CN101697963B - Method for preparing PLGA slow-release microsphere carrying docetaxel and application thereof in chemotherapy of mesenchyma stroma of tumors under ultrasonic mediation - Google Patents
Method for preparing PLGA slow-release microsphere carrying docetaxel and application thereof in chemotherapy of mesenchyma stroma of tumors under ultrasonic mediation Download PDFInfo
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Abstract
The invention discloses a method for preparing a PLGA slow-release microsphere carrying docetaxel and an application thereof in the chemotherapy of the mesenchyma stroma of tumors under ultrasonic mediation. The PLGA slow-release microsphere carrying the docetaxel is a medicine-carrying microsphere prepared from PLGA and the docetaxel by a single emulsification method, the molecular weight of the PLGA in the medicine-carrying microsphere is 5000-50000dal, the mole ratio of lactic acid to glycollic acid is 75:25-50:50, the feeding ratio of the PLGA to the docetaxel is 100/1-100/10, and the PLGA slow-release microsphere carrying the docetaxel is prepared by emulsification in an organic solvent. The slow-release microsphere preparation carrying the docetaxel is injected into the tumor tissues of nude mice with human liver cancer, beast cancer and ovarian cancer, and the necrosis situation of the tumors is checked by pathological histology; the result shows that the slow-release microsphere carrying the docetaxel can thoroughly ablate and inactivate the tumors, reduces the whole-body toxic or side effect of the medicine obviously and is a novel method for the chemotherapy of the mesenchyma stroma of the tumors under ultrasonic intervention with very good clinical application prospect.
Description
Technical field:
The present invention relates to a kind of slow releasing preparation that is used for chemotherapy of mesenchyma stroma of tumors; Particularly; The present invention is the slow releasing preparation of a kind of Docetaxel of preparation, and learning a skill to guide through ultrasonic image is expelled in the tumor tissues, sets up a kind of thoroughly deactivation tumor; Chemotherapy of mesenchyma stroma of tumors new method easy and simple to handle, that the whole body toxic and side effects is low.
Background technology:
Docetaxel is a kind of new type antineoplastic medicine, and main passing through suppresses the cell microtubule depolymerization, makes spindle lose normal function, causes cell death.In addition, Docetaxel can also suppress cell DNA, RNA or proteinic synthetic, to tumors such as hepatocarcinoma, ovarian cancer, breast carcinoma, peripheral type carcinoma of lung, cancer of pancreas, incidence etc. effectively.Because Docetaxel is insoluble in water, existing preparation uses surfactant Tween 80 and ethanol solubilising usually, causes the patient allergy reaction easily.Can be distributed in rapidly after the administration of Docetaxel whole body in the nearly all tissue except that the maincenter nerve, often cause bone marrow depression, neutrophilic granulocyte reduces, peripheral nervous toxicity, and blood system toxicity, body fluid storage such as stay at toxic and side effects.Therefore, improve Docetaxel dosage form and administering mode, improve the tumor by local drug level, it is significant to alleviate the whole body toxic and side effects.
The tumor by local drug level is low after the administration of tradition chemotherapy whole body, and systemic adverse reactions is obvious, and is relatively poor to the curative effect of part solid tumor such as hepatocarcinoma etc.Along with the application of macromolecular material in the medicine and pharmacology field, medicine control slow release novel formulation such as liposome, microsphere, gel continue to bring out in recent years, and chemotherapy of mesenchyma stroma of tumors becomes one of focus of oncotherapy research gradually.Cancer therapy drug is prepared into drug-supplying system with slow releasing function; Through different modes; As ultrasonic image learn a skill that mediation organizes in implantation tumour tissue, tumor week down between tumor bed behind matter or the tumor resection; Make medicine in slow, the lasting release of tumor by local, keep local higher drug level, reduce the whole body toxic and side effects simultaneously.The present invention adopts the Docetaxel that the effect of polylactic acid-glycolic guanidine-acetic acid (PLGA) bag carrying anti-tumor is strong, antitumor spectra is wide, prepares a kind of slow releasing preparation, can make a bet and is mapped to tumor by local and carries out chemotherapy of mesenchyma stroma in the ultrasonic image guiding that learns a skill, and reaches the effect of highly effective and safe.
