纳米递送系统介导的血脑屏障跨越策略和脑靶向药物递送研究进展

叶镇宁; 吴正红; 张华清

doi:10.11665/j.issn.1000-5048.2024052202

纳米递送系统介导的血脑屏障跨越策略和脑靶向药物递送研究进展

中国药科大学药学院药剂系, 南京211198

基金项目: 国家自然科学基金项目（No. 82104097）；江苏省自然科学基金项目（BK20210426）；中国药科大学双一流建设计划项目（CPU2022QZ18）

详细信息

作者简介:
吴正红，男，中国药科大学教授，博士生导师，现任药剂系党支部书记，药剂系副主任；兼世界中医药学会联合会儿童医药健康产品产业分会常务理事，中国颗粒学会生物颗粒专业委员会委员，江苏省药学会药剂专业委员会委员。担任《中国医药科学》《医学综述》以及Journal of Nanomedicine，British Journal of Medicine and Medical Research，World Journal of Drug Delivery等多本中外期刊编委。国家“重大新药创制”科技重大专项评审专家；国家自然科学基金和教育部奖励网评专家；中国（南京）知识产权保护中心技术专家库专家。曾任中国药科大学药学实验中心副主任；新疆医科大学药学院副院长（援疆）；泰兴市市长助理（挂职）。主编专著、教材等12部，主持和参加国家级科研项目13项、省部级5项，发表科研论文120余篇，授权专利13项

张华清，女，副研究员，药剂学硕士生导师。主持国家自然科学基金青年基金项目，江苏省自然科学基金青年基金项目，中国药科大学基本科研业务费（自然科学）团队项目，中国博士后站前特别资助、面上项目，江苏省博士后日常资助和科研资助等9项科研项目，指导省级大学生创新创业项目1项。以第一作者（含共一）和通信作者（含共通）在PNAS, Adv Mater，Nano Lett，Adv Sci，Nano-Micro Lett，Biomaterials 和J Control Release等期刊发表SCI论文14篇，授权国内发明专利4项，申请PCT国际专利1项。荣获美国药学科学家协会Travel Award（2018），最佳摘要奖（2018、2019），百特中国优秀青年研究者一等奖（2020），卡乐康奖教金（2021），江苏省优秀本科论文/团队指导教师（2022、2023）等多项荣誉，参与《药物制剂工程学》等省级研究生精品课程编写

通讯作者:
吴正红: Tel：15062208341　E-mail：zhenghongwu66@126.com

张华清: Tel：15250962078　E-mail：zhanghq0527@163.com

中图分类号: R944
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出版历程
- 收稿日期: 2024-05-21
- 刊出日期: 2024-10-24

Research progress of blood-brain barrier crossing strategies and brain-targeted drug delivery mediated by nano-delivery system

Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China

Funds: This study was supported by the National Natural Science Foundation of China (No. 82104097), the Natural Science Foundation of Jiangsu Province (BK20210426); and the Double First-Rate Construction Plan of China Pharmaceutical University (CPU2022QZ18)

