CN103284951B - A kind of photosensitive liposomes of water soluble medicament-entrapping - Google Patents
A kind of photosensitive liposomes of water soluble medicament-entrapping Download PDFInfo
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- CN103284951B CN103284951B CN201310152171.1A CN201310152171A CN103284951B CN 103284951 B CN103284951 B CN 103284951B CN 201310152171 A CN201310152171 A CN 201310152171A CN 103284951 B CN103284951 B CN 103284951B
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- rice
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- 239000002502 liposome Substances 0.000 title claims abstract description 178
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims description 21
- 239000003814 drug Substances 0.000 claims abstract description 81
- 235000013339 cereals Nutrition 0.000 claims abstract description 72
- 241000209094 Oryza Species 0.000 claims abstract description 67
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 67
- 235000009566 rice Nutrition 0.000 claims abstract description 67
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 66
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 33
- 230000000694 effects Effects 0.000 claims abstract description 30
- 239000002245 particle Substances 0.000 claims abstract description 29
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 23
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 11
- 238000010521 absorption reaction Methods 0.000 claims abstract description 6
- 238000009826 distribution Methods 0.000 claims abstract description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 52
- 239000000243 solution Substances 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical group C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 claims description 20
- 229930195573 Amycin Natural products 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 17
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 15
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 15
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 15
- -1 3-mercaptopropionic acid dodecane ester Chemical class 0.000 claims description 14
- 239000010409 thin film Substances 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 13
- 239000002246 antineoplastic agent Substances 0.000 claims description 13
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- 238000006703 hydration reaction Methods 0.000 claims description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- 230000006837 decompression Effects 0.000 claims description 11
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 8
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 229960004316 cisplatin Drugs 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 6
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 6
- 229960000975 daunorubicin Drugs 0.000 claims description 6
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 6
- 229960001904 epirubicin Drugs 0.000 claims description 6
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 6
- 229960001756 oxaliplatin Drugs 0.000 claims description 6
- 229960004528 vincristine Drugs 0.000 claims description 6
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 6
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 6
- 239000006185 dispersion Substances 0.000 claims description 4
- 230000002209 hydrophobic effect Effects 0.000 claims description 4
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- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 3
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims description 3
- 229960004562 carboplatin Drugs 0.000 claims description 3
- 190000008236 carboplatin Chemical compound 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 229910052743 krypton Inorganic materials 0.000 claims description 3
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 229910052754 neon Inorganic materials 0.000 claims description 3
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
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- 229910052724 xenon Inorganic materials 0.000 claims description 3
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 abstract description 33
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- 239000010931 gold Substances 0.000 description 16
- 229910052737 gold Inorganic materials 0.000 description 16
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 10
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000000118 anti-neoplastic effect Effects 0.000 description 3
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
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- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 1
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- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention provides the photosensitive liposomes that a kind of bag carries water-soluble anti-tumor medicine, be made up of temperature-sensitive phospholipid, cholesterol, long circulating material and the hollow Jenner grain of rice, the hollow Jenner grain of rice has characteristic absorption peak in wavelength 700 ~ 900nm near-infrared region, and the particle size distribution range of the hollow Jenner grain of rice is 20 ~ 100nm.The present invention, by thermal sensitive liposome coated water-soluble medicine and the hollow Jenner grain of rice, is combined into brand-new photosensitive liposomes.Under extraneous near infrared light shines, the hollow Jenner grain of rice wrapped up produces photo-thermal therapy effect, meanwhile, utilizes this photo-thermal effect to control medicine location release quick and a large amount of from photosensitive liposomes, the blood vessel at injuring tumor position or killing tumor cell effectively, plays chemotherapy effect.Drug-loaded liposome of the present invention achieves the therapeutical effect of synchronous photo-thermal and drug molecule, significantly improves the therapeutic effect of disease as tumor, has possessed the therapeutic potential of clinical practice and reality.
Description
Technical field
The present invention relates to a kind of novel photosensitive liposomes drug-supplying system carrying water soluble drug, relate to the preparation method of this photosensitive liposomes and it is in conjunction with extraneous near infrared light photograph, the application in antitumor.
Background technology
Since Yatvin1978 deliver first on Science about dipalmitoyl phosphatidyl choline (DPPC) liposome responsive to temperature effect and it can be used as heat sensitive target medicine carrier probability since, thermal sensitive liposome is a focus of liposome targeting research field always, and from the beginning it just and tumor thermotherapy combine.Thermal sensitive liposome usually with the phase transition temperatures such as DPPC (41 DEG C) a little more than normal temperature temperature sensing material prepared by form.More than phase transition temperature, liposomal phospholipids bilayer becomes loose chaotic liquid crystal state from arranging fine and close glue crystalline state, and the permeability of liposome membrane changes, thus can make the drug release that wraps up out.
Main and the tumor thermotherapy combination of current thermal sensitive liposome, institute's entrapped drug is generally antitumor drug.The affinity of water soluble drug and immobilized artificial membrane is little, can discharge rapidly when liposome undergoes phase transition, and is best suited for the entrapped drug as thermal sensitive liposome.Utilize the characteristic that can discharge its entrapped drug when liposome is this reaches liquid crystal state phase transition temperature in a large number, then can greatly improve the dose being delivered to tumor in conjunction with tumor by local heating, reduce systemic side effects, improve topical therapeutic effect.Although thermal sensitive liposome is adapted at the release of solid tumor site location and does not need special installation, its injection enters after in body and is easily removed fast by reticuloendothelial system (RES) picked-up.The hydrophilic PEG of general employing
2000etc. being mounted to thermal sensitive liposome surface, reduce identification and the picked-up of RES, the circulation time in extension body.
