control.
Embodiment 3
The preparation method of the mesoporous door-control type copper sulfide pharmaceutical composition of near infrared light remote control and regulation of the present invention, by following step
It is rapid to realize:
(1) hollow mesoporous nano copper sulfate particle is prepared: by the CuSO of 0.4g4·5H2O is dissolved in 110ml water, stirring
Under, 3.25g polyvinylpyrrolidone is added, reacts at room temperature 20min, 0.75g sodium hydroxide is added, stirs evenly, 7ml water is added dropwise
Hydrazine is closed, 10min is stirred, adds 0.65ml ammonium sulfate, stirs 1h, 10min is centrifuged in 15000rpm with ultrapure water, must precipitate,
Precipitating is washed with water to neutrality, is freeze-dried 22-26h, obtains hollow mesoporous nano copper sulfate particle；
(2) it prepares the hollow mesoporous vulcanization copper complex of amination: being added to hollow mesoporous nano copper sulfate particle 55mg
55ml ultrapure water, ultrasonic disperse 30min, then 110mg mercaptoethylmaine is added under stiring, for 24 hours, 15000rpm is centrifuged for stirring
10min must be precipitated, and precipitating is redissolved with ultrapure water, then 15000rpm is centrifuged 10min, must precipitate, and precipitating is redissolved with ultrapure water again, directly
To neutrality, freeze-drying obtains the hollow mesoporous vulcanization copper complex of amination；
(3) it prepares the hollow mesoporous copper sulfide of hyaluronic acid modified with folic acid: N, N- dimethyl formyl is added in 60mg folic acid
In amine 5ml, it is sub- that 150mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide, 90mg hydroxysuccinimidyl acyl is added in stirring and dissolving
Amine is activator, and 30min is stirred at room temperature, and obtains the folic acid n,N-Dimethylformamide dispersion liquid of activation, instills step under ice bath
(2) the hollow mesoporous vulcanization copper complex of amination prepared, is warmed to room temperature, and reacts 3h, and 15000rpm centrifugation 10min must be precipitated,
Precipitating plus water dispersion, dialyse 2d in water, is freeze-dried the hollow mesoporous copper sulfide to get hyaluronic acid modified with folic acid；
(4) it prepares copper sulfide pharmaceutical composition: dispersing 3- for the hollow mesoporous copper sulfide of 5mg hyaluronic acid modified with folic acid
It in 5ml methanol, is instilled at 55 DEG C dissolved in the 5ml 7- tetradecyl alchohol of 5mg Bleomycin Sulphate, 4h is stirred in oil bath at 55 DEG C, is waved
80 DEG C of water 5ml is added in dry methanol, then 15000rpm is centrifuged 10min, must precipitate, and freeze-drying is remotely adjusted to get near infrared light
The mesoporous door-control type copper sulfide pharmaceutical composition of control.
Through scientific experimentation, the mesoporous door-control type copper sulfide and its medicine group of near infrared light remote control and regulation obtained by the present invention
Close object can efficient targeting to tumor locus, bleomycin and Cu are discharged after near infrared light2+, copper ion occurs after the two complexing
The DNA that the active oxygen that redox reaction generates then is fitted into bleomycin causes to damage, and greatly enhances the anti-swollen of drug
Tumor effect.Obtained compound is provided simultaneously with the multi-efficiencies such as targeting, controlled release, chemotherapy combined phototherapy, diagnosing tumor, with tradition
Chemotherapy, which is compared, has efficient, controllable advantage, also, the combination of its photo-thermal therapy and chemotherapy technology more embodies cancer complex treatment
The problem of.Relevant information is as follows:
One, the characterization of the hollow mesoporous vulcanization copper complex of the modified with folic acid of bleomycin and menthol is loaded
1, in the hollow mesoporous copper sulfide medicinal composition of modified with folic acid bleomycin content measurement
Using ultraviolet spectrophotometry, the content of bleomycin is measured at 291nm wavelength.Sample is calculated with formula (1)
Drugloading rate.Drugloading rate reaches 33.6% or so.
2, the survey of hollow mesoporous vulcanization the copper complex partial size and current potential of the modified with folic acid of bleomycin and menthol is loaded
It is fixed
It takes the hollow mesoporous copper sulfide of the modified with folic acid of appropriate load bleomycin and menthol to be dispersed in water, uses
Nano-ZS90 type laser nano Particle Size Analyzer measures its partial size and current potential is respectively 115nm and -12.4 ± 2.8mV.
