Construction of Targeting-Clickable and Tumor-Cleavable Polyurethane Nanomicelles for Multifunctional Intracellular Drug Delivery
Construction of Targeting-Clickable and Tumor-Cleavable Polyurethane Nanomicelles for Multifunctional Intracellular Drug Delivery
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用于多功能细胞内药物递送的靶向可点击和肿瘤可裂解的聚氨酯纳米胶束的构建
DOI：
10.1021/bm401342t
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发表时间：
2013-12-01
影响因子：
6.2
通讯作者：
Fu, Qiang
中科院分区：
文献类型：
--
作者：
Song, Nijia;Ding, Mingming;Fu, Qiang
构建多用途纳米载体以克服靶向递送的多重挑战是癌症治疗迫切需要的新策略。为了满足这些需求，我们开发了一种新的靶向可点击和肿瘤可切割的聚氨酯纳米胶束，用于多功能抗肿瘤药物的递送。该聚氨酯由可生物降解的聚己内酯（PCL）和l-赖氨酸乙酯二异氰酸酯（LDI）合成而成，并由一种新型的l-胱氨酸衍生扩链剂（Cys-PA）延伸，该扩链剂带有氧化还原反应的二硫键和可点击的炔基（Cys-PA），最后由一种具有高度ph敏感性的苯甲酸亚胺（BPEG）连接的可分离的甲氧基聚乙二醇（乙二醇）终止。获得的聚合物具有良好的自组装特性和刺激响应性，具有良好的细胞相容性和高的阿霉素（DOX）负载能力。此外，叶酸（FA）作为模型靶配体通过有效的点击反应与聚氨酯胶束结合。在体外实验中，FA修饰增强了细胞摄取，提高了对FA受体阳性HeLa癌细胞的药物疗效。作为概念验证，这项工作为设计用于肿瘤靶向和程序化细胞内药物递送的细胞外可激活纳米载体提供了一种简便的方法。
New strategies for the construction of versatile nanovehicles to overcome the multiple challenges of targeted delivery are urgently needed for cancer therapy. To address these needs, we developed a novel targeting-clickable and tumor-cleavable polyurethane nanomicelle for multifunctional delivery of antitumor drugs. The polyurethane was synthesized from biodegradable poly(epsilon-caprolactone) (PCL) and L-lysine ethyl ester diisocyanate (LDI), further extended by a new designed L-cystine-derivatized chain extender bearing a redox-responsive disulfide bond and clickable alkynyl groups (Cys-PA), and finally terminated by a detachable methoxyl-poly(ethylene glycol) with a highly pH-sensitive benzoic-imine linkage (BPEG). The obtained polymers show attractive self-assembly characteristics and stimuli-responsiveness, good cytocompatibility, and high loading capacity for doxorubicin (DOX). Furthermore, folic acid (FA) as a model targeting ligand was conjugated to the polyurethane micelles via an efficient click reaction. The decoration of FA results in an enhanced cellular uptake and improved drug efficacy toward FA-receptor positive HeLa cancer cells in vitro. As a proof-of-concept, this work provides a facile approach to the design of extracellularly activatable nanocarriers for tumor-targeted and programmed intracellular drug delivery.