In the research of antitumor drug thermal sensitive liposome, existing greatest problem how to improve its drug level at tumor locus, reduces the toxicity of the internal skin reticular system of antitumor drug and normal structure.In practical application, carrying the thermal sensitive liposome of water soluble drug is only the high temperature relying on local, can not make to be wrapped medicine fast and discharge in large quantities.The drug release of parcel is too slow, and the drug level that directly results in tumor by local is too low.Select new mode, controllably trigger thermal sensitive liposome rapidly and discharge the medicine of parcel in large quantities, improve the local concentration of medicine at tumor locus, improve antitumous effect, become one, this field problem that need solve.
In recent years, novel inorganic gold nano-material has strong eliminate optical property due to its surface plasma resonance (localizedsurfaceplasmaresonance), produces photo-thermal effect, becomes one of domestic and international study hotspot.The gold nano structure that some grow up is as golden nanometer particle (goldnanoparticles), gold nanorods (goldnanorods), gold nanometer cage (goldnanocages), the hollow Jenner grain of rice (hollowgoldnanospheres) etc. has been applied to transmission and the therapeutic field of tumor of medicine.Surface plasma resonance absorbtion peak can be adjusted to near-infrared (700 ~ 900nm) region by above-mentioned gold nano-material, can absorb near infrared light efficiently and be converted into heat, and the high temperature of generation can suppress or directly kill tumor cell, as Visaria
etal.devise the thermotherapy treatment strategy based on gold nanosphere (sphericalgoldnanostructures), by irradiating near infrared light at tumor locus, gold nanosphere can produce heat and result in the blood vessel injury of tumor locus.In addition, above-mentioned optothermal material is owing to having avirulence, and disimmune, biocompatibility, good stability, the feature can drained by body, is widely used in drug delivery field.As YounanXia
etal.the hollow gold nanometer cage of synthesis, utilizes the structure of its kernel hollow, can wrap up antitumor drug amycin efficiently and be delivered to tumor locus, and under near infrared light, the amycin that the high heat effect of nanocages triggers parcel discharges fast.Can from the Synergistic treatment achieving thermotherapy and chemotherapy.
After thermal sensitive liposome parcel is had the inorganic gold nano-material of near infrared light heat effect, under extraneous near infrared light shines, near infrared luminous energy can be converted to heat energy by inorganic gold nano-material efficiently, the heat produced can make thermal sensitive liposome obtain lipid film to become liquid crystal state from glue crystalline state, thus can change the permeability of liposome membrane.Extraneous near infrared light is equivalent to light source, and inorganic gold nano-material is equivalent to be positioned at thermal sensitive liposome heat production source, and therefore, the change of extraneous near infrared light photograph can cause the change of the permeability of thermal sensitive liposome film, causes the rapid release being wrapped medicine.Visible, the thermal sensitive liposome wrapping up inorganic gold nano-material has obvious near-infrared light sensitive characteristic, forms a kind of novel photosensitive liposomes.
Summary of the invention
Novelty of the present invention is thermal sensitive liposome to combine with the hollow Jenner grain of rice, by thermal sensitive liposome coated water-soluble medicine and the hollow Jenner grain of rice, is combined into brand-new photosensitive liposomes.Under extraneous near infrared light shines, the hollow Jenner grain of rice wrapped up produces photo-thermal therapy effect.Meanwhile, utilize this photo-thermal effect to control medicine quick and a large amount of discharging from photosensitive liposomes, and play chemotherapy effect.
First object of the present invention is to provide the composition of the photosensitive liposomes of a kind of year water-soluble anti-tumor medicine, this photosensitive liposomes is made up of temperature-sensitive phospholipid, cholesterol, long circulating material and the hollow Jenner grain of rice, the hollow Jenner grain of rice has the absorption of characteristic peak at near-infrared region (wavelength 700 ~ 900nm), maximum absworption peak scope is 750 ~ 850nm, preferably 790 ~ 810nm; The fat material of every 100mg, adds 0.01 ~ 3 × 10
13the individual hollow Jenner grain of rice, preferably 0.2 ~ 1.5 × 10
13the individual hollow Jenner grain of rice; The particle size distribution range of the hollow Jenner grain of rice is 20 ~ 100nm, preferably 30 ~ 60nm; The hollow Jenner grain of rice can directly be wrapped in liposome; In order to improve envelop rate, also first can carry out hydrophobic surface modification to hollow gold nano grain, and then being wrapped in liposome; Dressing agent is selected: 3-mercaptopropionic acid dodecane ester, 3-mercaptopropionic acid tridecane ester, 3-mercaptopropionic acid stearyl (OMP) and sulfhydrylation Polyethylene Glycol phospholipid (DSPE-PEG
1000-SH, DSPE-PEG
2000-SH, DSPE-PEG
3400-SH, DSPE-PEG
5000-SH, DSPE-PEG
10000-SH) in any one; The quality mol ratio of the hollow Jenner grain of rice and hydrophobically modified dose is 1:0.01 ~ 1:0.1w/mol, preferred 1:0.02 ~ 1:0.05w/mol; The ambient temperature of reaction is carried out at 10 ~ 70 DEG C, preferably 20 ~ 50 DEG C.The hollow Jenner grain of rice and dressing agent reaction carry out under inert gas shielding, and noble gas comprises in nitrogen, neon, argon, Krypton and xenon arbitrary a kind of; Response time is 2 ~ 48h.
Described photosensitive liposomes, near infrared light according under (wavelength 700 ~ 900nm), can photo-thermal effect be produced, namely absorb near infrared light, produce heat energy, and the release of photosensitive liposomes Chinese medicine described in control 1-7.
Described photosensitive liposomes, under near infrared light shines (wavelength 700 ~ 900nm), presents photo-thermal therapy effect, presents the chemotherapy effect of medicine simultaneously.
Described photosensitive liposomes, involved medicine is the water ease of solubility antitumor drug such as amycin, daunorubicin, epirubicin, pirarubicin, methotrexate, vincristine, cisplatin, carboplatin and oxaliplatin.
