Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University , Chengdu 610031, P. R. China.
ACS Appl Mater Interfaces. 2017 Sep 27;9(38):32534-32544. doi: 10.1021/acsami.7b09519. Epub 2017 Sep 13.
The tumor accumulation of micelles is essential to enhance the cellular uptake and extend the release of chemotherapeutic agents. In the previous study camptothecin (CPT)-conjugated micelles (M) were constructed with disulfide linkages and folate moieties for reduction-sensitive release and cell-selective uptake. This study proposes a strategy to integrate the promicelle polymers (PM) into fiber fragments for intratumoral injection, realizing acid-liable release of PM in response to acidic tumor microenvironment and spontaneous self-assembly into M. Acid-liable 2-propionic-3-methylmaleic anhydride (CDM)-linked poly(ethylene glycol) initiates the ring-opening polymerization of dl-lactide as the fiber matrix. There is no apparent burst release of M from fiber fragments and around 80% of accumulated releases after incubation in pH 6.5 buffers for 40 days. Compared to M freshly prepared via solvent evaporation, the micelles released from fiber fragments reveal similar profiles, such as folate-mediated cellular uptake and glutathione-sensitive drug release. Taking advantage of the aggregation-induced emission (AIE) effect of tetraphenylethylene (TPE) derivatives, TPE-conjugated micelles (M) have been successfully been used to track the self-assembly into micelles after release from fibers and subsequent cell internalization into cytosol. The self-assembly induced fluorescence light-up was also detected after intratumoral injection of fiber fragments. Compared with CPT-loaded fiber fragments and intratumoral or intravenous injection of free M, the sustained release from fiber fragments and high accumulation of micelles in tumors result in significantly higher inhibition of tumor growths, prolongation of animal survival, and induction of tumor cell apoptosis. Thus, the integration of double targeting and double stimuli responsiveness into fragmented fibers provides a feasible strategy to realize the sustained micelle release from fibers and promote the therapeutic efficacy.
胶束的肿瘤积累对于增强细胞摄取和延长化疗药物的释放至关重要。在之前的研究中，通过二硫键和叶酸部分构建了喜树碱（CPT）缀合胶束（M），用于还原敏感释放和细胞选择性摄取。本研究提出了一种将前药聚合物（PM）整合到纤维片段中的策略，用于肿瘤内注射，实现了 PM 在酸性肿瘤微环境下的酸响应释放，并自发自组装成 M。酸敏感的 2-丙稀-3-甲基马来酸酐（CDM）连接的聚乙二醇引发 dl-丙交酯的开环聚合，作为纤维基质。纤维片段中没有明显的 M 突释，在 pH6.5 的缓冲液中孵育 40 天后，约 80%的累积释放。与通过溶剂蒸发新制备的 M 相比，从纤维片段释放的胶束显示出相似的特性，如叶酸介导的细胞摄取和谷胱甘肽敏感的药物释放。利用四苯乙烯（TPE）衍生物的聚集诱导发射（AIE）效应，成功地将 TPE 缀合的胶束（M）用于跟踪从纤维释放后自组装成胶束以及随后进入细胞质的细胞内化。在纤维片段的肿瘤内注射后，也检测到了自组装诱导的荧光点亮。与 CPT 负载的纤维片段以及肿瘤内或静脉内注射游离 M 相比，纤维片段的持续释放和大量的胶束在肿瘤中的积累导致肿瘤生长的显著抑制、动物存活时间的延长和肿瘤细胞凋亡的诱导。因此，将双重靶向和双重刺激响应整合到纤维碎片中提供了一种可行的策略，可实现纤维的持续胶束释放并提高治疗效果。
