State Key Laboratory of Natural Medicines, Department of Pharmaceutics , China Pharmaceutical University , 24 Tongjiaxiang , Nanjing 210009 , China.
Department of Pharmaceutics , Guizhou Medical University , Huaxi University Town , Guian new district, Guiyang 550025 , Guizhou , People's Republic of China.
ACS Appl Mater Interfaces. 2018 Oct 24;10(42):35693-35704. doi: 10.1021/acsami.8b09342. Epub 2018 Oct 11.
Currently, tumor-targeted nanocarriers self-assembled from amphiphilic polymer-drug conjugates are of great demand. The appeal of these carriers arises mainly through their excellent loading efficiency of homologous drug molecules with microenvironment-triggered drug release. Herein, doxorubicin (DOX) was constructed to a hyaluronic acid (HA) backbone through hydrazone and disulfide linkages to construct pH and reduction coresponsive prodrug conjugates (HA-ss-DOX). During formulation, the amphipathic HA-ss-DOX spontaneously assembled into distinct core/shell micelles in aqueous media and showed conspicuous physical DOX loading capabilities (29.1%, DOX/HA-ss-DOX) based on homologous compatibility. DOX/HA-ss-DOX micelles were shown to be stable in normal physiological environments, while accomplishing selective, rapid DOX release at acidic pH and/or highly reducing conditions. The efficacy of DOX/HA-ss-DOX micelles was tested on A549 human lung cancer cells, wherein flow cytometry and confocal microscopy analysis revealed their HA receptor-mediated endocytosis mechanism. In comparison, DOX-loaded redox-insensitive micelles (DOX/HA-DOX) still demonstrated pH-dependent drug release. However, a more rapid intracellular DOX release profile was achieved in DOX/HA-ss-DOX micelles because of their sensitivity to both acidic and reducing environments. Resultantly, DOX/HA-ss-DOX exhibited the strongest cytotoxicity and apoptosis-inducing ability among all tested groups when tested on an A549 cell line and xenograft model.
目前，由两亲性聚合物-药物偶联物自组装而成的肿瘤靶向纳米载体需求量很大。这些载体之所以具有吸引力，主要是因为它们具有极好的同源药物分子的载药效率，并具有微环境触发的药物释放。在这里，阿霉素（DOX）通过腙键和二硫键连接到透明质酸（HA）主链上，构建了 pH 和还原双重响应前药偶联物（HA-ss-DOX）。在制剂过程中，两亲性 HA-ss-DOX 可在水介质中自发组装成明显的核/壳型胶束，并表现出明显的物理 DOX 载药能力（29.1%，DOX/HA-ss-DOX），这是基于同源相容性。DOX/HA-ss-DOX 胶束在正常生理环境中稳定，而在酸性 pH 和/或高度还原条件下能选择性、快速地释放 DOX。将 DOX/HA-ss-DOX 胶束用于 A549 人肺癌细胞的功效测试中，流式细胞术和共聚焦显微镜分析显示了其 HA 受体介导的内吞作用机制。相比之下，载 DOX 的氧化还原不敏感胶束（DOX/HA-DOX）仍表现出 pH 依赖性药物释放。然而，由于 DOX/HA-ss-DOX 对酸性和还原环境均敏感，因此在 DOX/HA-ss-DOX 胶束中实现了更快的细胞内 DOX 释放。因此，在 A549 细胞系和异种移植模型上进行测试时，DOX/HA-ss-DOX 表现出最强的细胞毒性和诱导凋亡能力。