Second object of the present invention is to provide the preparation method of described photosensitive liposomes, is realized by following steps:
(1) the hollow Jenner grain of rice and hydrophobic dressing agent react according to certain quality mol ratio (w/mol), obtain the hydrophobically modified hollow Jenner grain of rice.The dressing agent adopted comprises 3-mercaptopropionic acid dodecane ester, 3-mercaptopropionic acid tridecane ester, 3-mercaptopropionic acid stearyl (OMP) and sulfhydrylation Polyethylene Glycol phospholipid (DSPE-PEG
1000-SH, DSPE-PEG
2000-SH, DSPE-PEG
3400-SH, DSPE-PEG
5000-SH, DSPE-PEG
10000-SH) in any one; The quality mol ratio of reaction is 1:0.01 ~ 1:0.1w/mol, preferred 1:0.02 ~ 1:0.05w/mol; The ambient temperature of reaction is carried out at 10 ~ 70 DEG C, preferably 20 ~ 50 DEG C; Reaction carries out under inert gas shielding, and noble gas comprises in nitrogen, neon, argon, Krypton and xenon arbitrary a kind of; Response time is 2 ~ 48 hours;
(2) by temperature-sensitive phospholipid, cholesterol, long circulating material and the hollow Jenner grain of rice or the hydrophobically modified hollow Jenner grain of rice are dissolved in the middle of organic solvent, adopt film dispersion method to be prepared, and vacuum decompression removing organic solvent, forms thin film; Organic solvent comprises: one or both mixed solvent of chloroform and dichloromethane;
(3) in thin film, add pharmaceutical aqueous solution or ammonium sulfate, hydration a period of time under uniform temperature, obtain multilamellar liposome solution.Hydration temperature is 60 DEG C; Hydration time is 1 ~ 2 hour;
(4) this liposome solutions is through supersound process, crosses SephadexG50 column purification, obtains drug-loaded liposome, or hatch with pharmaceutical aqueous solution further, complete the loading of medicine, and crosses SephadexG50 column purification.
The photosensitive liposomes that 3rd object of the present invention is to provide the parcel hollow Jenner grain of rice is preparing the application in antitumor drug.Described medicine is wrapped in liposome by the hollow Jenner grain of rice and water miscible antitumor drug, is combined into the photosensitive liposomes with photo-thermal effect.Involved water miscible antitumor drug is the water ease of solubility antitumor drug such as amycin, daunorubicin, epirubicin, pirarubicin, methotrexate, vincristine, cisplatin, carboplatin and oxaliplatin.
The photosensitive liposomes having wrapped up the hollow Jenner grain of rice provided by the invention, in antineoplastic treatment, photosensitive liposomes targeting is to tumor locus, tumor locus irradiates near infrared light and shines, the photothermal deformation effect of photosensitive liposomes makes tumor by local regional temperature raise, can the blood vessel at injuring tumor position or killing tumor cell effectively, realize photo-thermal therapy effect; By the radiation parameters (power, prolonged exposure time, frequency and pattern etc.) of regulating near-infrared light, the thermotherapy effect of photosensitive liposomes can be controlled.
The photosensitive liposomes having wrapped up the hollow Jenner grain of rice provided by the invention, in antineoplastic treatment, photosensitive liposomes targeting is to tumor locus, and tumor locus irradiates near infrared light photograph, produces heat and environment temperature is raised; The temperature raised makes photosensitive liposomes become loose liquid crystal state from the glue crystalline state of densification, and membrane permeability becomes large, makes the drug release of parcel out.By the radiation parameters (power, prolonged exposure time, frequency and pattern etc.) of regulating near-infrared light, the medicine release in vivo of photosensitive liposomes parcel can be controlled.
The hollow Jenner grain of rice and water miscible antitumor drug are creatively wrapped in thermal sensitive liposome by the present invention, are combined into the photosensitive liposomes with photo-thermal effect.And the particle diameter <200nm of this liposome, can intravenous injection, in conjunction with extraneous near infrared light photograph, be applied to antineoplastic field.Photosensitive liposomes prepared by this invention has following advantage:
(1) drug controlled release.In conjunction with near infrared light photograph, controlled and discharge the water soluble drug of parcel in large quantities, solve traditional thermal liposome release medicine problem too slowly.In antineoplaston, apply this photosensitive liposomes, in conjunction with extraneous near infrared light photograph, effectively can improve the drug level of tumor locus.In addition, near infrared light has stronger body tissue penetrance.Therefore, this invention has possessed the therapeutic potential of clinical practice and reality.
(2) therapeutical effect of synchronous photo-thermal and drug molecule is produced.Photosensitive liposomes possesses photo-thermal effect, effectively can damage the blood vessel of solid tumor, and even directly killing off tumor cells, presents effective photo-thermal therapy action effect.Meanwhile, photo-thermal effect triggers the release of drug molecule in liposome, plays its chemotherapy effect.Two kinds of therapeutic modalities work in coordination with onset, significantly improve the therapeutic effect of disease as tumor.
(3) photosensitive liposomes of the present invention, can by extraneous near infrared light according to controllably realizing the release of self packaging medicine location, and produce synchronous photo-thermal therapy and drug molecule chemotherapy effect, in disease treatment, particularly present huge advantage in therapeutic field of tumor, there is important invention and be worth.
The technical term that the present invention relates to:
" OMP-HAuNS " represents the hollow Jenner grain of rice that 3-mercaptopropionic acid stearyl is hydrophobically modified, and the two is combined by mercapto-Jin covalent bond.
