CN103768598B - A kind of implantable fullerene polylactic acid is from the preparation method of reunion carried medicine sustained-release microsphere and application - Google Patents
A kind of implantable fullerene polylactic acid is from the preparation method of reunion carried medicine sustained-release microsphere and application Download PDFInfo
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Abstract
The present invention relates to implantable fullerene polylactic acid from the preparation method of reunion carried medicine sustained-release microsphere and application, effectively can solve implantable fullerene polylactic acid from the preparation of reunion carried medicine sustained-release microsphere and preparing the application problem in optical dynamic treatment of tumor medicine, its technical scheme solved is, fullerene molecule is connected to polylactic acid by chemical bond-linking, polylactic acid relative molecular weight is 1,0000-1,8000, fullerene is C
60fullerene, microspherulite diameter is 1-10 μm, and preparation method of the present invention is simple, preparation condition easily meets, and can not destroy the characteristic of fullerene itself, effectively solution optical dynamic therapy and chemotherapy play oncotherapy effect, are the innovations on anti-tumor medicine simultaneously.
Description
Technical field
The present invention relates to field of medicaments, particularly a kind of implantable fullerene polylactic acid is from the preparation method of reunion carried medicine sustained-release microsphere and application.
Background technology
Fullerene (Fullerene), has another name called C
60, being the third allotrope of carbon, is one of great discovery of twentieth century.C
60have pi-electron system, it can absorb the photon energy of certain wavelength, becomes excited state by ground state, the C of excited state
60have an effect with in-house oxygen, the generation of catalytic activity oxygen and super oxygen negative radical group, the macromole effect in these products and tumor cell, the 26S Proteasome Structure and Function of damaging cells, thus killing tumor cell.Fullerene can be used for photodynamic therapy (photodynamic therapy, PDT) treatment as photosensitizer.
After optical dynamic therapy (photodynamic therapy, PDT) refers to and gives photosensitizer, under the illumination of certain wavelength is penetrated, just produce a kind of emerging Therapeutic Method of therapeutical effect.The advantage of PDT is optionally to eliminate former of local, recurrent tumor but not damaging normal tissue, and can carry out with radiotherapy, chemotherapy simultaneously, plays certain synergism.
Polylactic acid (PLA) is a kind of nontoxic, nonirritant, has the novel high polymer material of good biocompatibility, is take lactic acid as the Biodegradable polymer material that monomer synthesizes through polycondensation reaction.It decomposes through enzyme in vivo, and final formation carbon dioxide and water, medically have application prospect very widely.
C
60itself there is strong hydrophobicity, be difficult to directly use in Physiological Medium, and limited by the medication amount of physical absorption, be difficult to the requirement reaching treatment, with water-soluble amino acid to C
60chemical modification synthesis C is carried out on surface
60soluble derivative, saves C
60spherical structure and heliosensitivity, on this basis polylactic acid is connected on aminoacid by chemical bond-linking, can prepares and there is the fullerene polylactic acid polymer of biodegradation from reunion function.Application fullerene polylactic acid polymer can prepare the fullerene polylactic acid medicine carrying microballoons that medicine carrying meets treatment needs, increases the water soluble drug holdup time in vivo, improves the stability of medicine in body, simultaneously C
60itself has heliosensitivity, and therefore, fullerene polylactic acid medicine carrying microballoons not only has chemotherapeutic, has phototherapy simultaneously.So, fullerene polylactic acid how is prepared from reunion carried medicine sustained-release microsphere so far there are no open report.
Summary of the invention
For above-mentioned situation, for overcoming the defect of prior art, the object of the present invention is just to provide a kind of implantable fullerene polylactic acid from the preparation method of reunion carried medicine sustained-release microsphere and application, effectively can solve implantable fullerene polylactic acid from the preparation of reunion carried medicine sustained-release microsphere and preparing the application problem in optical dynamic treatment of tumor medicine.