Summary of the invention:
The object of the present invention is to provide a kind of PLGA sustained-release micro-spheres of carrying docetaxel of chemotherapy of mesenchyma stroma of tumors; This microsphere wraps carrying docetaxel with PLGA; Can learn a skill to mediate through ultrasonic image and be expelled in the tumor tissues; Improve the tumor by local drug level, alleviate the toxic and side effects of whole body administration, reach purpose safely and efficiently.
The technical scheme that the present invention adopts is, the PLGA sustained-release micro-spheres of described carrying docetaxel is the medicine carrying microballoons that PLGA and Docetaxel are processed through single emulsion process.Specifically: be the medicine carrying microballoons that PLGA and Docetaxel are processed through single emulsion process; PLGA molecular weight in the described medicine carrying microballoons is 5000-50000dal; Lactic acid/hydroxyacetic acid mol ratio is 75: 25～50: 50; The rate of charge of PLGA and Docetaxel is 100/1～100/10, and emulsifying is prepared from organic solvent, and wherein water disperse medium employing concentration is 1～6% polyvinyl alcohol.The PLGA sustained-release micro-spheres of carrying docetaxel is called for short (medicine carrying microballoons) hereinafter.
PLGA slow-release microsphere carrying docetaxel of the present invention is host material with PLGA, and the rate of charge of PLGA and Docetaxel is 100/1 to 100/10, promptly 100/1～100/10, and through general single emulsion process preparation.Described carrying docetaxel PLGA microsphere; Its PLGA molecular weight is 5000～50000dal; Lactic acid (lactic acid, LA)/hydroxyacetic acid (glycolic acid, GA) mol ratio is 75: 25～50: 50; Organic solvent adopts dichloromethane, and emulsifying can be adopted methods such as electronic homogenate, ultrasonic emulsification or electronic stirring.The water disperse medium adopts polyvinyl alcohol, and model can be PVA1788, and concentration is 1～6%.The molecular weight of we preferred PLGA is 10000dal; The PLGA of LA/GA=50/50 (with molar ratio computing) is a host material, and the rate of charge of PLGA and Docetaxel is 50/3, and dichloromethane is an organic facies; 3%PVA is a water; 800 rev/mins of electronic stirring 2min add distilled water magnetic agitation 4hr then and are cured, and wash 3 times postlyophilization.The microsphere average grain diameter of result's preparation is 23.8 μ m, and is big or small than uniformity, smooth surface, no adhesion; Envelop rate reaches 98.6%; Carrying drug ratio reaches 5.59%, and Sustainable Stability discharges medicine and reached for 6 weeks, and slow release is best; And experiment shows: medicine carrying microballoons local injection anti-experimental character nude mice lotus people hepatocarcinoma effect the best under ultrasonic guidance, and can be in the application in the carried medicine sustained-release microsphere medicine of tumors such as preparation treatment hepatocarcinoma, breast carcinoma, ovarian cancer, peripheral type carcinoma of lung, cancer of pancreas, incidence.
PLGA slow-release microsphere carrying docetaxel of the present invention has the protective effect that reduces the Docetaxel degraded.Docetaxel is poor stability in aqueous solution, and along with time lengthening, Docetaxel is degraded gradually.Adopt PLGA microsphere bag carrying docetaxel, can significantly reduce drug hydrolysis.The hydrophobic high-efficient liquid phase technique testing result of anti-phase shows that release in vitro tangible degradation fragment absworption peak occurred in the Docetaxel of aqueous solution, and the Docetaxel structure that bag is loaded in the microsphere is more complete, and no obvious degradation fragment occurs.
Carrying docetaxel sustained release microsphere agents of the present invention is applicable to chemotherapy of mesenchyma stroma under the ultrasonic mediation of body overwhelming majority solid tumors; After comprising liver, kidney, pancreas, spleen, prostate, uterus, ovary, peritoneum, thyroid, mammary gland and cervical region and shallow table soft tissue neoplasms, comprise optimum and malignant tumor.
Carrying docetaxel sustained release microsphere agents of the present invention is especially in the nude mice tumor tissues that is expelled to lotus people hepatocarcinoma, breast carcinoma, ovarian cancer; Through histopathologic examination's neoplasm necrosis situation; The result shows that the sustained-release micro-spheres of carrying docetaxel can melt the deactivation tumor completely; And significantly reducing the whole body toxic and side effects of medicine, is a kind of new method that has the ultrasonic intervention tumour chemotherapy of mesenchyma stroma of potential applicability in clinical practice.