Hollow Jenner grain of rice buyable.The embodiment hollow Jenner used grain of rice synthesizes preparation for this experimenter, the gained hollow Jenner grain of rice has the absorption of characteristic peak at near-infrared region (wavelength 700 ~ 900nm), maximum absworption peak scope is 750 ~ 850nm, its preparation method is as follows: under the protection of argon, 1ml(1mol/L) cobalt chloride solution and 4.5ml(1mol/L) sodium borohydride be dispersed in 1000ml pure water, react half an hour, generate cobalt nanoparticle, then chlorauric acid solution is added, and mix rapidly, stirring two hours is continued under the protection of argon, then argon shield is removed, continue to stir, obtain the hollow Jenner grain of rice.
" water-repelling agent-S-HAuNS " represent comprise but a class of not limiting to OMP with sulfydryl, hydrophobically modified reagent can be played to hollow gold nano grain.
" DPPC " represents dipalmitoyl phosphatidyl choline.
" HSPC " represents hydrogenated soy phosphatidyl choline.
" Cholesterol " represents cholesterol.
" PBS " represents phosphate buffer.
Accompanying drawing explanation
Fig. 1 is the Electronic Speculum figure result of the hollow Jenner grain of rice (HAuNS).
Fig. 2 is the hollow Jenner grain of rice (HAuNS) and the absorption spectrum (maximum absorption band be 800nm) of the hydrophobically modified hollow Jenner grain of rice (OMP-HAuNS) near infrared light region.
Fig. 3 is the Electronic Speculum figure result of the photosensitive liposomes wrapping up the hydrophobic hollow Jenner grain of rice.
Fig. 4 is the differential scanning calorimetric thermogram of photosensitive liposomes.In figure, abscissa " temperature " expression " temperature ", vertical coordinate " heatflow " expression " hot-fluid ".
Fig. 5 be photosensitive liposomes near infrared light according under, the imaginary drawing of release packaging medicine.
Fig. 6 is the thermal sensitive liposome of medicine carrying and the experimental result of photosensitive liposomes release in vitro.
Fig. 7 is that the photosensitive liposomes of living imaging instrument shooting medicine carrying discharges result outward.
Fig. 8 is the cytotoxicity experiment result of the photosensitive liposomes of medicine carrying.
Fig. 9 is that the thermal sensitive liposome near infrared light of medicine carrying shines front and back, the experimental result of cellular uptake.
Figure 10 is that the photosensitive liposomes near infrared light of medicine carrying shines front and back, the experimental result of cellular uptake.
Figure 11 is after pharmacodynamic experiment terminates, and puts to death the image results that nude mice takes out solid tumor.
Figure 12 is the solid tumor quality results of matched group and experimental group.
Figure 13 is matched group and the antitumor result of experimental group on lotus BEL-7402 tumor nude mice.
Figure 14 is the H & E coloration result that the tumor tissues (A) organized of medicine carrying photosensitive liposomes (near infrared light) and scar tissue (B) are cut into slices.
Figure 15 is the H & E coloration result that the tumor tissues (C) organized of blank photosensitive liposomes (near infrared light) and scar tissue (D) are cut into slices.
Figure 16 is the H & E coloration result that tumor tissues (E) that normal saline (near infrared light) is organized is cut into slices.
Detailed description of the invention
The present invention is further described in conjunction with the accompanying drawings and embodiments.
Embodiment 1
The composition of photosensitive liposomes:
Doxorubicin hydrochloride (DOXHCI) 2.76mg
Dipalmitoyl phosphatidyl choline (DPPC
)31.64mg
Hydrogenated soy phosphatidyl choline (HSPC) 11.42mg
Cholesterol (Cholesterol) 5.0mg
Polyethylene Glycol phospholipid (DSPE-PEG
2000) 7.2mg
OMP modifies the hollow Jenner grain of rice (OMP-HAuNS) 1.0mg (~ 2.5 × 10
12individual particle)
DPPC, HSPC, Cholesterol, DSPE-PEG of recipe quantity
2000with OMP-HAuNS (HAuNS:OMP=1:0.0279w/mol), be placed in eggplant-shape bottle, add in organic solvent (chloroform: dichloromethane=1:1v/v) and dissolve, in 45 DEG C of water-baths, vacuum decompression rotary evaporation spends the night, and bottle wall forms thin film.In eggplant-shape bottle, add the ammonium sulfate of pH=5.4,60 DEG C of water-bath hydration 1h, film separation dissolves and forms multilamellar liposome solution.Use Probe Ultrasonic Searching by ultrasonic for above-mentioned solution to required particle diameter.The liposome solutions of gained is crossed SephadexG50 post, with PBS(pH=7.4) eluting, remove the ammonium sulfate of OMP-HAuNS and the liposome foreign minister do not wrapped up.Add the Doxorubicin solution of 2mg/mL in photosensitive liposomes, make medicine fat mass ratio be 1:20,50 DEG C of stirred in water bath hatch 30min.Again through SephadexG50 post, the doxorubicin hydrochloride that removing is free, is finally collected as the photosensitive liposomes carrying amycin.
Photosensitive liposomes prepared by investigation the present invention according under condition, resists the effect of pernicious humanized's hepatic carcinoma at extraneous near infrared light.For the photosensitive liposomes carrying amycin of example 1, carry out the investigation of following aspect:
1, the configuration of surface of the hollow Jenner grain of rice (HAuNS) and optical signature
Adopt transmission electron microscope (transmissionelectronmicroscope, TEM), observe the configuration of surface of hollow gold nano grain, its transmission electron microscope observation the results are shown in Figure 1.Show that the homogeneity of the hollow Jenner grain of rice synthesized is good, and particle diameter is all less than 50nm.Carry out uv scan to hollow gold nano grain (HAuNS) and the hydrophobically modified hollow Jenner grain of rice (OMP-HAuNS), its spectral scan the results are shown in Figure 2.Show that the hollow Jenner grain of rice has maximum absorbing wavelength (~ 800nm) near infrared light region; And the optical characteristics of dressing agent on hollow gold nano grain does not affect.
