脑靶向PI3Kgamma抑制剂纳米缓释载体对缺血性脑卒中的保护作用研究

BBB dysfunction, leucocytes infiltration and glia activation are the key steps in post-ischemic stroke inflammatory response. PI3Kgamma plays central role in regulation of vascular endothelial cells permeability, leukocyte chemotactic migration and microglia activation, which could be served as a effective target for inflammation intervention. In this study，a brain-targeting drug delivery nanocarrier will be constructed based on biodegredable PHBH nanoparticles to overcome the strong hydrophobility and poor pharmaceutical properties of PI3Kgamma inhibitor. The brain-targeting peptide will be absorbed on the surface of nanocarriers through the protein-material interaction without chemical crosslink reaction. Inhibition of PI3Kgamma activity will be achieved through the effective delivery of PI3Kgamma inhibitor to ischemic site and surrounding area, therefore, to maintain the stucture and function of BBB, reduce leucocyte infiltration, attanuate sustained strong inflammatory response and glia activation. These help to mitigate the neuron damage in ischemic area especially in penumbra, improve the neuron survival and reduce the Infarction volume, which will be beneficial for later brain repair therapeutic intervention. The construction of this brain-targeting sustained drug release carrier will establish novel view and new way to promote the effective delivery of therapeutic agent to brain, provide the innovative technology and new strategy of targeted nano-therapy for other central neural system diseases, and result in the positive social value and promising application prospects.

缺血性脑卒中后BBB功能障碍、炎症细胞浸润和胶质细胞活化引发强烈炎症反应是造成继发性神经损伤的关键环节。PI3Kgamma是重要的炎症反应干预靶点，参与血管通透性、白细胞趋化迁移和小胶质细胞活化的调节。但PI3Kgamma抑制剂的强疏水性严重制约了其体内抗炎效果。本项目拟建立一种新型脑靶向PI3Kgamma抑制剂纳米缓释载体，通过向缺血性脑卒中损伤部位及周边区域进行有效的药物递送，维护BBB结构和功能，减少炎症细胞浸润，减轻炎症反应和胶质细胞活化程度，从而减少脑缺血部位特别是半影区内神经元的损伤，增加存活神经元数量，缩小脑缺血损伤范围，为后期修复治疗创造有利环境，对促进损伤后神经功能恢复和重建具有积极作用。这一新型脑靶向药物递送的新技术可为脑损伤后炎症反应控制、降低继发性神经损伤提供切实有效的干预手段，并可为其它中枢性疾病的纳米靶向治疗提供新思路新策略，具有重要的学术意义和良好的应用前景。