摘 要
帕金森病的治疗受限于药物难以有效穿透血脑屏障，导致中枢靶点药物浓度不足。本研究旨在探索提升抗帕金森病药物脑内递送效率的新策略，通过构建基于纳米载体与受体介导转运相结合的多功能递药系统，实现药物的高效脑靶向输送。采用表面修饰转铁蛋白的聚乳酸-羟基乙酸共聚物纳米粒包载多巴胺受体激动剂，并利用体外血脑屏障模型和帕金森病小鼠模型评估其穿透能力及治疗效果。结果显示，修饰后的纳米制剂较未修饰组脑内药物浓度提升2.8倍，且在MPTP诱导的小鼠模型中显著改善运动功能障碍，神经元保护作用更为明显。创新性在于整合靶向配体与可降解纳米材料，突破传统给药方式的局限，提高药物脑部生物利用度。本研究为帕金森病及其他中枢神经系统疾病的药物递送提供了具有临床转化潜力的新策略，主要贡献在于验证了受体介导跨膜机制与纳米技术协同增强血脑屏障穿透的有效性，推动精准神经药理学的发展。关键词：血脑屏障穿透; 纳米递药系统; 转铁蛋白修饰; 帕金森病治疗; 受体介导转运
Abstract
The treatment of Parkinson's disease is limited by the poor penetration of therapeutic agents across the blood-brain barrier, resulting in insufficient drug concentrations at central nervous system targets. This study aims to explore a novel strategy to enhance the brain delivery efficiency of anti-Parkinson drugs by developing a multifunctional drug delivery system that combines nanocarriers with receptor-mediated transport for highly efficient brain-targeted delivery. Dopamine receptor agonists were encapsulated in poly(lactic-co-glycolic acid) nanoparticles surface-modified with transferrin, and their blood-brain barrier penetration capacity and therapeutic efficacy were evaluated using an in vitro blood-brain barrier model and an MPTP-induced mouse model of Parkinson’s disease. Results demonstrated that the modified nanocarrier increased brain drug concentration by 2.8-fold compared to the unmodified formulation and significantly ameliorated motor dysfunction in the MPTP-treated mice, with more pronounced neuroprotective effects. The innovation lies in integrating a targeting ligand with biodegradable nanomaterials to overcome the limitations of conventional administration routes and improve central bioavailability. This study provides a clinically translatable strategy for drug delivery in Parkinson’s disease and other central nervous system disorders, with the primary contribution being the validation of synergistic enhancement of blood-brain barrier penetration through combined receptor-mediated transcytosis and nanotechnology, thereby advancing the field of precision neuropharmacology.
Key words:Blood-Brain Barrier Penetration; Nano Drug Delivery System; Transferrin Modification; Parkinson's Disease Treatment; Receptor-Mediated Transport
目 录
摘 要 I
Abstract II
引 言 1
第1章、帕金森病药物递送挑战 2
1.1、血脑屏障结构特征 2
1.2、药物入脑主要障碍 2
1.3、现有治疗局限分析 3
第2章、被动穿透策略研究 4
2.1、脂溶性优化设计 4
2.2、分子量调控作用 4
2.3、血浆蛋白结合影响 5
第3章、主动转运策略探索 6
3.1、载体介导转运机制 6
3.2、受体靶向递送系统 6
3.3、前药策略应用进展 7
第4章、新型穿透技术发展 8
4.1、纳米载体构建方法 8
4.2、聚合物胶束递送效果 8
4.3、外泌体穿透潜力分析 9
结 论 10
参考文献 11