Two, the drug release experiment of the hollow mesoporous vulcanization copper complex of the modified with folic acid of bleomycin and menthol is loaded
It takes FA-HMCuS/BLM/LM nano-complex to be scattered in 50ml pH7.4 phosphate buffer salt dissolution medium, puts
(37 DEG C, 100rpm) are placed in shaking table, and respectively at 1h, 3h, 6h, 8h, 12h, 14h samples 1ml, adds the release of 1ml later
Medium, laser group use 808nm laser (2W/cm at every point of time2) irradiation 10min.With efficient liquid phase test sample, drug release
After 14h, the cumulative release amount (92.3%) of laser group is much higher than non-laser group (34.2%).Result explanation, preparation is close red
Phase-change material can be converted to liquid by solid-state after outer light irradiation, promote drug release, reach the mesh of near infrared light remote control and regulation
's.
Three, the cell for loading the hollow mesoporous vulcanization copper complex of the modified with folic acid of bleomycin and menthol generates activity
Oxygen tests the Hella human cervical carcinoma cell for selecting logarithmic growth phase, and adjustment cell number is 3 × 105/ ml is inoculated in 6 well culture plates, carefully
The rear dosing for 24 hours of born of the same parents' adherent growth, is followed successively by blank group, FA-HMCuS group, FA-HMCuS/BLM/LM group, BLM group (HMCuS:12 μ
G/ml, BLM:6 μ g/ml), and set up laser group (2W/cm separately2, 15min) and non-laser group.Pastille culture medium is discarded after dosing 4h,
The culture medium containing DCFH-DA activity oxygen probe is added, under the conditions of being protected from light after laser irradiation, continues to cultivate 30min, collect later
Cell, the active oxygen generated with flow cytometer to each group are quantitative.It finally obtains except FA-HMCuS group, FA-HMCuS/BLM/LM
Group is respectively outside 78.2%, 82.6% in the active oxygen under laser, remaining each group is generated without obvious active oxygen.The result and text
It is consistent to offer report, i.e., active oxygen generates not from bleomycin, but the copper ion by being complexed with bleomycin generates, into
One step could more effectively play its antitumor action after illustrating bleomycin and copper ion complexing.
Four, the cell inhibitory effect of the hollow mesoporous vulcanization copper complex of the modified with folic acid of bleomycin and menthol is loaded
Experiment
Using srb assay, the Hella human cervical carcinoma cell of logarithmic growth phase is selected, adjustment cell number is 5 × 104/ ml inoculation
In 96 well culture plates, every 100 μ 1 (edge hole is filled with sterile PBS) of hole, the rear dosing for 24 hours of cell adherent growth is followed successively by blank
Group, HMCuS group, FA-HMCuS group, BLM group, HMCuS/BLM/LM group, FA-HMCuS/BLM/LM group (HMCuS:12 μ g/ml,
BLM:6 μ g/ml), and set up laser group (2W/cm separately2, 3min) and non-laser group.Every group sets 6 multiple holes.After for 24 hours, every hole is added
The fixed cell of 50% trichloroacetic acid (TCA) of 50 4 DEG C of μ l pre-cooling moves into the fixed 1h of 4 DEG C of refrigerators after fixing 10min, and taking-up discards
Fixer is washed with deionized water 5 times, drying, natural drying at room temperature.After room temperature is dried, 50 μ 1 of SRB dye liquor, room temperature is added in every hole
15~30min of avoid light place dyeing, abandons dye liquor, washes 5 times with 1% glacial acetic acid, drying at room temperature.Later, non-buffered with 150 μ l
Dyestuff of Tris lye (10mM, the pH=10.5) dissolution in conjunction with cell protein, shaking table micro oscillation (37 DEG C, 100rpm,
10min), the OD value of each aperture is surveyed at microplate reader 515nm wavelength, calculates growth of tumour cell inhibiting rate (%)=(1- reality
Test a group OD value/control group OD value) × 100%, HMCuS group, HMCuS-laser group, FA-HMCuS group, FA- is calculated
HMCuS-laser group, BLM group, BLM-laser group, HMCuS/BLM/LM group, HMCuS/BLM/LM-laser group, FA-HMCuS/
BLM/LM group, the inhibitory rate of cell growth of FA-HMCuS/BLM/LM-laser group each group are respectively as follows: 3.5%, 22.6%,
6.1%, 24.8%, 26.3%, 26.7%, 20.3%, 71.5%, 21.8%, 88.6%.The result shows that carrier HMCuS and
FA-HMCuS has apparent photo-thermal to imitate in cell under test dose without overt toxicity, but under near infrared light (808nm) irradiation
It answers；Preparation group inhibiting rate in no near infrared light is not high, but most strong to Cell killing efficacy near infrared light, then
It is Cu2+Active oxygen direct losses DNA is generated with after BLM complexing, in addition the release of thermotherapy and BLM are also wherein reason.
