Graduate Institute of Applied Science and Technology , National Taiwan University of Science and Technology , Taipei 10607 , Taiwan.
Department of Materials Science and Engineering , National Taiwan University of Science and Technology , Taipei 10607 , Taiwan.
Biomacromolecules. 2018 Jul 9;19(7):2772-2781. doi: 10.1021/acs.biomac.8b00380. Epub 2018 Apr 26.
Self-assembled pH-responsive polymeric micelles, a combination of hydrophilic poly(ethylene glycol) segments and hydrogen bonding interactions within a biocompatible polyurethane substrate, can spontaneously self-assemble into highly controlled, nanosized micelles in aqueous solution. These newly developed micelles exhibit excellent pH-responsive behavior and biocompatibility, highly controlled drug (doxorubicin; DOX) release behavior, and high drug encapsulation stability in different aqueous environments, making the micelles highly attractive potential candidates for safer, more effective drug delivery in applications such as cancer chemotherapy. In addition, in vitro cell studies revealed the drug-loaded micelles possessed excellent drug entrapment stability and low cytotoxicity toward macrophages under normal physiological conditions (pH 7.4, 37 °C). When the pH of the culture media was reduced to 6.0 to mimic the acidic tumor microenvironment, the drug-loaded micelles triggered rapid release of DOX within the cells, which induced potent antiproliferative and cytotoxic effects in vitro. Importantly, fluorescent imaging and flow cytometric analyses confirmed the DOX-loaded micelles were efficiently delivered into the cytoplasm of the cells via endocytosis and then subsequently gradually translocated into the nucleus. Therefore, these multifunctional micelles could serve as delivery vehicles for precise, effective, controlled drug release to prevent accumulation and activation of tumor-promoting tumor-associated macrophages in cancer tissues. Thus, this unique system may offer a potential route toward the practical realization of next-generation pH-responsive therapeutic delivery systems.
自组装 pH 响应性聚合物胶束，是由亲水性聚乙二醇链段和生物相容性聚氨酯基质内氢键相互作用结合而成，可在水溶液中自发组装成高度可控的纳米级胶束。这些新开发的胶束表现出优异的 pH 响应性和生物相容性、高度可控的药物（阿霉素；DOX）释放行为，以及在不同水相环境中高的药物包封稳定性，使胶束成为更安全、更有效的药物递送应用（如癌症化疗）的有吸引力的候选者。此外，体外细胞研究表明，载药胶束在正常生理条件（pH7.4，37°C）下对巨噬细胞具有优异的药物包封稳定性和低细胞毒性。当培养基的 pH 值降低至 6.0 以模拟酸性肿瘤微环境时，载药胶束会在细胞内引发 DOX 的快速释放，从而在体外产生强大的抗增殖和细胞毒性作用。重要的是，荧光成像和流式细胞术分析证实，载 DOX 的胶束通过内吞作用有效地递送到细胞的细胞质中，随后逐渐转移到细胞核中。因此，这些多功能胶束可用作精确、有效、控制药物释放的递药载体，以防止肿瘤促进的肿瘤相关巨噬细胞在癌症组织中的积累和激活。因此，该独特系统可能为下一代 pH 响应性治疗递药系统的实际实现提供了一条潜在途径。
