目的 優(yōu)化紫杉醇/低分子肝素–胱胺–維生素E琥珀酸酯（PTX/LMWH-cys-TOS）膠束的處方，評(píng)價(jià)其制劑學(xué)特性和體外細(xì)胞活性。方法 以載藥率和包封率為指標(biāo)，考察有機(jī)溶劑、藥物載體比例對(duì)膠束載藥能力的影響，優(yōu)化最佳處方。利用冷凍干燥法制備了膠束凍干粉針并考察復(fù)溶穩(wěn)定性，采用透析法研究了膠束在不同濃度的二硫素糖醇溶液中的釋放動(dòng)力學(xué)，采用CCK8法研究了膠束在紫杉醇敏感和耐藥細(xì)胞上的抗腫瘤活性，利用HPLC法測(cè)定了紫杉醇在腫瘤細(xì)胞內(nèi)的質(zhì)量濃度。結(jié)果 紫杉醇和LMWH-cys-TOS的最佳比例是1∶3.6，使用乙醇作為有機(jī)溶劑。加入凍干保護(hù)劑的膠束產(chǎn)品外觀(guān)良好，復(fù)溶后的膠束應(yīng)該在4 ℃保存，而且要盡快使用；在二硫蘇糖醇存在的釋放介質(zhì)中，紫杉醇釋放速度隨著二硫蘇糖醇濃度的增加而增加，二硫蘇糖醇的濃度是20 mmol/L時(shí)，紫杉醇的36 h的累積釋放量高達(dá)93%。膠束能提高紫杉醇在耐藥細(xì)胞HCT-15/Taxol上的毒性和藥物在腫瘤細(xì)胞內(nèi)的質(zhì)量濃度。結(jié)論 PTX/LMWH-cys-TOS膠束改善了紫杉醇的溶解度，實(shí)現(xiàn)了靶向給藥。

Objective To optimize the preparation of paclitaxel/low molecular-weight heparin-cystamin-α-tocopherol succinate (PTX/ LMWH-cys-TOS) micelles, and to evaluate its pharmaceutical property and in vitro cytotoxicity. Methods Using drug loading rate and encapsulation rate as indicators, the influence of organic solvent and drug carrier ratio on micelle drug loading capacity were investigated, and the optimal prescription was optimized. The freeze-drying method was used to prepare micelle freeze-dried powder injection and investigate their re-dissolution stability. The release characteristics of micelles in different concentrations of dithiothreitol solution were studied using dialysis method. The anti-tumor activity of micelles on paclitaxel sensitive and resistant cells was studied using CCK8 method. The concentration of paclitaxel in tumor cells was determined by HPLC method. Results The optimal ratio of paclitaxel to LMWH-cys-TOS was 1:3.6, using ethanol as the organic solvent. Micelle products with freeze-dried protectants had a good appearance, and the re-dissolved micelles should be stored at 4 ℃, and used as soon as possible. In the release medium of dithiothreitol, the release rate of paclitaxel increased with the increase of dithiothreitol concentration. When the concentration of dithiothreitol was 20 mmol/L, the cumulative release of paclitaxel after 36 h was as high as 93%. Micelles could enhance the toxicity of paclitaxel on drug-resistant cells HCT-15/Taxol and the concentration of the drug in tumor cells. Conclusion LMWH-cys-TOS micelles can improve the solubility of paclitaxel and achieve targeted drug delivery.

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江西省衛(wèi)計(jì)委中醫(yī)藥課題（2019A213）；中央引導(dǎo)地方科技發(fā)展基金項(xiàng)目（20222ZDH04094）；江西省贛江新區(qū)重大科技攻關(guān)項(xiàng)目（2021007）