Five, the pharmacodynamic experiment of the hollow mesoporous vulcanization copper complex of the modified with folic acid of bleomycin and menthol is loaded
Kunming mice (female, 3~4 week old) are bought, it is thin in the right upper extremity dorsal sc inoculation S-180 ascites tumor of mouse
Born of the same parents measured gross tumor volume after 7 days, took 60 gross tumor volume >=100mm3And gross tumor volume and the similar mouse of weight, by its with
Machine is divided into 10 groups, every group 6.It is specifically grouped as follows: physiological saline group, physiological saline-laser group, HMCuS group, HMCuS-
Laser group, FA-HMCuS group, FA-HMCuS-laser group, BLM group, BLM-laser group, HMCuS/BLM/LM group, HMCuS/
BLM/LM-laser group, FA-HMCuS/BLM/LM group, FA-HMCuS/BLM/LM-laser group, the light source that laser group uses are
808nm near-infrared laser, power 2W/cm2, be administered 3h after laser irradiation tumor locus, the once irradiating time be 1min, 10 groups
The administration mode of mouse is all made of tail vein injection, is administered once within every two days, is administered 7 times altogether.Guarantee in whole experiment process small
The daily normal diet of mouse weighs to mouse in every two days, and uses the major diameter of electronic digital indicator measurement tumor-bearing mice sarcoma
(A) with minor axis (B), by formula gross tumor volume V=A × B2/ 2 calculate gross tumor volume.The data of record show, FA-HMCuS group,
FA-HMCuS-laser group, BLM group, BLM-laser group, HMCuS/BLM/LM group, HMCuS/BLM/LM-laser group, FA-
HMCuS/BLM/LM group, FA-HMCuS/BLM/LM-laser group each group tumour inhibiting rate be respectively 3.35%, 25.41%,
34.96%, 35.58%, 28.21%, 72.64%, 30.75%, 90.87%.The result shows that FA-HMCuS/BLM/LM-
The drug effect of laser group is significant, illustrates Cu2+Enhance antitumous effect with cooperateing with after BLM complexing, is additionally useful for chemotherapy and combines with thermotherapy
The therapeutic effect of tumour can be significantly increased.
When phase change material be respectively adopted 1- tetradecyl alchohol or 7- tetradecyl alchohol obtain it is identical or similar as a result, here no longer
It repeats.
Experiment shows compared with prior art, the present invention having advantageous effects following prominent:
(1) the mesoporous door-control type copper sulfide and its pharmaceutical composition of near infrared light remote control and regulation provided by the invention, can be real
Existing Cu2+Donor and Cu2+Synchronizing for dependent form drug bleomycin cotransports, the active oxygen direct losses generated after the two complexing
DNA plays tumour synergistic therapeutic action；
(2) the hollow mesoporous copper sulfide itself that the present invention selects has good photo and thermal stability and higher photothermal conversion
Efficiency can produce active oxygen under near infrared light and carry out photodynamic therapy, and copper sulfide can be used as image-forming contrast medium
For photoacoustic imaging, diagnoses and treatment is carried out to tumour, realizes diagnosis and treatment integration；
(3) the mesoporous door-control type copper sulfide and its pharmaceutical composition of near infrared light remote control and regulation provided by the invention, selection
Temperature response type material is phase-change material, is " gate " molecular Control drug release.When temperature is lower than the phase alternating temperature of phase-change material
When spending, it can prevent drug from revealing, and the copper sulfide heat production under near infrared light, phase-change material switch to liquid by solid-state, Ke Yishi
Existing near infrared light remote control and regulation drug release, existing drug cannot achieve, and be the big innovation on anti-tumor drug, medicine of the present invention
Compositions are on probation through clinical 18 tumor patients, wherein 8 people of cervical carcinoma, 5 people of liver cancer, 5 people of lung cancer, and symptom removes cervical carcinoma one
Outside people, other have different degrees of improvement, improve 30% or more than similar drugs curative effect, it is not expected that effect is very good
, there is very strong clinical practice application value, economic and social benefit is huge.