2, the physicochemical property of photosensitive liposomes characterizes
Adopt the envelop rate of the amycin of fluorescence spectrophotometry photosensitive liposomes, result is more than 90%.Dynamic light scattering method (dynamiclightscattering, DLS) is adopted to measure its particle diameter and current potential.The results are shown in Table 1.Can see from table, the particle size distribution of photosensitive liposomes is more homogeneous.Adopt transmission electron microscope (transmissionelectronmicroscope, TEM), the configuration of surface of photosensitive liposomes is observed.Its transmission electron microscope observation the results are shown in Figure 3.Result display photosensitive liposomes outward appearance is spherical in shape, and has wrapped up the hollow Jenner grain of rice, the result of mensuration and the measurement result of particle diameter potential measurement instrument basically identical.Carry out differential scanning calorimetric analysis (differentialscanningcalorimetry, DSC) respectively to the photosensitive liposomes of blank and the photosensitive liposomes of medicine carrying, its analysis result is shown in Fig. 4.Show that in the present invention, the preparation method of photosensitive liposomes is feasible and good.
3, extracorporeal releasing test
At the constant temperature water bath shaker of 37 DEG C, PBS(pH7.4) in carry out release in vitro.The release in vitro mechanism imaginary drawing of the photosensitive liposomes of medicine carrying as shown in Figure 5.The thermal sensitive liposome of the medicine carrying of matched group and photosensitive liposomes are in series of time-points (0.5,1,2,4,6,8,12 and 24h) sampling and measuring fluorescence intensity (Ex/Em=505/565nm).The medicine carrying thermal sensitive liposome of experimental group 1 irradiates (3w, 5min), same time point sampling and measuring with iraser respectively at 2h and 6h.The medicine carrying photosensitive liposomes of experimental group 2 irradiates (3w, 5min), same time point sampling and measuring with iraser respectively at 2h and 6h.The medicine carrying photosensitive liposomes of experimental group 3 irradiates (6w, 5min), same time point sampling and measuring with iraser respectively at 2h and 6h.Formulae discovery: total release percentage=F
t-F
i/ F
f-F
i× 100%.The results are shown in Figure 6, show that the present invention can, by the power of regulating near-infrared laser and irradiation time, controllably impel the amycin that photosensitive liposomes bag carries to discharge fast.
4, living imaging instrument shooting release in vitro
Preparation, containing the agarose aquogel (agarose: water=1:100w/v) of circular groove, carries the photosensitive liposomes labelling nir dye DiR of amycin.The thermal sensitive liposome of the medicine carrying of 300 μ L labelling DiR and photosensitive liposomes solution are joined in groove respectively, irradiates near-infrared laser (6w, 20min), then take the fluorescence of amycin and liposome with living imaging instrument respectively.The drug-loaded liposome not irradiating the labelling DiR of near-infrared laser is used as matched group.The results are shown in Figure 7, show that the thermal sensitive liposome of medicine carrying is in conjunction with near infrared light photograph, the amycin of parcel can not be impelled to discharge; Also show that the photosensitive liposomes of medicine carrying is in conjunction with near infrared light photograph, the release of wrapping up amycin can be controlled significantly.(red fluorescence represents amycin, and green fluorescence represents photosensitive liposomes.）
5, cytotoxicity experiment
By BEL-7402 humanized hepatoma carcinoma cell with 10
5individual/mL, the amount grafting in 200 μ L/ holes is on 96 orifice plates.After 24h cell attachment, the photosensitive liposomes of the photosensitive liposomes of blank and medicine carrying, according to series concentration (116ng/mL, the 580ng/mL of carrier, 1.16 μ g/mL, 5.8 μ g/mL, 11.6 μ g/mL, 58 μ g/mL, 116g/mL, 0.58mg/mL, 1.16mg/mL) join in tumor cell.Near-infrared laser (3w, 3min) is irradiated in every hole immediately, then hatches 72h.Every hole adds the MTT aqueous solution (5mg/mL) of 20 μ L again, and after continuing to hatch 4h, discard culture fluid, every hole adds the DMSO of 100 μ L, and after shaking table vibrates 20 minutes, microplate reader measures light absorption value at 570nm place.The photosensitive liposomes non-laser group of medicine carrying is used as matched group.Free doxorubicin hydrochloride group is used as positive control.The results are shown in Figure 8, show that sharp light-struck blank photosensitive liposomes inhibits the growth of tumor cell to a certain extent; The photosensitive liposomes swashing light-struck medicine carrying, than free amycin, shows the effect of more excellent antitumor cell, presents thermotherapy and chemotherapy double effects.
6, cellular uptake experiment (laser co-focusing)
By BEL-7402 humanized hepatoma carcinoma cell by 5 × 10
4individual/hole is inoculated in the 10mm in the 24 every holes of orifice plate
2slide on.After 24h is adherent, every hole add respectively content of dispersion 20 μ g/mL by the fluorescently-labeled medicine carrying thermal sensitive liposome of DiD and medicine carrying photosensitive liposomes.Then near-infrared laser (3w, 5min) is irradiated in every hole, and non-laser hole is with comparing.Sop up the culture medium in hole after 2h, wash every hole 3 times with PBS.Every hole adds the paraformaldehyde solution fixed cell of 4%, takes out slide and carries out mounting, observe under being placed in laser confocal microscope after 20 minutes.The results are shown in Figure 9, after showing to irradiate infrared light, amycin does not discharge from thermal sensitive liposome, is not ingested and enters nucleus; The results are shown in Figure 10, show that amycin discharges from photosensitive liposomes and is ingested and enter nucleus.(red fluorescence represents amycin, and green fluorescence represents photosensitive liposomes.）
7, effect experiment
Every left axil subcutaneous vaccination 5 × 10 of nude mice
6individual BEL-7402 cell, obtains BEL-7402 model of nude mice bearing tumor.When the volume of tumor is about 150mm
3start administration.Be divided into normal saline group+laser group at random, the photosensitive liposomes+laser group of medicine carrying, the photosensitive liposomes group of medicine carrying, blank photosensitive liposomes+laser group.All groups are all at the the 1st, 3,5 day administration or injecting normal saline.Laser group gave near-infrared laser and irradiates (2w, 3min/ Mus) at the the 2nd, 4,6 day.The results are shown in Figure 11 ~ 16, show that the medicine carrying photosensitive liposomes of near infrared light not only inhibits the growth of tumor, and tumor slowly disappears, show very significant antitumous effect.
