State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Colloids Surf B Biointerfaces. 2013 Jun 1;106:93-101. doi: 10.1016/j.colsurfb.2013.01.047. Epub 2013 Feb 4.
In this work, we developed a biodegradable and injectable composite drug delivery system (DDS), camptothecine (CPT) loaded polymeric microsphere in thermosensitive hydrogel, for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administrated to form microsphere or thermosensitive hydrogel, respectively. Therefore, the composite DDS was composed of CPT loaded microsphere (CPT-MS) and thermosensitive hydrogel. CPT-MS was prepared by CPT and PCEC copolymer (Mn=31,600) using an oil-in-water emulsion solvent evaporation method. Besides, biodegradable and injectable thermosensitive PCEC hydrogel (Mn=3150) with lower sol-gel transition temperature at around body temperature was also prepared. The CPT-MS in thermosensitive hydrogel (CPT-MS/hydrogel) composite is a free-flowing sol at ambient temperature and instantly converts into a non-flowing gel at body temperature. Furthermore, cytotoxicity assay indicated that both microsphere and hydrogel were biocompatible with very low cytotoxicity. In vitro release profile demonstrated a significant difference between rapid release of free CPT and much slower and sustained release of CPT-MS/hydrogel. In addition, intraperitoneal administration of CPT-MS/hydrogel could effectively suppress growth and metastasis of CT26 peritoneal carcinomatosis in vivo, and prolonged the survival of tumor bearing mice. Compared with CPT-MS or free CPT, CPT-MS/hydrogel induced a stronger anti-tumor effect by increasing apoptosis of tumor cells and inhibiting microvessel density of tumor tissue. Besides, side effects of CPT were also alleviated in CPT-MS/hydrogel-treated mice. Thus, our results suggested that CPT-MS/hydrogel may have great potential applications in clinic.
在这项工作中，我们开发了一种可生物降解和可注射的复合药物输送系统（DDS），即载有喜树碱（CPT）的聚合物微球在温敏水凝胶中，用于结直肠腹膜转移癌（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）（PCL-PEG-PCL，PCEC）共聚物可以分别被给药形成微球或温敏水凝胶。因此，复合 DDS 由载有喜树碱的微球（CPT-MS）和温敏水凝胶组成。CPT-MS 通过 CPT 和 PCEC 共聚物（Mn=31,600）采用油包水乳状液溶剂蒸发法制备。此外，还制备了具有更低溶胶-凝胶转变温度（接近体温）的可生物降解和可注射温敏 PCEC 水凝胶（Mn=3150）。CPT-MS 在温敏水凝胶（CPT-MS/水凝胶）中的复合在环境温度下是自由流动的溶胶，在体温下会立即转变为不可流动的凝胶。此外，细胞毒性试验表明微球和水凝胶均具有生物相容性，细胞毒性非常低。体外释放曲线表明，游离 CPT 的快速释放与 CPT-MS/水凝胶的更慢和持续释放之间存在显著差异。此外，腹腔内给予 CPT-MS/水凝胶可以有效抑制 CT26 腹膜转移瘤的生长和转移，并延长荷瘤小鼠的存活时间。与 CPT-MS 或游离 CPT 相比，CPT-MS/水凝胶通过增加肿瘤细胞凋亡和抑制肿瘤组织微血管密度，诱导更强的抗肿瘤作用。此外，CPT 引起的副作用在 CPT-MS/水凝胶治疗的小鼠中也得到了缓解。因此，我们的研究结果表明，CPT-MS/水凝胶可能具有很大的临床应用潜力。