Description of drawings:
Figure 1A is scanning electron microscope * 500 figure of Docetaxel of the present invention-polylactic-co-glycolic acid microsphere.
Figure 1B is scanning electron microscope * 2000 figure of Docetaxel of the present invention-polylactic-co-glycolic acid microsphere.
Fig. 2 is the outer releasing curve diagram of Docetaxel of the present invention-polylactic-co-glycolic acid microsphere.
Fig. 3 A is the HPLC figure that detects before Docetaxel of the present invention-polylactic-co-glycolic acid microsphere release in vitro, the absworption peak of Docetaxel when retention time is about 7.6min, occurred.
Fig. 3 B figure is the HPLC figure of Docetaxel of the present invention-supernatant of 7 days of polylactic-co-glycolic acid microsphere release in vitro, new absworption peak when 9.3min, occurred, and peak area is 28.1% of a Docetaxel.
Fig. 3 C new absworption peak when 9.3min, also occurred, but peak area is merely 5.2% of Docetaxel for the HPLC figure of the present invention from 7 days Docetaxel microsphere extracting Docetaxel of release in vitro.
The specific embodiment:
Below in conjunction with accompanying drawing the present invention is elaborated:
Embodiment
1. the preparation of the PLGA sustained-release micro-spheres of carrying docetaxel
Adopt solvent evaporation method to prepare the PLGA microsphere of carrying docetaxel.Precision takes by weighing PLGA 50mg, is dissolved in the 1ml dichloromethane, adds Docetaxel 3mg, and fully dissolving of vortex vibration is organic facies.Draw organic facies with the 1ml syringe, slowly inject 50ml 3%PVA aqueous solution, the electronic stirring of 800rpm 2 minutes continued magnetic agitation 3 hours.The medicine carrying microballoons that is cured with 500ml distilled water cyclic washing, is collected medicine carrying microballoons through 0.22 μ m microporous filter membrane sucking filtration, and vacuum lyophilization promptly gets the PLGA microsphere of carrying docetaxel.
The experiment proof: when the rate of charge of PLGA and Docetaxel was 50mg/3mg, the PLGA sustained-release micro-spheres of the carrying docetaxel that is obtained had best envelop rate and carrying drug ratio, is respectively 98.6% and 5.59%.
The molecular weight of above-mentioned PLGA host material is 10000dal, and LA/GA=50/50 (with molar ratio computing), this material can be the commercially available prod or adopt general ring-opening polymerisation method to synthesize and process.
2. the medicine carrying microballoons configuration of surface is observed and particle size determination
Get an amount of medicine carrying microballoons lyophilized powder, put on the two-sided tape, evenly coating, after the ion film plating appearance spatters gold, scanning electron microscopic observation, the microsphere size is more even, smooth surface, good dispersion, Figure 1A and Figure 1B are seen in no adhesion.Measure the particle diameter of 300 medicine carrying microballoonss, mean diameter is 23.8 μ m.
3. the mensuration of medicine carrying microballoons envelop rate and carrying drug ratio
Adopt HPLC (HPLC) to detect.Chromatographic condition is following: mobile phase is methanol=70/30, and flow velocity is 1.0ml/min, and 30 ℃ of column temperatures detect wavelength 227nm.It is an amount of that precision takes by weighing Docetaxel, and it is the standard stock solution of 1mg/ml that the adding dissolve with methanol becomes concentration.Precision measures Docetaxel storing solution 0.05,0.1,0.25,0.5 and 1.0ml puts in the 10ml measuring bottle, and methanol constant volume gets the contrast solution of series concentration.20 μ l sample introductions carry out rectilinear regression with peak area (Y) to contrast solution concentration (X mg/L).
Precision takes by weighing medicine carrying microballoons 10mg in the 5ml centrifuge tube, adds the 0.5ml dichloromethane, and the ultrasonic microsphere that makes dissolves, and adds 2.5ml methanol again, vortex 10min, and the centrifugal 10min of 5000 * g gets supernatant sample introduction 20 μ l.Measure peak area, the substitution standard curve calculates Docetaxel concentration.As a result, when the rate of charge of PLGA and Docetaxel can obtain best envelop rate and carrying drug ratio during for 50mg/3mg, be respectively 98.6% and 5.59%.
