肿瘤pH响应药物结合的胶束从纤维碎片的肿瘤内化学疗法释放。,ACS Applied Materials & Interfaces

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肿瘤pH响应药物结合的胶束从纤维碎片的肿瘤内化学疗法释放。
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2017-09-13 00:00:00 , DOI: 10.1021/acsami.7b09519
Nan He ₁ , Zhoujiang Chen ₁ , Jiang Yuan ₁ , Long Zhao ₁ , Maohua Chen ₁ , Tao Wang ₁ , Xiaohong Li ₁

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胶束的肿瘤积累对于增强细胞摄取和延长化学治疗剂的释放是必不可少的。在先前的研究中，喜树碱（CPT）偶联的胶束（M _CPT）具有二硫键和叶酸部分，可用于还原敏感性释放和细胞选择性摄取。本研究提出的promicelle聚合物（PM集成的策略_CPT）成纤维碎片用于瘤内注射，实现PM的酸容易释放_CPT响应于酸性肿瘤微环境和自发自组装成M _CPT。酸敏感的2-丙-3-甲基马来酸酐（CDM）连接的聚乙二醇引发dl的开环聚合-丙交酯作为纤维基质。在pH 6.5缓冲液中孵育40天后，没有明显的M _CPT从纤维碎片中突然释放，并且累积释放的80％左右。与通过溶剂蒸发新鲜制备的M _CPT相比，从纤维碎片释放的胶束具有相似的特征，例如叶酸介导的细胞摄取和谷胱甘肽敏感性药物释放。利用四苯乙烯（TPE）衍生物，TPE共轭胶束（M _TPE）的聚集诱导发射（AIE）效应）已成功用于追踪自纤维释放后的自组装成胶束，随后细胞内化到细胞质中。瘤内注射纤维碎片后也检测到自组装诱导的荧光点亮。与载有CPT的纤维片段和瘤内或静脉内注射游离M _CPT相比，纤维片段的持续释放和胶束在肿瘤中的高积累导致对肿瘤生长的抑制作用明显提高，动物存活时间延长，并诱导肿瘤细胞凋亡。因此，将双重靶向和双重刺激响应性整合到破碎的纤维中提供了可行的策略，以实现从纤维中持续释放胶束并促进治疗功效。

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Tumor pH-Responsive Release of Drug-Conjugated Micelles from Fiber Fragments for Intratumoral Chemotherapy

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_CPT) 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_CPT) into fiber fragments for intratumoral injection, realizing acid-liable release of PM_CPT in response to acidic tumor microenvironment and spontaneous self-assembly into M_CPT. 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_CPT from fiber fragments and around 80% of accumulated releases after incubation in pH 6.5 buffers for 40 days. Compared to M_CPT 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_TPE) 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_CPT, 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.

更新日期：2017-09-14

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