Embodiment 2
The composition of photosensitive liposomes:
Doxorubicin hydrochloride (DOXHCI) 2.76mg
Dipalmitoyl phosphatidyl choline (DPPC) 31.64mg
Hydrogenated soy phosphatidyl choline (HSPC) 11.42mg
Cholesterol (Cholesterol) 5.0mg
Polyethylene Glycol phospholipid (DSPE-PEG
2000) 7.2mg
The hollow Jenner grain of rice (HAuNS) 1.0mg (~ 2.5 × 10
12individual particle)
DPPC, HSPC, Cholesterol, DSPE-PEG of recipe quantity
2000and HAuNS, be placed in eggplant-shape bottle, add in organic solvent (chloroform: dichloromethane=1:1v/v) and dissolve, in 45 DEG C of water-baths, vacuum decompression rotary evaporation spends the night, and bottle wall forms thin film.In eggplant-shape bottle, add the ammonium sulfate of pH=5.4,60 DEG C of water-bath hydration 1h, film separation dissolves and forms multilamellar liposome solution.Use Probe Ultrasonic Searching by ultrasonic for above-mentioned solution to required particle diameter.The liposome solutions of gained is crossed SephadexG50 post, with PBS(pH=7.4) eluting, remove the ammonium sulfate of HAuNS and the liposome foreign minister do not wrapped up.Add the Doxorubicin solution of 2mg/mL in photosensitive liposomes, make medicine fat mass ratio be 1:20,50 DEG C of stirred in water bath hatch 30min.Again through SephadexG50 post, the doxorubicin hydrochloride that removing is free, is finally collected as the photosensitive liposomes carrying amycin.
Embodiment 3
The composition of photosensitive liposomes:
Doxorubicin hydrochloride (DOXHCI) 2.76mg
Dipalmitoyl phosphatidyl choline (DPPC) 31.64mg
Hydrogenated soy phosphatidyl choline (HSPC) 11.42mg
Cholesterol (Cholesterol) 5.0mg
Polyethylene Glycol phospholipid (DSPE-PEG
2000) 7.2mg
The Polyethylene Glycol phospholipid modified hollow Jenner grain of rice (DSPE-PEG
2000-HAuNS) 1.0mg (~ 2.5 × 10
12individual particle)
DPPC, HSPC, Cholesterol, DSPE-PEG of recipe quantity
2000and DSPE-PEG
2000-HAuNS (HAuNS:DSPE-PEG
2000-SH=1:0.0279w/mol), be placed in eggplant-shape bottle, add in organic solvent (chloroform: dichloromethane=1:1v/v) and dissolve, in 45 DEG C of water-baths, vacuum decompression rotary evaporation spends the night, and bottle wall forms thin film.In eggplant-shape bottle, add the ammonium sulfate of pH=5.4,60 DEG C of water-bath hydration 1h, film separation dissolves and forms multilamellar liposome solution.Use Probe Ultrasonic Searching by ultrasonic for above-mentioned solution to required particle diameter.The liposome solutions of gained is crossed SephadexG50 post, with PBS(pH=7.4) eluting, remove the DSPE-PEG do not wrapped up
2000the ammonium sulfate of-HAuNS and liposome foreign minister.Add the Doxorubicin solution of 2mg/mL in photosensitive liposomes, make medicine fat mass ratio be 1:20,50 DEG C of stirred in water bath hatch 30min.Again through SephadexG50 post, the doxorubicin hydrochloride that removing is free, is finally collected as the photosensitive liposomes carrying amycin.
Embodiment 4
The composition of photosensitive liposomes:
Daunorubicin (DNRHCl) 2.76mg
Dipalmitoyl phosphatidyl choline (DPPC
)31.64mg
Hydrogenated soy phosphatidyl choline (HSPC) 11.42mg
Cholesterol (Cholesterol) 5.0mg
Polyethylene Glycol phospholipid (DSPE-PEG
2000) 7.2mg
OMP modifies the hollow Jenner grain of rice (OMP-HAuNS) 1.0mg (~ 2.5 × 10
12individual particle)
DPPC, HSPC, Cholesterol, DSPE-PEG of recipe quantity
2000with OMP-HAuNS (HAuNS:OMP=1:0.0279w/mol), be placed in eggplant-shape bottle, add in organic solvent (chloroform: dichloromethane=1:1v/v) and dissolve, in 45 DEG C of water-baths, vacuum decompression rotary evaporation spends the night, and bottle wall forms thin film.In eggplant-shape bottle, add the ammonium sulfate of pH=5.4,60 DEG C of water-bath hydration 1h, film separation dissolves and forms multilamellar liposome solution.Use Probe Ultrasonic Searching by ultrasonic for above-mentioned solution to required particle diameter.The liposome solutions of gained is crossed SephadexG50 post, with PBS(pH=7.4) eluting, remove the ammonium sulfate of OMP-HAuNS and the liposome foreign minister do not wrapped up.Add the daunorubicin solution of 2mg/mL in photosensitive liposomes, make medicine fat mass ratio be 1:20,50 DEG C of stirred in water bath hatch 30min.Again through SephadexG50 post, the daunorubicin hydrochloride that removing is free, is finally collected as the photosensitive liposomes carrying daunorubicin.