4. the release in vitro of medicine carrying microballoons
Precision takes by weighing medicine carrying microballoons 10mg and places penicillin bottle; Add 5ml pH and be 7.2 phosphate buffer (containing 3%PEG 6000), behind the vortex 1min 37 ℃, (75 ± 5) rpm vibration, respectively at the 1st, 7,14,21,28,35,42 day; The centrifugal 10min of 5000 * g; Take out all supernatant, replenish equivalent simultaneously and discharge liquid, continue vibration.The HPLC method is measured and is discharged Docetaxel concentration in the liquid.As a result, it is more steady that the PLGA sustained-release micro-spheres of carrying docetaxel discharges, and discharged 4.2% on the 1st day, do not have obviously " prominent releasing " behavior, to the 42nd day cumulative release 65.3%, see the release in vitro curve chart of the carrying docetaxel PLGA microsphere of Fig. 2.
5. the structural stability of release in vitro Docetaxel detects
Precision takes by weighing medicine carrying microballoons 50mg and places penicillin bottle, adds 10ml and discharges liquid, 37 ℃, (75 ± 5) rpm vibration; At the 7th day, the centrifugal 10min separation of supernatant of 5000 * g was after the sedimentary medicine carrying microballoons residue dried under vacuum; Dissolve with dichloromethane; Methanol extraction Docetaxel, HPLC method are measured the Docetaxel that discharges liquid and deposition microsphere, the relatively difference of absworption peak.Fig. 3 A that is used for reference is the HPLC figure that detects before the external release of medicine carrying microballoons, the absworption peak of Docetaxel when retention time is about 7.6min, occurred.One new absworption peak appears in the external release supernatant of medicine carrying microballoons when retention time is about 9.3min, peak area is about 28.1% of Docetaxel peak area, sees 3B, explains that degraded has appearred in the Docetaxel of release in vitro.Medicine carrying microballoons after the release in vitro is about also visible this absorption peak-to-peak of 9.3min in retention time, but peak area is minimum, is merely 5.2% of Docetaxel peak area, sees Fig. 3 C.It is more stable than the medicine that is released in the buffer that this shows that bag is loaded in the Docetaxel of PLGA microsphere, and the PLGA carrier has protection Docetaxel medicine, reduces it effect of degrading takes place.
6. medicine carrying microballoons local injection anti-experimental character nude mice lotus people hepatocarcinoma effect under the ultrasonic guidance
People's hepatocarcinoma Bel-7404 cells in vitro is incubated at the RPMI-1640 culture fluid that contains 10% hyclone, after cell fusion grows to 90%, and collecting cell preparation 5 * 10
7The single cell suspension of cells/ml.Get male BALB/c-nu nude mouse; Right oxter inoculation 0.2ml cell suspension; Choose diameter of tumor 1.5-2.0cm after 14 days 50; Be divided into 5 groups at random, be model control group, blank microsphere group, Docetaxel intravenously administrable group, Docetaxel microsphere intratumor injection administration high and low dose group, 10 every group.Microsphere administration group nude mice is expelled to tumor by local with microsphere under ultrasonic guidance, make medicine be evenly distributed to whole tumor.As a result, the tumor of model group and blank microsphere nude mice continues growth, and each administration group all shows certain antitumor action, and wherein injection high dose group antitumor action is the most remarkable in the Docetaxel microsphere tumor body, and tumour inhibiting rate is up to 72.67%.Inject back 14 days every group get 3 nude mice tumors and carry out pathologic finding, visible tumor tissues is large stretch of downright bad, microvessel density lowers.Get tumor tissues and carry out fluorescence quantitative PCR detection tumor-blood-vessel growth related gene VEGF, Ang2, bFGF change of Expression, the result sees that the gene expression of medicine carrying microballoons group obviously reduces (table 1).Remaining nude mice was observed 42 days, peeled off tumor and claimed quality, and each is organized the tumour inhibiting rate of nude mice and sees table 2.
The Δ Ct value that table 1 is respectively organized nude mice tumor tissues VEGF, Ang2, bFGF gene expression compares
Table 2 Docetaxel microsphere is to lotus people hepatocarcinoma nude mice antitumor action
7. medicine carrying microballoons local injection anti-experimental character nude mice lotus human breast carcinoma effect
Human breast carcinoma MDA-MB-231 cells in vitro is incubated at the L-15 culture fluid that contains 10% hyclone, after cell fusion grows to 90%, and collecting cell preparation 5 * 10
7The single cell suspension of cells/mL.Get female BALB/c-nu nude mouse,, be divided into model group, blank microsphere matched group, Docetaxel intravenous injection group, Docetaxel microsphere injection groups after 14 days at random, 6 every group in right oxter inoculation 0.2ml.Peeled off tumor in 42 days after the administration and claim quality, Docetaxel microsphere group inhibitory rate 83.5% as a result, apparently higher than 33.8% of intravenous injection group.
