一种兼具靶向、活性氧自由基响应性的聚前药载体非侵袭性协同治疗帕金森病的研究

Parkinson’s disease (PD) is a serious threat to the health and life of the elderly. With the aggravation of aging population in China, the research on PD treatment becomes more and more important. Mesenchymal stem cell (MSC)-derived exosome can serve as a powerful drug carrier of neuroprotective drug curcumin for synergistic therapy of PD and bypass the intrinsic deficiencies and monotherapy limitation of curcumin. However, there are some bottlenecks of MSC-derived exosome, including how to achieve the high accumulation of drug in target cell and noninvasive synergistic therapy of PD. To overcome these problems, a polyprodrug carrier with targeting and reactive oxygen species (ROS)-responsive ability is developed for noninvasive synergistic therapy of PD. The carrier takes targeted MSC-derived exosome as the shell and ROS-responsive polyCurcumin prodrug nanoparticle as the inner core. The advantages of the carrier are as following: (1) The carrier can efficiently cross the nasal mucosa and enter the brain after noninvasive nasal administration. (2) The carrier can release the inner core of polyCurcumin prodrug nanoparticle into the cytoplasm of dopaminergic neuron via the targeting peptide RVG29 and the membrane fusion capacity of exosome. (3) The inner core of polyCurcumin prodrug nanoparticle is controlled release of free curcumin under high ROS microenvironment in the cytoplasm of dopaminergic neuron of PD. The curcumin and miR-133b of MSC-derived exosome can then play a synergistic role for effective treatment of PD. Furthermore, the mechanism of treatment will be elucidated. Based on the above research, the optimized drug carrier will be exploited as a safe and efficient treatment of PD.

帕金森病严重威胁着中老年人的健康和生命，随着我国人口老龄化加剧，帕金森病的治疗研究越发重要。采用间充质干细胞（mesenchymal stem cell，MSC）来源外泌体负载姜黄素的帕金森病协同治疗策略，克服了姜黄素自身性质不足和单一药物治疗局限性。然而，如何实现药物靶细胞高效富集的帕金森病非侵袭性协同治疗是MSC来源外泌体面临的瓶颈问题。针对这些问题，项目拟构建一种兼具靶向、活性氧自由基响应性的聚前药载体。载体以靶向性的MSC来源外泌体为外壳，以活性氧自由基响应的聚姜黄素前药纳米颗粒为内核，具有以下优势：（1）非侵袭性鼻腔给药后高效快速入脑；（2）靶向释放药物内核进入多巴胺能神经元；（3）药物内核在细胞高活性氧自由基条件可控释放姜黄素，与外泌体的miR-133b协同治疗帕金森病。项目通过对载体结构与药效的评价及治疗机理的阐释，有望获得一种安全、高效的帕金森病治疗载体。

帕金森病（PD）是一种常见的神经退行性疾病，严重威胁着中老年人的健康和生命，随着我国人口老龄化加剧，PD的治疗研究越发重要。PD的主要病理特征是α-突触核蛋白（α-syn）在中脑黑质多巴胺能神经元内异常聚集。采用神经保护类药物姜黄素可以降低α-syn聚集体的神经毒性，然而姜黄素自身性质不足和单一药物治疗局限性限制其应用。采用间充质干细胞（MSC）源外泌体负载姜黄素的帕金森病协同治疗策略可以克服以上不足。然而，由于存在多重膜屏障，如何实现药物靶细胞高效富集的帕金森病非侵袭性协同治疗是MSC源外泌体面临的瓶颈问题。针对这些问题，项目成功构建了兼具靶向、活性氧自由基（ROS）响应性的药物载体。载体以穿膜肽（P）和狂犬病病毒糖蛋白肽（RVG29）修饰的靶向性MSC源外泌体为外壳，以ROS响应的聚硫化丙烯-聚乙二醇（PPS-PEG）负载的姜黄素纳米颗粒为内核。体外和体内实验证明，经鼻给药后，载体利用MSC源外泌体外壳的靶向性、病灶迁移性和膜融合性，跨越鼻黏膜、多巴胺能神经元细胞膜和内涵体/溶酶体膜屏障，提高了药物内核在目标细胞多巴胺能神经元胞质的富集。在病变多巴胺能神经元胞质高ROS微环境，药物内核可控释放姜黄素。实验证明载体三管齐下协同治疗PD，姜黄素可以有效清除α-syn聚集体，MSC源外泌体含有的miR-133b促进神经元轴突生长和功能恢复，且随着α-syn聚集体的减少和MSC源外泌体的调节，载体有效缓解了神经炎症。载体显著改善了PD模型小鼠的运动能力，实现了PD的非侵袭性协同高效治疗。同时项目阐明了载体协同治疗PD的机理，为PD以及其他神经退行性疾病的治疗研究积累了实验数据并提供了新的策略和药物载体。