The technical scheme that the present invention solves, fullerene molecule is connected to polylactic acid by chemical bond-linking, and polylactic acid relative molecular weight is 1,0000-1,8000, fullerene is C
60fullerene, microspherulite diameter is 1-10 μm, is realized by following steps:
1) 2.0-4.0g aminoacid and 2.0-4.0g sodium hydroxide are added in the mixed solvent of 40-50mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 4-5h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 10-20mg is put into container, add lactic acid 5-10mL, then add anhydrous stannous chloride 6-12mg, pass into nitrogen (N
2), the saturated 5-10min of room temperature, in evacuation environment, under 110 DEG C of oil bath magnetic agitation, under preheating 1h, 140-150 DEG C of oil bath magnetic agitation, react 4-5h, reaction terminates product dichloromethane and dissolves, again by deionized water precipitation, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtains fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 150-200mg, add in 2-3mL dichloromethane solution and dissolve, add 1-2ml antitumor drug aqueous solution, vortex mixing 10-15min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, dispersed with stirring 10min, under 80-120r/min low speed, stir 2h, place 10min for 4 DEG C, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeatedly rinse 5-6 time with deionized water again, lyophilization, obtain fullerene polylactic acid from reuniting carried medicine sustained-release microsphere, described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
Fullerene polylactic acid prepared by the inventive method can be effective to from reunion carried medicine sustained-release microsphere the medicine preparing optical dynamic treatment of tumor, preparation method is simple, preparation condition easily meets, and can not destroy the characteristic of fullerene itself, effective solution optical dynamic therapy and chemotherapy play oncotherapy effect simultaneously, are the innovations on anti-tumor medicine.
Detailed description of the invention
Below in conjunction with embodiment, the specific embodiment of the present invention is described in further detail.
Embodiment 1
1) 2.0g aminoacid and 2.0g sodium hydroxide are added in the mixed solvent of 40mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 4h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 10mg is put into container, add lactic acid 5mL, then add anhydrous stannous chloride 6-12mg, pass into nitrogen (N
2), the saturated 5min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, reacts 4h under 140 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, again by deionized water precipitation, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtains fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 150mg, add in 2mL dichloromethane solution and dissolve, add 1ml antitumor drug aqueous solution, vortex mixing 10min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, under dispersed with stirring 10min, 80r/min low speed, stir 2h, place 10min, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, more repeatedly rinse 5 times with deionized water for 4 DEG C, lyophilization, obtains fullerene polylactic acid from reuniting carried medicine sustained-release microsphere; Described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
Embodiment 2
1) 2.5g aminoacid and 2.5g sodium hydroxide are added in the mixed solvent of 42mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 4.5h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 13mg is put into container, add lactic acid 6mL, then add anhydrous stannous chloride 8mg, pass into nitrogen (N
2), the saturated 6min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, reacts 4.5h under 143 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, again by deionized water precipitation, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtains fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 160mg, add in 2mL dichloromethane solution and dissolve, add 1ml antitumor drug aqueous solution, vortex mixing 12min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, under dispersed with stirring 10min, 90r/min low speed, stir 2h, place 10min, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, more repeatedly rinse 5 times with deionized water for 4 DEG C, lyophilization, obtains fullerene polylactic acid from reuniting carried medicine sustained-release microsphere; Described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
Embodiment 3
1) 3g aminoacid and 3g sodium hydroxide are added in the mixed solvent of 45mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 4.5h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 15mg is put into container, add lactic acid 8mL, then add anhydrous stannous chloride 9mg, pass into nitrogen (N
2), the saturated 8min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, reacts 4.5h under 145 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, again by deionized water precipitation, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtains fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 180mg, add in 2.5mL dichloromethane solution and dissolve, add 1.5ml antitumor drug aqueous solution, vortex mixing 13min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, under dispersed with stirring 10min, 100r/min low speed, stir 2h, place 10min, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, more repeatedly rinse 5 times with deionized water for 4 DEG C, lyophilization, obtains fullerene polylactic acid from reuniting carried medicine sustained-release microsphere; Described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
