Department of Pathophysiology, College of Preclinical and Forensic Medical Sciences, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.
Int J Nanomedicine. 2013;8:971-82. doi: 10.2147/IJN.S39532. Epub 2013 Mar 8.
Star-shaped polymer micelles have good stability against dilution with water, showing promising application in drug delivery. In this work, biodegradable micelles made from star-shaped poly(ε-caprolactone)/poly(ethylene glycol) (PCL/PEG) copolymer were prepared and used to deliver doxorubicin (Dox) in vitro and in vivo. First, an acrylated monomethoxy poly (ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) diblock copolymer was synthesized, which then self-assembled into micelles, with a core-shell structure, in water. Then, the double bonds at the end of the PCL blocks were conjugated together by radical polymerization, forming star-shaped MPEG-PCL (SSMPEG-PCL) micelles. These SSMPEG-PCL micelles were monodispersed (polydispersity index = 0.11), with mean diameter of ≈25 nm, in water. Blank SSMPEG-PCL micelles had little cytotoxicity and did not induce obvious hemolysis in vitro. The critical micelle concentration of the SSMPEG-PCL micelles was five times lower than that of the MPEG-PCL micelles. Dox was directly loaded into SSMPEG-PCL micelles by a pH-induced self-assembly method. Dox loading did not significantly affect the particle size of SSMPEG-PCL micelles. Dox-loaded SSMPEG-PCL (Dox/SSMPEG-PCL) micelles slowly released Dox in vitro, and the Dox release at pH 5.5 was faster than that at pH 7.0. Also, encapsulation of Dox in SSMPEG-PCL micelles enhanced the anticancer activity of Dox in vitro. Furthermore, the therapeutic efficiency of Dox/SSMPEG-PCL on colon cancer mouse model was evaluated. Dox/SSMPEG-PCL caused a more significant inhibitory effect on tumor growth than did free Dox or controls (P < 0.05), which indicated that Dox/SSMPEG-PCL had enhanced anticolon cancer activity in vivo. Analysis with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) showed that Dox/SSMPEG-PCL induced more tumor cell apoptosis than free Dox or controls. These results suggested that SSMPEG-PCL micelles have promising application in doxorubicin delivery for the enhancement of anticancer effect.
星形聚合物胶束在水中稀释时具有良好的稳定性，在药物输送方面具有广阔的应用前景。在这项工作中，我们制备了可生物降解的星形聚（ε-己内酯）/聚乙二醇（PCL/PEG）共聚物胶束，并将其用于体外和体内递送阿霉素（Dox）。首先，合成了一种丙烯酰化单甲氧基聚乙二醇-聚（ε-己内酯）（MPEG-PCL）两嵌段共聚物，该共聚物在水中自组装成具有核壳结构的胶束。然后，通过自由基聚合将 PC 段末端的双键连接在一起，形成星形 MPEG-PCL（SSMPEG-PCL）胶束。这些 SSMPEG-PCL 胶束在水中单分散（多分散指数=0.11），平均直径约为 25nm。空白 SSMPEG-PCL 胶束的细胞毒性很小，体外不会引起明显的溶血。SSMPEG-PCL 胶束的临界胶束浓度比 MPEG-PCL 胶束低五倍。Dox 通过 pH 诱导的自组装方法直接载入 SSMPEG-PCL 胶束。Dox 载药对 SSMPEG-PCL 胶束的粒径没有显著影响。载 Dox 的 SSMPEG-PCL（Dox/SSMPEG-PCL）胶束在体外缓慢释放 Dox，在 pH5.5 时的释放速度快于 pH7.0。此外，Dox 包封在 SSMPEG-PCL 胶束中增强了 Dox 的体外抗癌活性。进一步评价了 Dox/SSMPEG-PCL 对结肠癌小鼠模型的治疗效果。与游离 Dox 或对照组相比，Dox/SSMPEG-PCL 对肿瘤生长的抑制作用更显著（P<0.05），表明 Dox/SSMPEG-PCL 在体内增强了结肠癌的抗癌活性。末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）分析表明，Dox/SSMPEG-PCL 诱导的肿瘤细胞凋亡比游离 Dox 或对照组更多。这些结果表明，SSMPEG-PCL 胶束在阿霉素传递方面具有广阔的应用前景，可增强抗癌效果。
