MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
Biomaterials. 2017 Mar;121:41-54. doi: 10.1016/j.biomaterials.2017.01.002. Epub 2017 Jan 3.
Undesired physiological instability of nanocarriers and premature drug leakage during blood circulation result in compromised therapeutic efficacy and severe side effects, which have significantly impeded the development of nanomedicine. Facile crosslinking of drug-loaded nanocarriers while keeping the potency of site-specific degradation and drug release has emerged as a viable strategy to overcome these drawbacks. Additionally, combination therapy has already shown advantages in inhibiting advanced tumors and life extension than single drug therapy. Herein, three kinds of diselenide-rich polymers were fabricated with distinct hydrophobic side chains. The component effect was interrogated to screen out PEG-b-PBSe diblock copolymer due to its favorable self-assembly controllability and high drug loading of camptothecin (CPT) and doxorubicin (DOX) that had synergistic antitumor property. Facile visible light-induced diselenide metathesis and regeneration was employed to crosslink nanocarriers for the first time. The dual drug-loaded crosslinked micelles (CPT/DOX-CCM) were stable in physiological conditions with minimal drug leakage, possessing extended blood circulation, whereas hand-in-hand dual drug release was significantly accelerated in tumor's redox microenvironments. In vitro cytotoxicity evaluation and in vivo tumor suppression with low dosage drugs further demonstrated the favorable potency of the redox-responsive nanoplatform in tumor combination chemotherapy.
纳米载体在血液循环过程中出现的非理想生理不稳定性和药物过早泄漏，导致治疗效果受损和严重的副作用，这极大地阻碍了纳米医学的发展。在保持靶向降解和药物释放效力的同时，实现载药纳米载体的简便交联，已成为克服这些缺陷的可行策略。此外，联合治疗在抑制晚期肿瘤和延长寿命方面已经显示出优于单一药物治疗的优势。在此，我们制备了三种富二硒聚合物，它们具有不同的疏水侧链。通过成分效应的研究，筛选出 PEG-b-PBSe 两亲嵌段共聚物，因其具有良好的自组装可控性和较高的喜树碱（CPT）和阿霉素（DOX）载药量，且具有协同抗肿瘤特性。我们首次采用简便的可见光诱导二硒键交换和再生来交联纳米载体。载双药的交联胶束（CPT/DOX-CCM）在生理条件下稳定，药物泄漏最小，具有延长的血液循环时间，而在肿瘤的氧化还原微环境中，双药的协同释放明显加速。体外细胞毒性评估和体内低剂量药物肿瘤抑制进一步证明了该氧化还原响应纳米平台在肿瘤联合化疗中的良好疗效。
