State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Nanoscale. 2012 May 21;4(10):3095-104. doi: 10.1039/c2nr30278k. Epub 2012 Apr 25.
In this work, we aim to develop a dual drug delivery system (DDDS) of self-assembled micelles in thermosensitive hydrogel composite to deliver hydrophilic and hydrophobic drugs simultaneously for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administered to form micelles or thermosensitive hydrogels, respectively. Therefore, the DDDS was constructed from paclitaxel (PTX) encapsulated PCEC micelles (PTX-micelles) and a fluorouracil (Fu) loaded thermosensitive PCEC hydrogel (Fu-hydrogel). PTX-micelles were prepared by self-assembly of biodegradable PCEC copolymer (M(n) = 3700) and PTX without using any surfactants or excipients. Meanwhile, biodegradable and injectable thermosensitive Fu-hydrogel (M(n) = 3000) with a lower sol-gel transition temperature at around physiological temperature was also prepared. The obtained PTX-micelles in thermosensitive Fu-hydrogel (PTX-micelles-Fu-hydrogel) composite is a free-flowing sol at ambient temperature and rapidly turned into a non-flowing gel at physiological temperature. In addition, the results of cytotoxicity, hemolytic study, and acute toxicity evaluation suggested that the PTX-micelles-Fu-hydrogel was non-toxic and biocompatible. In vitro release behaviors of PTX-micelles-Fu-hydrogel indicated that both PTX and Fu have a sustained release behavior. Furthermore, intraperitoneal application of PTX-micelles-Fu-hydrogel effectively inhibited growth and metastasis of CT26 peritoneal carcinomatosis in vivo (p < 0.001), and induced a stronger antitumor effect than that of Taxol® plus Fu (p < 0.001). The pharmacokinetic study indicated that PTX-micelles-Fu-hydrogel significantly increased PTX and Fu concentration and residence time in peritoneal fluids compared with Taxol® plus Fu group. Thus, the results suggested the micelles-hydrogel DDDS may have great potential clinical applications.
在这项工作中，我们旨在开发一种自组装胶束的温敏水凝胶复合双重药物递送系统（DDDS），以同时递送亲水性和疏水性药物，用于结直肠腹膜癌转移（CRPC）的治疗。在我们之前的研究中，我们发现具有不同分子量和 PEG/PCL 比的聚（ε-己内酯）-聚（乙二醇）-聚（ε-己内酯）（PCEC）共聚物可以分别给药以形成胶束或温敏水凝胶。因此，DDDS 由紫杉醇（PTX）包封的 PCEC 胶束（PTX-胶束）和载有氟尿嘧啶（Fu）的温敏 PCEC 水凝胶（Fu-水凝胶）组成。PTX-胶束通过自组装可生物降解的 PCEC 共聚物（M(n) = 3700）和 PTX 制备，而无需使用任何表面活性剂或赋形剂。同时，还制备了具有较低溶胶-凝胶转变温度（约生理温度）的可生物降解和可注射的温敏 Fu-水凝胶（M(n) = 3000）。在环境温度下，所得的 PCEC 共聚物（M(n) = 3700）和 PTX 自组装而成的 PTX-胶束在温敏 Fu-水凝胶（PTX-胶束-Fu-水凝胶）复合材料中是自由流动的溶胶，而在生理温度下迅速转变为非流动的凝胶。此外，细胞毒性、溶血研究和急性毒性评价的结果表明，PTX-胶束-Fu-水凝胶无毒性且生物相容性良好。PTX-胶束-Fu-水凝胶的体外释放行为表明，PTX 和 Fu 均具有持续释放行为。此外，PTX-胶束-Fu-水凝胶的腹腔内应用有效地抑制了 CT26 腹膜癌转移在体内的生长和转移（p < 0.001），并诱导了比 Taxol®加 Fu 更强的抗肿瘤作用（p < 0.001）。药代动力学研究表明，与 Taxol®加 Fu 组相比，PTX-胶束-Fu-水凝胶显著增加了腹腔液中 PTX 和 Fu 的浓度和驻留时间。因此，结果表明胶束-水凝胶 DDDS 可能具有巨大的临床应用潜力。
