Acid-active supramolecular anticancer nanoparticles based on cyclodextrin polyrotaxanes damaging both mitochondria and nuclei of tumor cells
Acid-active supramolecular anticancer nanoparticles based on cyclodextrin polyrotaxanes damaging both mitochondria and nuclei of tumor cells
复制标题
基于环糊精聚轮烷的酸活性超分子抗癌纳米颗粒同时损伤肿瘤细胞的线粒体和细胞核
DOI：
10.1039/c8bm01020j
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发表时间：
2018-12-01
影响因子：
6.6
通讯作者：
Xu, Zhigang
中科院分区：
文献类型：
--
作者：
Bai, Shuang;Zhang, Xiaoli;Xu, Zhigang
作为一种超分子大环聚合物，环糊精（CD）聚轮烷（PRs）在开发纳米药物方面具有诸多优势，例如化学成分稳定、具有丰富的官能化羟基、能够跨越生物屏障、纳米粒子尺寸可调节以及良好的生物相容性。在此，我们合成了一类酸激活治疗性纳米粒子，它由一种基于α - CD的PR聚合物前药组成，即聚轮烷 - 聚（阿霉素） - 共 - 聚[（乙二醇）甲醚甲基丙烯酸酯]（PR - PDOX - co - POEGMA，记为PRMO@DOX），以减少药物泄漏并选择性地将药物递送至肿瘤细胞，旨在实现超分子疗法的最大治疗效果。所获得的PRMO@DOX显示出理想的特性，包括高载药率（>25 wt%）、快速的细胞摄取、酸激活控制释放、有效的抗肿瘤活性以及低全身毒性。得益于其独特的两亲性纳米结构，PRMO@DOX能够在水性介质中形成水溶性前药纳米粒子。前药中的酸激活腙键能够在酸性肿瘤微环境下断裂，从而精确且及时地释放药物分子，损伤肿瘤细胞的细胞核和线粒体。体外和体内实验都清楚地表明了这种治疗平台具有显著的抗肿瘤功效，这为开发基于聚轮烷的纳米药物以增强癌症治疗提供了一种新策略。
As a supramolecular macrocyclic polymer, cyclodextrin (CD) polyrotaxanes (PRs) have many advantages for developing nanomedicines, such as stable chemical composition, abundant functionalized hydroxyl groups, moving across biological barriers, adjustable nanoparticle size and good biocompatibility. Herein, we synthesized a class of acid-active therapeutic nanoparticles comprising a alpha-CD-based PR polymeric prodrug of PRs-poly(doxorubicin)-co-poly[(ethylene glycol) methyl ether methacrylate] (PR-PDOX-co-POEGMA, denoted as PRMO@DOX) to reduce drug leakage and selectively deliver drugs into tumor cells, aiming to achieve maximal treatment efficacy of supramolecular therapeutics. The obtained PRMO@DOX showed desirable features of high drug loading rates (> 25 wt%), fast cellular uptake, acid-active controlled release, effective anti-tumor activity and low systemic toxicity. Benefiting from its unique amphiphilic nanostructure, PRMO@DOX can form water-soluble prodrug nanoparticles in aqueous media. The acid-active hydrazone bond in the prodrug can break and thus release drug molecules precisely and in a timely manner under an acidic tumor microenvironment, damaging the nuclei and mitochondria of tumor cells. Both in vitro and in vivo experiments clearly demonstrated a remarkable antitumor efficacy of this therapeutic platform, which provided a new strategy for the development of polyrotaxane-based nano-medicine for enhanced cancer therapy.