Embodiment 5
The composition of photosensitive liposomes:
Oxaliplatin (L-OHP) 2.76mg
Dipalmitoyl phosphatidyl choline (DPPC) 31.64mg
Hydrogenated soy phosphatidyl choline (HSPC) 11.42mg
Cholesterol (Cholesterol) 5.0mg
Polyethylene Glycol phospholipid (DSPE-PEG
2000) 7.2mg
OMP modifies the hollow Jenner grain of rice (OMP-HAuNS) 1.0mg (~ 2.5 × 1012 particles)
DPPC, HSPC, Cholesterol, DSPE-PEG of recipe quantity
2000with OMP-HAuNS (HAuNS:OMP=1:0.0279w/mol), be placed in eggplant-shape bottle, add in organic solvent (chloroform: dichloromethane=1:1v/v) and dissolve, in 45 DEG C of water-baths, vacuum decompression rotary evaporation spends the night, and bottle wall forms thin film.In eggplant-shape bottle, add oxaliplatin aqueous solution, concentration is 2mg/mL, and 60 DEG C of water-bath hydration 1h, film separation dissolves and forms multilamellar liposome solution.Use Probe Ultrasonic Searching by ultrasonic for above-mentioned solution to required particle diameter.The liposome solutions of gained is crossed SephadexG50 post, with PBS(pH=7.4) eluting, must carry the photosensitive liposomes of oxaliplatin.
Embodiment 6
The composition of photosensitive liposomes
Vincristine (VCRH
2sO
4) 2.76mg
Dipalmitoyl phosphatidyl choline (DPPC
)31.64mg
Hydrogenated soy phosphatidyl choline (HSPC) 11.42mg
Cholesterol (Cholesterol) 5.0mg
Polyethylene Glycol phospholipid (DSPE-PEG
2000) 7.2mg
OMP modifies the hollow Jenner grain of rice (OMP-HAuNS) 1.0mg (~ 2.5 × 10
12individual particle)
DPPC, HSPC, Cholesterol, DSPE-PEG of recipe quantity
2000and DSPE-PEG
2000-HAuNS (HAuNS:DSPE-PEG
2000-SH=1:0.0279w/mol), be placed in eggplant-shape bottle, add in organic solvent (chloroform: dichloromethane=1:1v/v) and dissolve, in 45 DEG C of water-baths, vacuum decompression rotary evaporation spends the night, and bottle wall forms thin film.In eggplant-shape bottle, add the ammonium sulfate of pH=5.4,60 DEG C of water-bath hydration 1h, film separation dissolves and forms multilamellar liposome solution.Use Probe Ultrasonic Searching by ultrasonic for above-mentioned solution to required particle diameter.The liposome solutions of gained is crossed SephadexG50 post, with PBS(pH=7.4) eluting, remove the DSPE-PEG do not wrapped up
2000the ammonium sulfate of-HAuNS and liposome foreign minister.Add the vincristine solution of 2mg/mL in photosensitive liposomes, make medicine fat mass ratio be 1:20,50 DEG C of stirred in water bath hatch 30min.Again through SephadexG50 post, the vincristine sulfate that removing is free, is finally collected as the photosensitive liposomes carrying vincristine.
Embodiment 7
The composition of photosensitive liposomes:
Epirubicin (EPIHCI) 2.76mg
Dipalmitoyl phosphatidyl choline (DPPC
)31.64mg
Hydrogenated soy phosphatidyl choline (HSPC) 11.42mg
Cholesterol (Cholesterol) 5.0mg
Polyethylene Glycol phospholipid (DSPE-PEG
2000) 7.2mg
OMP modifies the hollow Jenner grain of rice (OMP-HAuNS) 1.0mg (~ 2.5 × 10
12individual particle)
DPPC, HSPC, Cholesterol, DSPE-PEG of recipe quantity
2000with OMP-HAuNS (HAuNS:OMP=1:0.0279w/mol), be placed in eggplant-shape bottle, add in organic solvent (chloroform: dichloromethane=1:1v/v) and dissolve, in 45 DEG C of water-baths, vacuum decompression rotary evaporation spends the night, and bottle wall forms thin film.In eggplant-shape bottle, add the ammonium sulfate of pH=5.4,60 DEG C of water-bath hydration 1h, film separation dissolves and forms multilamellar liposome solution.Use Probe Ultrasonic Searching by ultrasonic for above-mentioned solution to required particle diameter.The liposome solutions of gained is crossed SephadexG50 post, with PBS(pH=7.4) eluting, remove the ammonium sulfate of OMP-HAuNS and the liposome foreign minister do not wrapped up.Add the epirubicin solution of 2mg/mL in photosensitive liposomes, make medicine fat mass ratio be 1:20,50 DEG C of stirred in water bath hatch 30min.Again through SephadexG50 post, the Farmorubine Hydrochloride that removing is free, is finally collected as the photosensitive liposomes carrying epirubicin.
Embodiment 8
The composition of photosensitive liposomes:
Cisplatin (CDP) 2.76mg
Dipalmitoyl phosphatidyl choline (DPPC
)31.64mg
Hydrogenated soy phosphatidyl choline (HSPC) 11.42mg
Cholesterol (Cholesterol) 5.0mg
Polyethylene Glycol phospholipid (DSPE-PEG
2000) 7.2mg
OMP modifies the hollow Jenner grain of rice (OMP-HAuNS) 1.0mg (~ 2.5 × 10
12individual particle)
DPPC, HSPC, Cholesterol, DSPE-PEG of recipe quantity
2000with OMP-HAuNS (HAuNS:OMP=1:0.0279w/mol), be placed in eggplant-shape bottle, add in organic solvent (chloroform: dichloromethane=1:1v/v) and dissolve, in 45 DEG C of water-baths, vacuum decompression rotary evaporation spends the night, and bottle wall forms thin film.Be dissolved in by cisplatin in appropriate 0.9%NaCI-5% mannitol solution, concentration is 2mg/mL, in eggplant-shape bottle, add cisplatin solution, and 60 DEG C of water-bath hydration 1h, film separation dissolves and forms multilamellar liposome solution.Use Probe Ultrasonic Searching by ultrasonic for above-mentioned solution to required particle diameter.The liposome solutions of gained is crossed SephadexG50 post, with PBS(pH=7.4) eluting, must carry the photosensitive liposomes of cisplatin.