Claims (9)
1. a kind of preparation method of the mesoporous door-control type copper sulfide pharmaceutical composition of near infrared light remote control and regulation, which is characterized in that
It is realized by following steps:
(1) hollow mesoporous nano copper sulfate particle is prepared: by the CuSO of 0.3-0.4g4·5H2O is dissolved in 90-110ml water, is stirred
It mixes down, 2.75-3.25g polyvinylpyrrolidone is added, react at room temperature 10-20min, add 0.50-0.75g sodium hydroxide,
It stirs evenly, 5-7ml hydrazine hydrate is added dropwise, stir 5-10min, 0.55-0.65ml ammonium sulfate is added, stir 1h, existed with ultrapure water
15000rpm is centrifuged 5-10min, must precipitate, and precipitating is washed with water to neutrality, is freeze-dried 22-26h, obtains hollow mesoporous copper sulfide nano
Rice grain；
(2) it prepares the hollow mesoporous vulcanization copper complex of amination: 45- is added to hollow mesoporous nano copper sulfate particle 45-55mg
55ml ultrapure water, ultrasonic disperse 10-30min, then under stiring be added 90-110mg mercaptoethylmaine, stirring for 24 hours, 15000rpm from
Heart 5-10min must be precipitated, and precipitating is redissolved with ultrapure water, then 15000rpm is centrifuged 5-10min, must precipitate, and precipitating uses ultrapure water again
It redissolves, until neutral, freeze-drying obtains the hollow mesoporous vulcanization copper complex of amination；
(3) it prepares the hollow mesoporous copper sulfide of modified with folic acid: 50-60mg folic acid is added in n,N-Dimethylformamide 4-5ml,
Stirring and dissolving, is added 130-150mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide and 80-90mg hydroxysuccinimidyl acyl is sub-
Amine is activator, and 30min is stirred at room temperature, and is obtained in the folic acid n,N-Dimethylformamide dispersion liquid of activation, and step is instilled under ice bath
Suddenly the hollow mesoporous vulcanization copper complex of amination of (2) preparation, is warmed to room temperature, and reacts 3h, and 15000rpm centrifugation 5-10min must sink
It forms sediment, precipitating plus water dispersion, dialyse 2d in water, is freeze-dried the hollow mesoporous copper sulfide to get modified with folic acid；
(4) it prepares copper sulfide pharmaceutical composition: dispersing the hollow mesoporous copper sulfide of 3-5mg modified with folic acid in 3-5ml methanol,
It is instilled at 50-55 DEG C dissolved in the 3-5ml phase-change material of 3-5mg Bleomycin Sulphate, 4h is stirred in oil bath at 50-55 DEG C, is waved
70-80 DEG C of water 3-5ml is added in dry methanol, then 15000rpm is centrifuged 5-10min, must precipitate, freeze-drying, near-infrared
The mesoporous door-control type copper sulfide pharmaceutical composition of light remote control and regulation, partial size 100-150nm；
The phase-change material is one kind of menthol, 1- tetradecyl alchohol or 7- tetradecyl alchohol.
