姜黄素缓释胶束的制备、表征及其抗细胞毒类药物的多药耐药性评价

Polymeric Micelles for Sustained Release of Curcumin:Preparation,Characterization and in vivo Evaluation of Overcoming Multidurg Resistance for Cytotoxic Drugs

姜黄素为传统中药姜黄中提取的多酚类化合物,具有多靶点的抗肿瘤活性及确切的抗炎和抗氧化等作用。但姜黄素几乎不溶于水,口服不吸收,且存在严重的肝首过效应,因此系统生物利用度很低,难以充分发挥其抗肿瘤活性。合成了叔丁氧羰基苯丙氨酸封端的甲氧基聚乙二醇-聚己内酯嵌段共聚物,并采用固体分散工艺制备了可注射给药的姜黄素共聚物胶束,结果表明:胶束在体内具有良好的稳定性和缓释效果,能显著减缓姜黄素在体内的代谢速度,从而提高生物利用度;该胶束和阿霉素联用不仅能提高药效,还能有效降低阿霉素的毒性,具有良好的临床应用前景。

Curcumin, a polyphenolic natural extract of curcuma longa, exhibits a wide range of pharmacological influence including anti-oxidant, anti-inflammatory, and anti-tumor activities in various preclinical models. However, the low systemic bioavailability of curcumin is also highlighted, which has been mainly attributed to its extremely low aquous solubility and severe liver first pass effect. In the present study, N-t-butoxycarbonyl- phenylalanine （Boc-Phe） terminated monomethoxyl poly （ethylene glycol）-b-poly（ε-caprolactone） block copolymer （mPEG-PCL-Phe（Boc）） was synthesized and characterized by 1H-NMR and gel permeation chromatography. The curcumin-loaded mPEG-PCL-Phe（Boc） micelles were prepared by a solid dispersion method and showed significant improved stability in plasma compared with free curcumin upon parenteral administration. So the internal metabolism velcocity of curcumin was slow down and the bioavailabity was improved. The combination of parenteral curcumin micelle with doxorubicin resulted in enhanced tumor growth inhibition versus either single agent. Furthermore, a simultaneous decrease in doxorubicin-induced systemic toxicity by curcumin-loaded micelle was also observed. Overall, curcumin-loaded micelle is a promising new formulation that is able to enhance the efficacy of chemotherapeutic drugs and combat multi-drug resistance.