双层多功能纳米载体靶向传输雄激素剥夺治疗和化疗药物协同治疗前列腺癌

At present, there are still many limitations in the androgen deprivation therapy (ADT) and chemotherapy of prostate cancer (PCa), such as, severe side effects, easily emerged drug resistance, and poor prognosis. In this aspect, the smartnanoscale drug delivery system provides a powerful strategy to solve these problems. This project is to prepare one kind of bilayer multifunctional drug delivery system to realize the on-demand release of ADT and chemotherapy drugs. In detail, the core of drug delivery system is the bicalutamide (BCL)- and docetaxel (DTX)-loaded disulfide-cross-linked poly(lactide-co-glycolide) (PLGA) nanoparticle, and the responsiveness is controlled by the density of disulfide bond. The shell is the erythrocyte membrane decorated with luteinizing hormone-releasing hormone (LHRH). This nanocarrier can not only improve the solubility and prolong the in vivo metabolism half-lives of drugs, but also realize the targeted release of BCL and DTX in tumor cells. As a result, the smart bilayer drug delivery systems reduce the systematic toxicity, reverse the drug resistance, and improve the treatment efficacies of drugs. In addition, we further fit the photosensitizer indocyanine green (ICG) or chlorin e6 (Ce6) to the erythrocyte membrane. The generated hyperthermia or reactive oxygen species (ROS) by them are utilized to disrupt the erythrocyte membrane, upregulate cell endocytosis and drug release, and improve the therapeutic effect. In summary, implementation of the project will provide a novel combined treatment strategy for PCa, especially the drug-resistant and advanced ones.

目前，前列腺癌雄激素剥夺治疗和化疗存在副作用大、易产生耐药性和治疗效果差等问题，而智能纳米载药体系为解决上述问题提供了有力的策略。本项目拟制备一类双层药物传输体系，实现雄激素剥夺治疗和化疗药物的“按需”释放。该体系内核为负载比卡鲁胺和多西他赛的二硫键连接的聚乙丙交酯（PLGA）纳米粒子，其响应性可以通过二硫键密度调节；外壳为嵌合促黄体生成激素释放激素（LHRH）的红细胞膜。该体系不仅改善了药物的溶解性和延长了代谢半衰期，而且实现了两种药物在肿瘤细胞内的靶向释放，从而降低了系统毒性、逆转了多药耐药性。此外，我们进一步将光敏剂吲哚菁绿和二氢卟吩e6分别嵌合到细胞膜外壳上，利用它们产生的过高热和活性氧类物质（ROS）破坏包被的红细胞膜，增加肿瘤细胞对纳米药物的内吞并加快药物的释放，进而提高治疗效果。本项目的实施将为前列腺癌，特别是耐药和晚期前列腺癌，提供新型的雄激素剥夺治疗和化疗联合治疗新策略。

前列腺癌雄激素剥夺治疗和化疗存在副作用大、易产生耐药性和治疗效果差等问题，而智能纳米载药体系为解决上述问题提供了有力的策略。申请人前期研究表明促黄体生成激素释放激素（Luteinizing hormone-releasing hormone，LHRH）修饰的纳米键合药物能够有效的靶向前列腺癌细胞，体内实验结果证明了其有效的体内抑瘤效果。本项目将在前期工作基础上，构建一种新型的双层纳米药物传输体系，利用具有还原响应性的聚氨基酸纳米凝胶负载化疗药物作为内核，红细胞膜负载光动力药物作为外壳，再将具有靶向前列腺癌细胞功能的LHRH镶嵌到红细胞膜表面，在延长纳米粒子血液循环时间的同时实现了药物的靶向传输，通过联合化疗和光动力治疗，实现有效抑制前列腺癌进展的目的。本项目的实施将为前列腺癌，特别是耐药和晚期前列腺癌，提供新型的化疗和光动力联合治疗新策略。