Embodiment 4
1) 3.5g aminoacid and 3.5g sodium hydroxide are added in the mixed solvent of 47mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 5h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 18mg is put into container, add lactic acid 9mL, then add anhydrous stannous chloride 11mg, pass into nitrogen (N
2), the saturated 9min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, reacts 5h under 147 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, again by deionized water precipitation, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtains fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 190mg, add in 2.7mL dichloromethane solution and dissolve, add 1.8ml antitumor drug aqueous solution, vortex mixing 14min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, under dispersed with stirring 10min, 110r/min low speed, stir 2h, place 10min, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, more repeatedly rinse 6 times with deionized water for 4 DEG C, lyophilization, obtains fullerene polylactic acid from reuniting carried medicine sustained-release microsphere; Described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
Embodiment 5
1) 4.0g aminoacid and 4.0g sodium hydroxide are added in the mixed solvent of 50mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 5h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 20mg is put into container, add lactic acid 10mL, then add anhydrous stannous chloride 12mg, pass into nitrogen (N
2), the saturated 10min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, reacts 5h under 150 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, again by deionized water precipitation, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtains fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 200mg, add in 3mL dichloromethane solution and dissolve, add 2ml antitumor drug aqueous solution, vortex mixing 15min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, under dispersed with stirring 10min, 120r/min low speed, stir 2h, place 10min, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, more repeatedly rinse 6 times with deionized water for 4 DEG C, lyophilization, obtains fullerene polylactic acid from reuniting carried medicine sustained-release microsphere; Described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
Fullerene polylactic acid is observed from blank microspherulite diameter of reuniting at 5-10 μm under field emission scanning electron microscope. after being disperseed in blank microsphere water of reuniting by fullerene polylactic acid, optical microphotograph Microscopic observation, microspherulite diameter is even, good dispersion, soilless sticking phenomenon.
The fullerene polylactic acid that foregoing invention content part and embodiment 1-5 provide is from reuniting carried medicine sustained-release microsphere, there is heliosensitivity, the medicine preparing optical dynamic treatment of tumor can be effective to, realize fullerene polylactic acid and preparing the application in light power tumour medicine from reunion carried medicine sustained-release microsphere.And achieve useful technique effect through test, regarding assay data is as follows:
Fullerene polylactic acid of the present invention has photodynamic therapy function of tumor from reunion carried medicine sustained-release microsphere, proves by following test.
Obtained fullerene polylactic acid is scattered in the sodium chloride injection of 0.9% from reunion microsphere is molten, in-situ injection, in tumor-bearing mice A tumor, is irradiated with light source B, light application time 30s for after administration every 2 days, within every 6 days, be administered once, measure the gross tumor volume size of tumor-bearing mice A every other day.
Tumor-bearing mice A in above-mentioned steps is: organ surface or the inner various solid tumors occurred, pulmonary carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, gastric cancer, hepatocarcinoma, colorectal cancer, breast carcinoma, ovarian cancer, bladder cancer, white leukemia, cancer of pancreas, cervical cancer, laryngeal carcinoma, thyroid carcinoma, carcinoma of tongue, the brain cancer, carcinoma of small intestine, carcinoma of gallbladder, cancer of biliary duct, renal carcinoma, carcinoma of prostate, cancer of vagina, carcinoma of testis, carcinoma of endometrium, choriocarcinoma, For Primary Vaginal Carcinoma, Vulvar, Hodgkin, non-Hodgkin lymphoma, skin carcinoma, the one in malignant melanoma.
Light source B in above-mentioned steps 1 is: the one in the wide wavelength light source of 400-800nm or laser.Preferred 532nm laser.
Fullerene polylactic acid of the present invention when reunion microsphere carries out photodynamic therapy deep tumor, these light sources can not transillumination time, by being suitable for the illuminating method at position, the penetration capacity improving external light source carries out oncotherapy.
Fullerene polylactic acid of the present invention can make the medicament form of pharmaceutical preparation of multiple route of administration from blank microsphere of reuniting.Such as: intravenous injection, intramuscular injection, intratumor injection, subcutaneous implantation etc.Fullerene polylactic acid of the present invention can add the additive of various preparation from blank microsphere of reuniting, and such as normal saline, glucose, freeze drying protectant etc. are to make suitable dosage form needs.
