State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Biomedical Materials and Engineering Research Center of Hubei Province, Wuhan University of Technology, Wuhan 430070, China.
School of Materials Science and Engineering, Wuhan University of Technology, Wuhan 430070, China.
Biomacromolecules. 2023 Sep 11;24(9):4303-4315. doi: 10.1021/acs.biomac.3c00702. Epub 2023 Aug 16.
Stimuli-responsive polymer nanocarriers, capable of exploiting subtle changes in the tumor microenvironment for controlled drug release, have gained significant attention in cancer therapy. Notably, NAD(P)H: quinone oxidoreductase 1 (NQO1), found to be upregulated in various solid tumors, represents a promising therapeutic target due to its effective capability to enzymatically reduce trimethyl-locked (TML) benzoquinone structures in a physiological condition. In this study, a novel redox-sensitive carbonate monomer, MTC, was synthesized, and its amphiphilic block copolymers were prepared through ring-opening polymerization. By successfully self-assembling poly(ethylene glycol)--PMTC micelles, the model drug doxorubicin (DOX) was encapsulated with high efficiency. The micelles exhibited redox-responsive behavior, leading to rapid drug release. In vitro assessments confirmed their excellent biocompatibility and hemocompatibility. Furthermore, the inhibition of the NQO1 enzyme reduced drug release in NQO1-overexpressed cells but not in control cells, resulting in decreased cytotoxicity in the presence of NQO1 enzyme inhibitors. Overall, this study showcases the potential of MTC-based polycarbonate micelles to achieve targeted and specific drug release in the NQO1 enzyme-mediated tumor microenvironment. Therefore, the self-assembly of MTC-based polymers into nanomicelles holds immense promise as intelligent nanocarriers in drug delivery applications.
刺激响应性聚合物纳米载体能够利用肿瘤微环境中的微妙变化来控制药物释放，在癌症治疗中受到了广泛关注。值得注意的是，在各种实体瘤中发现上调的烟酰胺腺嘌呤二核苷酸（磷酸）：醌氧化还原酶 1（NQO1）由于其在生理条件下有效还原三甲基锁定（TML）苯醌结构的能力，成为有前途的治疗靶点。在这项研究中，合成了一种新型氧化还原敏感的碳酸酯单体 MTC，并通过开环聚合制备了其两亲嵌段共聚物。通过成功地自组装聚乙二醇 - PMTC 胶束，高效地封装了模型药物阿霉素（DOX）。胶束表现出氧化还原响应行为，导致药物快速释放。体外评估证实了它们具有良好的生物相容性和血液相容性。此外，抑制 NQO1 酶可减少 NQO1 过表达细胞中的药物释放，但不能减少对照细胞中的药物释放，因此在存在 NQO1 酶抑制剂的情况下降低了细胞毒性。总体而言，这项研究展示了基于 MTC 的聚碳酸酯胶束在 NQO1 酶介导的肿瘤微环境中实现靶向和特异性药物释放的潜力。因此，基于 MTC 的聚合物自组装成纳米胶束作为智能纳米载体在药物输送应用中具有巨大的潜力。