2. the preparation side of the mesoporous door-control type copper sulfide pharmaceutical composition of near infrared light remote control and regulation according to claim 1
Method, which is characterized in that realized by following steps:
(1) hollow mesoporous nano copper sulfate particle is prepared: by the CuSO45H of 0.35g2O is dissolved in 100ml water, under stirring,
3.00g polyvinylpyrrolidone is added, reacts at room temperature 10min, 0.60g sodium hydroxide is added, stirs evenly, 6ml hydration is added dropwise
Hydrazine stirs 8min, adds 0.60ml ammonium sulfate, stirs 1h, is centrifuged 8min in 15000rpm with ultrapure water, must precipitate, precipitate
It is washed with water to neutrality, is freeze-dried 22-26h, obtains hollow mesoporous nano copper sulfate particle；
(2) prepare the hollow mesoporous vulcanization copper complex of amination: it is super that 50ml is added to hollow mesoporous nano copper sulfate particle 50mg
Pure water, ultrasonic disperse 10min, then 100mg mercaptoethylmaine is added under stiring, for 24 hours, 15000rpm centrifugation 8min must sink for stirring
It forms sediment, precipitating is redissolved with ultrapure water, then 15000rpm is centrifuged 8min, must precipitate, and precipitating is redissolved with ultrapure water again, until it is neutral, it is cold
It is lyophilized dry, obtains the hollow mesoporous vulcanization copper complex of amination；
(3) it prepares the hollow mesoporous copper sulfide of modified with folic acid: 55mg folic acid being added in n,N-Dimethylformamide 4.5ml, is stirred
Dissolution is mixed, 140mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide is added and 85mg HOSu NHS is activation
30min is stirred at room temperature in agent, obtains the folic acid n,N-Dimethylformamide dispersion liquid of activation, and step (2) preparation is instilled under ice bath
The hollow mesoporous vulcanization copper complex of amination, is warmed to room temperature, and reacts 3h, and 15000rpm centrifugation 8min must be precipitated, precipitating plus moisture
It dissipates, dialyse 2d in water, is freeze-dried the hollow mesoporous copper sulfide to get modified with folic acid；
(4) it prepares copper sulfide pharmaceutical composition: dispersing the hollow mesoporous copper sulfide of 4mg modified with folic acid in 4ml methanol, 52
It is instilled at DEG C dissolved in the 4ml menthol of 4mg Bleomycin Sulphate, 4h is stirred in oil bath at 52 DEG C, volatilizes methanol, is added 75 DEG C
Water 4ml, then 15000rpm are centrifuged 8min, must precipitate, and are freeze-dried and vulcanize to get the mesoporous door-control type of near infrared light remote control and regulation
Copper pharmaceutical composition.
3. the preparation side of the mesoporous door-control type copper sulfide pharmaceutical composition of near infrared light remote control and regulation according to claim 1
Method, which is characterized in that realized by following steps:
(1) hollow mesoporous nano copper sulfate particle is prepared: by the CuSO of 0.3g4·5H2O is dissolved in 90ml water, under stirring, is added
Enter 2.75g polyvinylpyrrolidone, react at room temperature 10min, 0.50g sodium hydroxide is added, stirs evenly, 5ml hydrazine hydrate is added dropwise,
5min is stirred, 0.55ml ammonium sulfate is added, stirs 1h, 5min is centrifuged in 15000rpm with ultrapure water, must precipitate, precipitating uses water
It is washed till neutrality, 22h is freeze-dried, obtains hollow mesoporous nano copper sulfate particle；
(2) prepare the hollow mesoporous vulcanization copper complex of amination: it is super that 45ml is added to hollow mesoporous nano copper sulfate particle 45mg
Pure water, ultrasonic disperse 10min, then 90mg mercaptoethylmaine is added under stiring, for 24 hours, 15000rpm centrifugation 5min must be precipitated for stirring,
Precipitating is redissolved with ultrapure water, then 15000rpm is centrifuged 5min, must precipitate, and precipitating is redissolved with ultrapure water again, until neutral, freezing is dry
It is dry, obtain the hollow mesoporous vulcanization copper complex of amination；
(3) it prepares the hollow mesoporous copper sulfide of modified with folic acid: 50mg folic acid is added in n,N-Dimethylformamide 4ml, stirring
Dissolution, addition 130mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide, 80mg HOSu NHS are activator,
30min is stirred at room temperature, obtains the folic acid n,N-Dimethylformamide dispersion liquid of activation, step (2) are instilled under ice bath and prepare amino
Changing hollow mesoporous vulcanization copper complex, be warmed to room temperature, reacts 3h, 15000rpm centrifugation 5min must be precipitated, precipitating plus water dispersion,
Dialyse 2d in water, is freeze-dried the hollow mesoporous copper sulfide to get modified with folic acid；
(4) it prepares copper sulfide pharmaceutical composition: dispersing the hollow mesoporous copper sulfide of 3mg modified with folic acid in 3ml methanol, 50
It is instilled at DEG C dissolved in the 3ml 1- tetradecyl alchohol of 3mg Bleomycin Sulphate, 4h is stirred in oil bath at 50 DEG C, volatilizes methanol, is added 70
DEG C water 3ml, then 15000rpm be centrifuged 5min, must precipitate, freeze-drying to get near infrared light remote control and regulation mesoporous door-control type
Copper sulfide pharmaceutical composition.