Fullerene polylactic acid polymer of the present invention is achieved by following technical scheme as the application of pharmaceutical carrier in oncotherapy:
Obtained fullerene polylactic acid is scattered in the sodium chloride injection of 0.9% from reunion medicine carrying microballoons, in-situ injection, in the tumor of tumor-bearing mice A, is administered once for every 6 days, within after administration every 2 days, irradiates tumor locus with light source B, light application time 30s, measures the gross tumor volume size of tumor-bearing mice A.
Tumor-bearing mice A in above-mentioned steps is: organ surface or the inner various solid tumors occurred, pulmonary carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, gastric cancer, hepatocarcinoma, colorectal cancer, breast carcinoma, ovarian cancer, bladder cancer, white leukemia, cancer of pancreas, cervical cancer, laryngeal carcinoma, thyroid carcinoma, carcinoma of tongue, the brain cancer, carcinoma of small intestine, carcinoma of gallbladder, cancer of biliary duct, renal carcinoma, carcinoma of prostate, cancer of vagina, carcinoma of testis, carcinoma of endometrium, choriocarcinoma, For Primary Vaginal Carcinoma, Vulvar, Hodgkin, non-Hodgkin lymphoma, skin carcinoma, the one in malignant melanoma.
Light source B in above-mentioned steps is: the one in the wide wavelength light source of 400-800nm or laser.Preferred 532nm laser.
The present invention has Phototherapy and the application of Chemotherapy in treatment tumor, and through test of many times, all obtain good result of the test, relevant experimental data is as follows:
After illumination, fullerene polylactic acid is antitumor cytolytic activity in reunion microsphere.After B16-F10 mouse melanin tumor cell is counted, become 2 × 106/mL cell suspension with normal saline dilution, be seeded in black rat right abdomen subcutaneous.Inoculated tumour is after 7 days, get the mice of wherein gross tumor volume >100mm3, be divided into 8 groups at random, often organize 5, be specifically grouped as follows: 1) normal saline group 2) normal saline light group 3) fullerene polylactic acid is from reunion medicine carrying microballoons light group 4) fullerene polylactic acid is from reuniting medicine carrying microballoons.5) fullerene polylactic acid is from blank microsphere group 6 of reuniting) the fullerene polylactic acid blank microsphere light group 7 of reunion certainly) simple medicine group 8) simple medicine light group.8 groups all adopt neoplasm in situ drug administration by injection mode, and wherein light group uses light source for the irradiation of 523nm laser, and power is 2W, within after administration every 2 days, irradiates tumor locus, is 30s at every turn.Within every 6 days, be administered once, per injection drug dose is 2.5mg/kg, per injection 100 μ L, altogether administration 2 times.Whole experimentation observes mice animation every day, within every 2 days, claim Mouse Weight and use the major diameter (A) of vernier caliper measurement murine melanoma and minor axis (B), calculating gross tumor volume. mouse tumor appreciation rate=(administration group the 11st day tumor volume-administration group the 0th day tumor volume)/(matched group the 11st day tumor volume-matched group the 0th day tumor volume) × 100%.
Verified, after laser irradiates, fullerene polylactic acid is 39.93% from blank microsphere group mouse tumor appreciation rate of reuniting, and fullerene polylactic acid is from blank microsphere group of reuniting, and the increase of mouse tumor volume obtains obvious suppression.Non-laser is irradiated, and fullerene polylactic acid adds the increase not affecting mouse tumor volume, mouse tumor volume appreciation rate 100.67% from blank microsphere of reuniting.Fullerene polylactic acid obtains from the increase of reunion medicine carrying microballoons light group mouse tumor volume and obviously suppresses even tumor volume obviously to reduce, and mouse tumor appreciation rate is-7.14%.And simple medicine group and simple medicine group light group all obviously can not suppress the increase of mouse tumor volume, mouse tumor volume appreciation rate is respectively 98.17% and 87.95%.
