一种微环境响应型的帕金森病纳米免疫治疗系统的研究

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Increasing evidence has revealed that accumulation of misfolded α-synuclein (α-syn) is the major pathological hallmarks of the disorder. Current dopamine replacement strategies could only improve the classical motor symptoms and alleviate the neurodegenerative process. Herein, treatments that provide disease-modifying effects remain an urgent unmet clinical need. Immunotherapy provides a viable and promising therapeutic approach to treat PD by using the immune system to clear the misfolded α-syn. Experimental evidence shows reduced neurodegeneration and improved function by immunotherapy approach. However, poor immune responses and individual difference induced by the increasing age are major risk factors for PD immunotherapy. Most importantly, failure to directly address the neuroinflammation in the trials also hampers the therapeutic effect. To solve these problems, an immunologic balance strategy is applied, which refers to the balance between the immune induction and inflammatory regulation in the immunotherapy for PD. With this concept, a step-wise targeting, microenvironment-responsive nanoimmunodelivery system is constructed. The antigens and the immunomodulators are designed to encapsulate on the same nanosystem. In the nanodelivery system, polyglutamic acids with BBB targeting act as the outer shell. Whereas, a diblock copolymer based on poly(lysine-alanine) is used as the inner shell-core structure, and plays the role of immunocyte targeting. After targeting into the immune cells in the brain, the site-specific released antigens actively induce the immune responses to clear the misfolded α-syn, whereas the simultaneously released immunomodulators regulate the neuroinflammation to protect the neuron. The optimized nanodelivery system will develop a synergistic immunotherapeutic effect for PD, and will be exploited as an efficient and safe treatment for PD therapy.

针对帕金森病免疫治疗过程中免疫反应差和易产生神经炎症的问题，本项目拟采取免疫诱导-调节炎症的免疫平衡策略，构建一个逐级靶向、微环境响应、免疫控炎的聚多肽纳米免疫输递体系。体系以具有BBB靶向的聚谷氨酸为外壳层，以具有免疫细胞靶向的聚赖氨酸-丙氨酸嵌段共聚物为内壳核层，形成一个核壳结构的多功能纳米输递体系。结合抗原的主动诱导和免疫调节剂对神经炎症的主动调控，将抗原和免疫调节剂合理地负载在同一纳米免疫治疗系统中，协同诱导机体产生高效的免疫反应和长效的免疫保护。在纳米体系通过两级靶向介导进入脑内免疫细胞后，利用微环境响应同时定点释放抗原和免疫调节剂。通过嵌段共聚物两嵌段单元的比例和主链上微环境响应来调控抗原和免疫调节剂的释放，优化免疫诱导和炎症反应调节的平衡。通过考察纳米免疫治疗体系在体外、体内的免疫水平和安全性评价，以及对帕金森病的治疗效果，以期获得一种高效、安全、持久的帕金森病免疫治疗系统。

帕金森病和阿尔茨海默病是老年人最为常见的神经退行性疾病，其病理进程常常伴随着神经炎症。现有药物治疗仅仅只是减缓疾病的进程，难以实现对神经退行性疾病的有效治疗。免疫治疗能够利用主体的免疫系统，清除错误蛋白，调控炎症反应。但是由于神经退行性疾病病发群体为50岁以上人群，主体免疫系统衰老化导致免疫反应差，需要多次重复免疫。而且，更为重要的是，在中枢神经系统疾病治疗中最大的困难是如何将治疗药物输递至脑组织。因此，针对神经退行性疾病治疗过程中药物递送效率低的共性关键问题，在本项目中，拟采用炎症调控、免疫控炎的平衡策略构建逐级靶向、微环境响应型纳米药物递送体系实现对药物的有效递送，以期获得一类高效、安全的免疫治疗体系。针对阿尔茨海默病中Aβ蛋白斑和神经炎症间的恶性循环，构建了逐级靶向释放、炎症调控的纳米药物递送体系。该体系不仅可以在细胞外清除Aβ蛋白斑，还可以在细胞内调控炎症水平。实验结果表明，纳米体系不仅显著提高了化药和基因药物在脑部的富集，降低了阿尔茨海默病模型鼠脑内Aβ蛋白水平，而且明显抑制了体内促炎水平，改善了模型鼠的学习和记忆能力。针对帕金森病易产生神经炎症的病理特点，构建了逐级靶向、双响应的免疫控炎的聚多肽纳米药物递送体系。结果表明，纳米药物递送体系提高了基因药物在脑内的富集靶向，显著抑制了小胶质细胞内NF-κB蛋白水平，明显降低了促炎因子的分泌。通过本项目的研究，开发了一类应用于神经退行性疾病免疫治疗的纳米药物递送体系，提高了药物的生物利用度和作用效果。这些纳米递送系统的开发将推动我国神经退行性疾病免疫治疗工作的研究进展，为神经退行性疾病的治疗奠定研究基础。