Claims (6)
1. the photosensitive liposomes of a bag year water-soluble anti-tumor medicine, it is characterized in that, be made up of temperature-sensitive phospholipid, cholesterol, long circulating material and the hollow Jenner grain of rice, the hollow Jenner grain of rice has the absorption of characteristic peak in the near-infrared region of wavelength 700-900nm, maximum absworption peak scope is 750-850nm, the fat material of every 100mg, adds 0.01-3 × 10
13the individual hollow Jenner grain of rice, the particle size distribution range of the hollow Jenner grain of rice is 20-100nm, and the hollow Jenner grain of rice is directly wrapped in liposome, and the particle diameter <200nm of liposome, is realized by following steps:
(1) by temperature-sensitive phospholipid, cholesterol, long circulating material and the hollow Jenner grain of rice are dissolved in the middle of organic solvent, employing film dispersion method is prepared, vacuum decompression removing organic solvent, form thin film, organic solvent selects one or both mixed solvent of chloroform and dichloromethane; Wherein temperature-sensitive phospholipid selects 31.64mg dipalmitoyl phosphatidyl choline and 11.42mg hydrogenated soy phosphatidyl choline;
(2) in thin film, add pharmaceutical aqueous solution or ammonium sulfate, 60 DEG C of hydration 1-2 hour, obtain multilamellar liposome solution;
(3) this liposome solutions is through supersound process, crosses SephadexG50 column purification, obtains medicine carrying photosensitive liposomes.
2. the photosensitive liposomes of a bag year water-soluble anti-tumor medicine, it is characterized in that, be made up of temperature-sensitive phospholipid, cholesterol, long circulating material and the hydrophobically modified hollow Jenner grain of rice, the hydrophobically modified hollow Jenner grain of rice has the absorption of characteristic peak in the near-infrared region of wavelength 700-900nm, maximum absworption peak scope is 750-850nm, the fat material of every 100mg, adds 0.01-3 × 10
13the individual hydrophobically modified hollow Jenner grain of rice, the particle size distribution range of the hydrophobically modified hollow Jenner grain of rice is 20-100nm, and the hydrophobically modified hollow Jenner grain of rice is directly wrapped in liposome; Select for hydrophobically modified dose: 3-mercaptopropionic acid dodecane ester, 3-mercaptopropionic acid tridecane ester, any one in 3-mercaptopropionic acid stearyl and sulfhydrylation Polyethylene Glycol phospholipid; The particle diameter <200nm of liposome, is realized by following steps:
(1) the hollow Jenner grain of rice and hydrophobic dressing agent react according to quality mol ratio, obtain the hydrophobically modified hollow Jenner grain of rice, the quality mol ratio of the hollow Jenner grain of rice and the reaction of hydrophobic dressing agent is 1:0.01-1:0.1w/mol, the ambient temperature of reaction is carried out at 10-70 DEG C, reaction carries out under inert gas shielding, noble gas is selected in nitrogen, neon, argon, Krypton and xenon arbitrary a kind of, and the response time is 2-48 hour;
(2) by temperature-sensitive phospholipid, cholesterol, long circulating material and the hydrophobically modified hollow Jenner grain of rice are dissolved in the middle of organic solvent, employing film dispersion method is prepared, vacuum decompression removing organic solvent, form thin film, organic solvent selects one or both mixed solvent of chloroform and dichloromethane; Wherein temperature-sensitive phospholipid selects 31.64mg dipalmitoyl phosphatidyl choline and 11.42mg hydrogenated soy phosphatidyl choline;
(3) in thin film, add pharmaceutical aqueous solution or ammonium sulfate, 60 DEG C of hydration 1-2 hour, obtain multilamellar liposome solution;
(4) this liposome solutions is through supersound process, crosses SephadexG50 column purification, obtains medicine carrying photosensitive liposomes.
3. a kind of bag according to claim 2 carries the photosensitive liposomes of water-soluble anti-tumor medicine, and it is characterized in that, sulfhydrylation Polyethylene Glycol phospholipid selects DSPE-PEG
1000-SH, DSPE-PEG
2000-SH, DSPE-PEG
3400-SH, DSPE-PEG
5000-SH or DSPE-PEG
10000-SH.
4. a kind of bag according to claim 1 and 2 carries the photosensitive liposomes of water-soluble anti-tumor medicine, and it is characterized in that, maximum absworption peak scope selects 790-810nm, adds 0.2-1.5 × 10
13the individual hollow Jenner grain of rice, the particle size distribution range of the hollow Jenner grain of rice selects 30-60nm.
5. the photosensitive liposomes that a kind of bag according to claim 1 and 2 carries water-soluble anti-tumor medicine is preparing the application in antitumor drug; it is characterized in that; described medicine is wrapped in liposome by the hollow Jenner grain of rice or the hydrophobically modified hollow Jenner grain of rice and water miscible antitumor drug, is combined into the photosensitive liposomes with photo-thermal effect.
6. the photosensitive liposomes that a kind of bag according to claim 5 carries water-soluble anti-tumor medicine is preparing the application in antitumor drug, it is characterized in that, described water-soluble anti-tumor medicine is amycin, daunorubicin, epirubicin, pirarubicin, methotrexate, vincristine, cisplatin, carboplatin or oxaliplatin.
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