4. the preparation side of the mesoporous door-control type copper sulfide pharmaceutical composition of near infrared light remote control and regulation according to claim 1
Method, which is characterized in that realized by following steps:
(1) hollow mesoporous nano copper sulfate particle is prepared: by the CuSO of 0.4g4·5H2O is dissolved in 110ml water, under stirring, is added
Enter 3.25g polyvinylpyrrolidone, react at room temperature 20min, 0.75g sodium hydroxide is added, stirs evenly, 7ml hydrazine hydrate is added dropwise,
10min is stirred, 0.65ml ammonium sulfate is added, stirs 1h, 10min is centrifuged in 15000rpm with ultrapure water, must precipitate, precipitating is used
It is washed to neutrality, 22-26h is freeze-dried, obtains hollow mesoporous nano copper sulfate particle；
(2) prepare the hollow mesoporous vulcanization copper complex of amination: it is super that 55ml is added to hollow mesoporous nano copper sulfate particle 55mg
Pure water, ultrasonic disperse 30min, then 110mg mercaptoethylmaine is added under stiring, for 24 hours, 15000rpm centrifugation 10min must sink for stirring
It forms sediment, precipitating is redissolved with ultrapure water, then 15000rpm is centrifuged 10min, must precipitate, and precipitating is redissolved with ultrapure water again, until it is neutral, it is cold
It is lyophilized dry, obtains the hollow mesoporous vulcanization copper complex of amination；
(3) it prepares the hollow mesoporous copper sulfide of modified with folic acid: 60mg folic acid is added in n,N-Dimethylformamide 5ml, stirring
Dissolution, addition 150mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide, 90mg HOSu NHS are activator,
30min is stirred at room temperature, obtains the folic acid n,N-Dimethylformamide dispersion liquid of activation, the ammonia of step (2) preparation is instilled under ice bath
The hollow mesoporous vulcanization copper complex of baseization, is warmed to room temperature, and reacts 3h, and 15000rpm centrifugation 10min must be precipitated, precipitating plus moisture
It dissipates, dialyse 2d in water, is freeze-dried the hollow mesoporous copper sulfide to get modified with folic acid；
(4) it prepares copper sulfide pharmaceutical composition: dispersing the hollow mesoporous copper sulfide of 5mg modified with folic acid in 3-5ml methanol,
It is instilled at 55 DEG C dissolved in the 5ml 7- tetradecyl alchohol of 5mg Bleomycin Sulphate, 4h is stirred in oil bath at 55 DEG C, volatilizes methanol, is added
80 DEG C of water 5ml, then 15000rpm are centrifuged 10min, must precipitate, and are freeze-dried the mesoporous door to get near infrared light remote control and regulation
Control type copper sulfide pharmaceutical composition.
5. according to claim 1 or the mesoporous door-control type of the described in any item near infrared light remote control and regulations of claim 2-4 vulcanizes
The preparation method of copper pharmaceutical composition, which is characterized in that the Bleomycin Sulphate drugloading rate of the step (4) is 25-35%.
6. the mesoporous door-control type of the near infrared light remote control and regulation of any one of claim 1 or claim 2-4 the method preparation
Copper sulfide pharmaceutical composition application in preparation of anti-tumor drugs.
7. the mesoporous door-control type of the near infrared light remote control and regulation of any one of claim 1 or claim 2-4 the method preparation
Copper sulfide pharmaceutical composition is preparing the application in photo-thermal therapy combined chemotherapy drug.
8. the mesoporous door-control type of the near infrared light remote control and regulation of any one of claim 1 or claim 2-4 the method preparation
Copper sulfide pharmaceutical composition is preparing the application near infrared light remote control and regulation drug release drug.
9. the mesoporous door-control type of the near infrared light remote control and regulation of any one of claim 1 or claim 2-4 the method preparation
Copper sulfide pharmaceutical composition is preparing the application in photoacoustic imaging drug.
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| CN108853494B (en) * | 2018-05-26 | 2021-05-11 | 西南大学 | Preparation method of temperature-triggered drug-loaded copper sulfide nanocage |
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| CN104940945A (en) * | 2015-07-22 | 2015-09-30 | 郑州大学 | Hollow mesoporous copper sulfide compound modified by hyaluronic acid and preparation method and application thereof |
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