载多西他赛的聚乙二醇-聚赖氨酸-维生素E聚合物胶束的制备及体内实体瘤分布研究

Preparation of Docetaxel-loaded PEG-polylysine-vitamin E Polymeric Micelles and Study on Its Biodistribution in Solid Tumor

紫杉烷类化疗药物用于实体瘤化疗时肿瘤递送效率低、不良反应较大,本研究合成了聚乙二醇-b-聚-L-赖氨酸-g-维生素E(PEG-PLL-VE)两亲性共聚物,并作为载体制备成聚合物胶束包载紫杉烷类药物多西他赛,通过流式细胞术、体外细胞毒性试验和体内活体成像考察该多西他赛聚合物胶束的MDA-MB-231乳腺癌细胞摄取效率、体外细胞毒性、细胞周期和体内实体瘤分布。制备的多西他赛聚合物胶束粒径约为60 nm,载药量可达10.3%。流式细胞分析和体外细胞毒性结果显示,MDA-MB-231细胞对PEG-PLL-VE胶束的摄取率高于聚乙二醇1000维生素E琥珀酸酯(TPGS)胶束,载多西他赛的PEG-PLL-VE胶束可通过G2/M期阻滞抑制MDA-MB-231细胞的增殖。体内荧光成像结果表明,PEG-PLL-VE胶束在小鼠体内肿瘤的分布量是TPGS胶束的2.4倍。综上所述,PEG-PLL-VE胶束能够高效包载多西他赛,可作为良好的紫杉烷类药物体内实体瘤递送载体。

The low tumor delivery efficiency and severe side effects of taxanes always exist in solid tumor chemotherapy in clinic.In this study,an amphiphilic copolymer polyethylene glycol-b-poly-L-lysine-g-vitamin E(PEG-PLL-VE)was synthesized and used as a carrier to prepare docetaxel-loaded polymeric micelles.The cell internalization of PEG-PLL-VE micelles in MDA-MB-231 breast tumor cells,in vitro cytotoxicity of docetaxel-loaded micelles,and in vivo tumor biodistribution in the breast tumor burdened mice were investigated.The size of PEG-PLL-VE polymeric micelles was around 60 nm with a narrow polydispersity index and docetaxel loading content in micelles was up to 10.3%.The?results?showed that the cellular uptake of PEG-PLL-VE micelles in MDA-MB-231 cells was higher than that of D-a-tocopherol polyethylene glycol 1000 succinate(TPGS)micelles.Docetaxel-loaded polymeric micelles inhibited MDA-MB-231 cell proliferation by G2/M arrest.The biodistribution amount of PEG-PLL-VE micelles in breast tumor in vivo was 1.4 times higher than that of TPGS micelles by fluorescence quantitation analysis.Collectively,PEG-PLL-VE micelles had the ability to encapsulate docetaxel with high loading content,and were suitable as drug delivery nanocarriers for solid tumor therapy in vivo.