8. medicine carrying microballoons local injection anti-experimental character nude mice lotus HOC effect
Proliferation of Human Ovarian Cell SKOV3 In vitro culture is in the RPMI-1640 culture fluid that contains 10% hyclone, and after cell fusion grew to 90%, collecting cell prepared 5 * 10
7The single cell suspension of cells/mL.Get female BALB/c-nu nude mouse,, be divided into model group, blank microsphere matched group, Docetaxel intravenous injection group, Docetaxel microsphere intratumor injection group after 14 days at random, 6 every group in right oxter inoculation 0.2ml.Peeled off tumor in 42 days after the administration and claim quality, Docetaxel microsphere group inhibitory rate 79.2% as a result, apparently higher than 29.4% of intravenous injection group.
Claims (2)
1. the application of the PLGA sustained-release micro-spheres of a carrying docetaxel in the ejection preparation of preparation treatment breast carcinoma, ovarian cancer; The PLGA sustained-release micro-spheres of described carrying docetaxel is the medicine carrying microballoons that PLGA and Docetaxel are processed through single emulsion process; PLGA molecular weight in the described medicine carrying microballoons is 5000-50000dal; Lactic acid/hydroxyacetic acid mol ratio is 75: 25～50: 50; The rate of charge of PLGA and Docetaxel is 100/1～100/10, and emulsifying is prepared from organic solvent, and wherein water disperse medium employing concentration is 1～6% polyvinyl alcohol.
2. the application of the PLGA sustained-release micro-spheres of a carrying docetaxel in the ejection preparation of preparation chemotherapy of mesenchyma stroma of tumors under ultrasonic mediation; The PLGA sustained-release micro-spheres of described carrying docetaxel is the medicine carrying microballoons that PLGA and Docetaxel are processed through single emulsion process; PLGA molecular weight in the described medicine carrying microballoons is 5000-50000dal; Lactic acid/hydroxyacetic acid mol ratio is 75: 25～50: 50; The rate of charge of PLGA and Docetaxel is 100/1～100/10, and emulsifying is prepared from organic solvent, and wherein water disperse medium employing concentration is 1～6% polyvinyl alcohol.
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| CN102091042B (en) * | 2011-01-14 | 2013-01-09 | 华南理工大学 | Method for preparing monodisperse nanosphere medicine carrier |
| CN102504766B (en) * | 2011-10-09 | 2014-12-17 | 上海工程技术大学 | Phase-change energy-storage microcapsule, and preparation method and application thereof |
| CN102728287B (en) * | 2012-06-07 | 2014-12-10 | 东南大学 | Preparation method of PLGA microsphere with porous surface |
| CN103585634A (en) * | 2013-10-22 | 2014-02-19 | 汤民 | Docetaxel polymer nano-medicament preparation and preparation method thereof |
| CN104645419B (en) * | 2014-12-02 | 2017-04-12 | 中国人民解放军第四军医大学 | Preparation method of porous titanium-alloy femoral head support rod in bionic bone trabecula structure |
| CN107049984A (en) * | 2017-03-14 | 2017-08-18 | 武汉理工大学 | A kind of preparation method for carrying taxol polylactic-co-glycolic acid microballoon |
| CN108096583B (en) * | 2017-12-17 | 2021-02-19 | 宋振川 | Preparation method of tumor targeting nanoparticle carrier co-loaded with breast cancer chemotherapeutic drug MTDH siRNA |
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| US20070154554A1 (en) * | 2005-12-29 | 2007-07-05 | Robert Burgermeister | Polymeric compositions comprising therapeutic agents in crystalline phases, and methods of forming the same |
| CN101091806A (en) * | 2006-06-20 | 2007-12-26 | 天津市凯迪亚医疗器械有限公司 | Slow release coating layer of degradable medication for bracket of coronary artery |
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| US20070154554A1 (en) * | 2005-12-29 | 2007-07-05 | Robert Burgermeister | Polymeric compositions comprising therapeutic agents in crystalline phases, and methods of forming the same |
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