Abstract

Acidic tumor microenvironment has been extensively explored to design pH-responsive paclitaxel prodrug micelles for cancer therapy. The object of this study is to investigate the pH-responsive drug release behavior and the anti-proliferation capacity of acetal-linked paclitaxel polymeric prodrug micelles. The prodrug was synthesized and evaluated for paclitaxel content. The prodrug micelles were fabricated and characterized for morphology, size, in vitro pH-responsive paclitaxel release, cellular uptake, and anti-proliferation. Paclitaxel content was 33 wt%. The prodrug micelles exhibited spherical structure with the hydrodynamic diameter of 154 nm. Besides, the in vitro paclitaxel release behavior was verified to be pH-responsive, and 77%, 38%, and 17% of parent free paclitaxel was released from the nano-sized prodrug micelles in 13 h at pH 5.5, 6.5, and 7.4, respectively. The cellular uptake assessment demonstrated the time-dependent internalization of prodrug micelles. Meanwhile, CCK-8 analysis showed that prodrug micelles possessed the potent anti-proliferation effects. Prodrug micelles based on aliphatic polycarbonates present a promising platform for cancer chemotherapy due to the pH-responsive characteristics of acetal bond, potent anti-proliferation effects, and outstanding cytocompatibility of aliphatic polycarbonates.

摘要

酸性肿瘤微环境已被广泛探索以设计用于癌症治疗的 pH 响应性紫杉醇前药胶束。本研究的目的是研究与缩醛相连的紫杉醇聚合物前药胶束的 pH 响应性药物释放行为和抗增殖能力。合成前药并评估紫杉醇含量。制备前药胶束并表征其形态、大小、体外pH 响应性紫杉醇释放、细胞摄取和抗增殖。紫杉醇含量为33重量％。前药胶束呈球形结构，流体动力学直径为 154 nm。此外，体外紫杉醇的释放行为被证实是 pH 响应性的，在 pH 5.5、6.5 和 7.4 下，13 小时内分别有 77%、38% 和 17% 的母体游离紫杉醇从纳米级前药胶束中释放出来。细胞摄取评估证明了前药胶束的时间依赖性内化。同时，CCK-8分析表明前药胶束具有有效的抗增殖作用。基于脂肪族聚碳酸酯的前药胶束由于缩醛键的 pH 响应特性、有效的抗增殖作用和脂肪族聚碳酸酯出色的细胞相容性，为癌症化疗提供了一个有前景的平台。