Ministry of Education (MOE), Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou 310027, China.
College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China.
ACS Appl Mater Interfaces. 2018 Feb 14;10(6):5213-5226. doi: 10.1021/acsami.7b16891. Epub 2018 Jan 30.
pH-responsive polymersomes have emerged as promising nanocarriers for antitumor drugs to realize their fast release and action in a weakly acidic microenvironment of tumor cells. Herein, however, we designed a remarkably pH-responsive polymersome self-assembled from amphiphilic benzimidazole-based polyphosphazenes via the incorporation of cholesteryl hemisuccinate (CholHS), a type of cholesteric molecule, into the polymersome bilayers to inhibit the drug release during blood circulation. Actually, unwanted premature drug leakage before arriving at the acidic tumor site has become a serious problem for polymersomes encapsulating water-soluble drugs, especially when the drug loading is at a high level, thus limiting the therapeutic efficacy. In this study, polymersomes displayed high loading capability of doxorubicin hydrochloride as 12.83%. More importantly, CholHS incorporation decreased the membrane permeability of the polymersome and effectively retarded the cargo release under physiological conditions but induced the fast drug-release rate at pH 5.5, demonstrating a more remarkably acid-responsive release behavior when compared to that of the CholHS-free polymersomes. Further in vivo investigations including pharmacokinetic and antitumor activity studies verified the extended circulation time and enhanced antitumor efficacy of the drug-loaded CholHS-incorporated polymersomes.
pH 响应聚合物囊泡作为抗肿瘤药物的载体具有广阔的应用前景，因为它们能够在肿瘤细胞的弱酸性微环境中快速释放药物并发挥作用。然而，在这里，我们设计了一种由两亲性苯并咪唑基聚膦腈通过在聚合物囊泡双层中掺入胆甾醇琥珀酸半酯（CholHS）自组装而成的具有显著 pH 响应性的聚合物囊泡。CholHS 是一种胆甾醇分子，它可以抑制药物在血液循环过程中的释放。实际上，对于包载水溶性药物的聚合物囊泡来说，在到达酸性肿瘤部位之前过早地释放药物已经成为一个严重的问题，尤其是当药物载药量较高时，这限制了其治疗效果。在这项研究中，聚合物囊泡对盐酸多柔比星的载药量高达 12.83%。更重要的是，CholHS 的掺入降低了聚合物囊泡的膜通透性，并在生理条件下有效地延缓了货物的释放，但在 pH 值为 5.5 时诱导了快速的药物释放速率，与不含 CholHS 的聚合物囊泡相比，表现出更显著的酸响应释放行为。进一步的体内研究，包括药代动力学和抗肿瘤活性研究，验证了载药 CholHS 掺入聚合物囊泡的延长循环时间和增强的抗肿瘤功效。