The present invention compared with prior art has following outstanding Advantageous Effects:
1) preparation method of the present invention is simple, and preparation condition easily meets, physics and chemical stability good, abundant raw material source, cost is low, and can not destroy the characteristic of fullerene itself;
2) the present invention has heliosensitivity after being agglomerated into microsphere, can be used for antitumor photodynamic therapy, can play anti-tumor activity, and during not illumination, anti-tumor activity is less during illumination;
3) the present invention can be used as pharmaceutical carrier, has minimum toxicity, good biocompatibility, has slow release effect, implantable tumor locus administration, extends water soluble drug in the tumor position holdup time, can play more outstanding anti-tumor activity in conjunction with illumination.Test result shows, fullerene polylactic acid prepared by the present invention is from reuniting carried medicine sustained-release microsphere, and uniform particle sizes, after lyophilizing, can be uniformly dispersed, in aqueous without adhesion phenomenon.It is the innovation in tumor.
Claims (7)
1. implantable fullerene polylactic acid is from a preparation method for reunion carried medicine sustained-release microsphere, it is characterized in that, fullerene molecule is connected to polylactic acid by chemical bond-linking, and polylactic acid relative molecular weight is 1,0000-1, and 8000, fullerene is C
60fullerene, microspherulite diameter is 1-10 μm, is realized by following steps:
1) 2.0-4.0g aminoacid and 2.0-4.0g sodium hydroxide are added in the mixed solvent of 40-50mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 4-5h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 10-20mg is put into container, add lactic acid 5-10mL, then anhydrous stannous chloride 6-12mg is added, pass into nitrogen, the saturated 5-10min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, react 4-5h under 140-150 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, then precipitates with deionized water, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtain fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 150-200mg, add in 2-3mL dichloromethane solution and dissolve, add 1-2ml antitumor drug aqueous solution, vortex mixing 10-15min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, dispersed with stirring 10min, under 80-120r/min low speed, stir 2h, place 10min for 4 DEG C, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeatedly rinse 5-6 time with deionized water again, lyophilization, obtain fullerene polylactic acid from reuniting carried medicine sustained-release microsphere, described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
2. implantable fullerene polylactic acid according to claim 1 is from the preparation method of reunion carried medicine sustained-release microsphere, it is characterized in that, is realized by following steps:
1) 2.0g aminoacid and 2.0g sodium hydroxide are added in the mixed solvent of 40mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 4h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 10mg is put into container, add lactic acid 5mL, then add anhydrous stannous chloride 6-12mg, pass into nitrogen, the saturated 5min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, react 4h under 140 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, then precipitates with deionized water, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtain fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 150mg, add in 2mL dichloromethane solution and dissolve, add 1ml antitumor drug aqueous solution, vortex mixing 10min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, under dispersed with stirring 10min, 80r/min low speed, stir 2h, place 10min, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, more repeatedly rinse 5 times with deionized water for 4 DEG C, lyophilization, obtains fullerene polylactic acid from reuniting carried medicine sustained-release microsphere; Described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
3. implantable fullerene polylactic acid according to claim 1 is from the preparation method of reunion carried medicine sustained-release microsphere, it is characterized in that, is realized by following steps:
1) 2.5g aminoacid and 2.5g sodium hydroxide are added in the mixed solvent of 42mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 4.5h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 13mg is put into container, add lactic acid 6mL, then add anhydrous stannous chloride 8mg, pass into nitrogen, the saturated 6min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, react 4.5h under 143 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, then precipitates with deionized water, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtain fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 160mg, add in 2mL dichloromethane solution and dissolve, add 1ml antitumor drug aqueous solution, vortex mixing 12min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, under dispersed with stirring 10min, 90r/min low speed, stir 2h, place 10min, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, more repeatedly rinse 5 times with deionized water for 4 DEG C, lyophilization, obtains fullerene polylactic acid from reuniting carried medicine sustained-release microsphere; Described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
