超声介导的黑磷微泡用于清除帕金森氏症患者中脑黑质路易小体的研究

Parkinson’s disease (PD) is the second common neurodegenerative disorder apart from Alzheimer’s disease. The symptoms show slowly over time. In early stage, patients always show symptoms of shaking, rigidity, slowness of movement, and difficulty with walking. Thinking and behavioral problems may occur later. Finally, dementia becomes common in the advanced stages of PD. Pathologically, PD is characterized by the loss of neurons in the substantia nigra pars compacta (SNpc), as well as by the presence of Lewy body in this area. Main compositions of Lewy body is accumulations of insolubleα-synucleins (α-syn). Normally,α-syn is soluble, however, once it shows misfolding structures, its mutations keep growing and spread among adjacent cells. Misfoldingα-syn monomers first associate into oligomers, then form into protofibril oligomers and further aggregate into fibers which yield Lewy body. Prevent spreading of misfolding α-syn aggregates may be an effective way to control PD. Here we propose to apply black phosphorus microbubbles (BPMBs) scavenger for clearance of Lewy body in substantia nigra. In order to extend neuron’s life, we load GDNF (glial cell line-derived neurotrophic factor) on surface of BPs and encapsulated into microbubbles, yielding G-BPMBs. After vein injection of G-BPMBs, focused ultrasound is performed for targeting release of GDNF into midbrain. After GDNF releasing, naked BPs is explored. This attracts α-syn aggragtes attachments onto BPs, yielding A-BPs. Further, A-BPs is cleared by lysosome degradation. In summary, we apply black phosphorus microbubbles as dual effects micro- nano-capsules for PD therapy.

帕金森病是一种危害极大且难以治愈的神经退行性疾病。主要病理特征是脑黑质多巴胺能神经元中α-突触核蛋白错误折叠，产生蛋白纤维化沉淀、聚集，在细胞核外围形成路易小体，屏障和阻断了细胞核与外界的信号传递，导致黑质多巴胺能神经元变性和凋亡。这一过程由病变神经元继续向正常神经细胞传播，造成大量神经元相继凋亡及多巴胺水平的下降，最终出现临床症状且病情持续加重。临床治疗主要是针对多巴胺能神经元的功能缺失而使用多巴胺或其激动剂缓解症状，但效果有限。若能阻断路易小体的形成和传播，或能将其清除，可能是治疗帕金森病的关键。本项目在前期相关研究的基础上，拟构建包载神经胶质细胞源性神经营养因子（GDNF）的黑磷微纳米泡，并在高能超声诱导下开放血脑屏障，同时使GDNF和黑磷在脑黑质内靶向释放，实现即能用GDNF维持神经元功能，又能通过黑磷俘获和清除路易小体，阻断其形成和传播的目的。旨在探索帕金森病的新治疗途径。

帕金森氏症是一种危害极大且难以治愈的神经退行性疾病，主要病理特征是神经元不可逆损伤，阻碍了神经细胞间的物质及信息传递，最终导致病灶部分不可逆的器质性病变。项目利用磷脂微泡包载具有抗氧化性质的皂苷分子，并在低频率低强度聚焦超声作用瞬时开放血脑屏障，并在病灶释放药物。皂苷通过减少受损神经细胞的氧化损伤，显示了延缓帕金森氏症的优势。为了进一步提高微泡对于皂苷的包载效率，团队利用比表面积丰富的黑磷量子点作为吸附皂苷的媒介，并进一步利用超声微泡脑靶向递送的方法实现病灶的精准药物释放，对延缓帕金森氏症病程进展起到了一定促进作用。