Department of Chemical Engineering, National Tsing Hua University, Hsinchu, 300 Taiwan, ROC.
Biomaterials. 2010 Mar;31(8):2293-301. doi: 10.1016/j.biomaterials.2009.11.059. Epub 2009 Dec 29.
Multifunctional mixed micelles that constructed from poly(HEMA-co-histidine)-g-PLA and diblock copolymer PEG-PLA with functional moiety was developed in this study. The mixed micelles had well defined core shell structure which was evaluated by TEM. The functional inner core of poly(HEMA-co-histidine)-g-PLA exhibited pH stimulate to enable intracellular drug delivery and outer shell of PEG-b-PLA with functional moiety Cy5.5 for biodistribution diagnosis and folate for cancer specific targeting were synthesized at the end of the polymer chain. The graft and diblock copolymer self assembled to nanospheres against water with an average diameter below 120 nm without doxorubicin, and an average diameter of around 200 nm when loaded with drug. From drug released study, a change in pH destroy the inner core to lead a significant doxorubicin(Dox) release from mixed micelles. Cellular uptake of folate-micelles was found to be higher than that of non-folate-micelles due to the folate-binding effect on the cell membrane, thereby providing a similar cytotoxic effect to drug only against the HeLa cell line. In vivo study revealed that specific targeting of folate-micelles exhibited cancer targeting and efficiency expression on tumor growth, indicating that multifunctional micelles prepared from poly(HEA-co-histidine)-g-PLA and folate-PEG-PLA have great potential in cancer chemotherapy and diagnosis.
本研究构建了由聚（HEMA-co-组氨酸）-g-PLA 和具有功能基团的两亲性嵌段共聚物 PEG-PLA 组成的多功能混合胶束。通过 TEM 评估了混合胶束具有良好定义的核壳结构。聚（HEMA-co-组氨酸）-g-PLA 的功能内核表现出 pH 刺激作用，能够实现细胞内药物传递，而聚合物链末端合成的 PEG-b-PLA 具有功能基团 Cy5.5 用于生物分布诊断和叶酸用于癌症特异性靶向。接枝和两亲嵌段共聚物自组装成纳米球，在水中平均直径低于 120nm 时无阿霉素，载药后平均直径约为 200nm。从药物释放研究中可以看出，pH 的变化破坏了内核，导致混合胶束中阿霉素（Dox）的显著释放。由于叶酸与细胞膜的结合作用，叶酸-胶束的细胞摄取被发现高于非叶酸-胶束，从而对 HeLa 细胞系表现出与仅药物相似的细胞毒性作用。体内研究表明，叶酸-胶束的特异性靶向表现出对肿瘤生长的癌症靶向和效率表达，表明由聚（HEA-co-组氨酸）-g-PLA 和叶酸-PEG-PLA 制备的多功能胶束在癌症化疗和诊断方面具有巨大潜力。