4. implantable fullerene polylactic acid according to claim 1 is from the preparation method of reunion carried medicine sustained-release microsphere, it is characterized in that, is realized by following steps:
1) 3g aminoacid and 3g sodium hydroxide are added in the mixed solvent of 45mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 4.5h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 15mg is put into container, add lactic acid 8mL, then add anhydrous stannous chloride 9mg, pass into nitrogen, the saturated 8min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, react 4.5h under 145 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, then precipitates with deionized water, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtain fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 180mg, add in 2.5mL dichloromethane solution and dissolve, add 1.5ml antitumor drug aqueous solution, vortex mixing 13min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, under dispersed with stirring 10min, 100r/min low speed, stir 2h, place 10min, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, more repeatedly rinse 5 times with deionized water for 4 DEG C, lyophilization, obtains fullerene polylactic acid from reuniting carried medicine sustained-release microsphere; Described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
5. implantable fullerene polylactic acid according to claim 1 is from the preparation method of reunion carried medicine sustained-release microsphere, it is characterized in that, is realized by following steps:
1) 3.5g aminoacid and 3.5g sodium hydroxide are added in the mixed solvent of 47mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 5h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 18mg is put into container, add lactic acid 9mL, then add anhydrous stannous chloride 11mg, pass into nitrogen, the saturated 9min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, react 5h under 147 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, then precipitates with deionized water, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtain fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 190mg, add in 2.7mL dichloromethane solution and dissolve, add 1.8ml antitumor drug aqueous solution, vortex mixing 14min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, under dispersed with stirring 10min, 110r/min low speed, stir 2h, place 10min, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, more repeatedly rinse 6 times with deionized water for 4 DEG C, lyophilization, obtains fullerene polylactic acid from reuniting carried medicine sustained-release microsphere; Described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
6. implantable fullerene polylactic acid according to claim 1 is from the preparation method of reunion carried medicine sustained-release microsphere, it is characterized in that, is realized by following steps:
1) 4.0g aminoacid and 4.0g sodium hydroxide are added in the mixed solvent of 50mL water and dehydrated alcohol, wherein the volume ratio of water and dehydrated alcohol is 8:30, stir, dropwise join again in the fullerene toluene solution of 60mL, wherein the weight ratio of fullerene and toluene is 5:3, under the rotating speed of 400r/min, under room temperature, magnetic agitation reaction 5h, remove the mixed solution of the toluene on upper strata, water and dehydrated alcohol, again through dehydrated alcohol filtering and washing 3 times, vacuum drying 24h, obtains fullerene aminoacid derivate; Described aminoacid is any one in phenylalanine, glycine, lysine, leucine, valine;
2) fullerene aminoacid derivate 20mg is put into container, add lactic acid 10mL, then add anhydrous stannous chloride 12mg, pass into nitrogen, the saturated 10min of room temperature, in evacuation environment, preheating 1h under 110 DEG C of oil bath magnetic agitation, react 5h under 150 DEG C of oil bath magnetic agitation, reaction terminates product dichloromethane and dissolves, then precipitates with deionized water, by the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, repeat operation 3 times, then lyophilization, obtain fullerene polylactic acid polymer;
3) by fullerene polylactic acid polymer 200mg, add in 3mL dichloromethane solution and dissolve, add 2ml antitumor drug aqueous solution, vortex mixing 15min, dropwise add in 40mL glycerol, 1200r/min magnetic agitation 10min, microsphere glycerin liquid is added in the aqueous gelatin solution of 0.5%, under dispersed with stirring 10min, 120r/min low speed, stir 2h, place 10min, with the mixed cellulose ester microporous membrane sucking filtration of 0.45 μm, more repeatedly rinse 6 times with deionized water for 4 DEG C, lyophilization, obtains fullerene polylactic acid from reuniting carried medicine sustained-release microsphere; Described antitumor drug is the one in amycin, mitoxantrone, 5-Fluorouracil, methotrexate water-soluble anti-tumor medicine.
7. the fullerene polylactic acid that prepared by claim 1 or the method described in any one of 2-6 is preparing the application in optical dynamic treatment of tumor medicine from reunion carried medicine sustained-release microsphere.
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