摘要

摘要:
血脑屏障（blood-brain barrier，BBB）是存在于脑组织与血浆之间的半通透性生物屏障，然而其物理特性、酶特性、免疫特性及独特的转运机制严重限制了治疗药物和诊断试剂入脑，为脑部疾病防治带来了巨大挑战。基于此，本文首先总结并分析了BBB复杂的结构组分和多样的转运机制，探讨了跨越BBB药物递送的难点及可行途径；进而，介绍并讨论了各类纳米递送系统在跨越BBB实现脑内药物递送的最新研究进展及未来发展趋势，为进一步完善其设计和推动其转化提供了参考；最后，就常见脑部疾病中BBB的病理变化探讨了如何针对病理BBB设计相应的药物递送策略。本文强调了基于纳米递送系统的跨越BBB药物递送策略的设计与优化，并为目前脑内药物递送所面临的机遇和挑战提供了解决思路。
- 血脑屏障 /
- 结构组分 /
- 转运机制 /
- 纳米递送系统 /
- 脑部疾病 /
- 脑内药物递送
Abstract:
The blood-brain barrier (BBB) is a semi-permeable biological barrier between brain tissue and plasma, however, its physical, enzymatic and immune properties, as well as its unique transport mechanism severely limit the entry of therapeutic drugs and diagnostic agents into the brain, which poses great challenges for the prevention and treatment of brain diseases. Hence, this review summarizes and discusses the complex structural components and various transport mechanisms of BBB, and interprets the difficulties and feasible ways of drug delivery across BBB. Furthermore, the latest research progress and future development trends of various delivery systems for brain drug delivery are introduced and discussed to provide references for further perfecting their design and driving their transformation. Finally, this review discusses the pathological changes of BBB in brain diseases and the design of drug delivery strategies for pathological BBB. Collectively, this review highlights the design and optimization of drug delivery strategies across the BBB based on nano-delivery system and provides accessible guide for current opportunities and challenges of intracerebral drug delivery.
- blood-brain barrier /
- structural constituent /
- transport mechanism /
- nano-delivery system /
- brain diseases /
- intracerebral drug delivery

HTML全文

图 1 神经血管网络及血脑屏障（blood-brain barrier，BBB）剖面结构示意图

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图 2 跨越BBB的生理运输机制

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表 1 基于纳米递送系统的代表性跨BBB药物递送策略

纳米递送系统类型	递送策略设计	相关应用	参考文献
脂质纳米制剂	由淀粉样前体蛋白部分片段修饰的脂质体	一种多巴胺脑靶向治疗帕金森病（PD）的新策略	[19]
	含SynO₄单抗的转铁蛋白偶联脂质体	减少α-突触核蛋白聚集并改善PD行为症状	[20]
	掺杂色胺衍生类脂质的脂质纳米颗粒（NT1-LNPs）	可通过静脉注射将小分子药物和生物大分子药物送入小鼠脑内的一种脂质纳米制剂修饰手段	[21]
	热响应性脂质纳米颗粒（TLN）	一种安全有效的热反应性药物递送系统，具有更高的跨BBB以及靶向胶质母细胞瘤细胞的潜力	[22]
聚合物纳米颗粒	装载姜黄素（Cur）并用糖肽修饰的PLGA纳米颗粒（g7-NPs-Cur）	用于治疗阿尔茨海默病（AD）的Cur脑靶向递送系统	[23]
	外部修饰甘露糖并负载芬戈莫德（FTY）PLGA-PEGn纳米骨架（FTY@Man NP）	一种用于治疗AD的智能口服脑靶向纳米颗粒	[24]
	分别在PCL-PEG末端修饰D-T7和MG1 （Asp@TMNPs）	用于治疗孤独症谱系障碍的阿司匹林胶囊级联给药系统	[25]
	PMPC双功能靶向性纳米载体（PAMAM-PMPC）	一种针对胶质母细胞瘤（GBM）的靶向治疗的创新化药物纳米递送策略	[26]
	负载DOX的PLGA-lysoGM1胶束（PLGA-lysoGM1/DOX）	在GBM大鼠模型中有良好的抗肿瘤作用	[27]
	以RGD和NIR830修饰并包被PEG-b-AGE聚合物作为递送SN38的超细磁性纳米颗粒（NIR830-RGD-uIONP/SN38）	在GBM小鼠模型中具有良好的肿瘤靶向递送和治疗效果	[28]
磁性纳米颗粒	DPA-PEG功能化超顺磁性超小氧化铁纳米颗粒（DPA-PEGylated USPIONs）	通过捕获β-淀粉样蛋白（Aβ）有效改善血脑屏障通透性以实现AD治疗	[29]
	利用OPD构建表面具有含氮多芳官能团的碳量子点（OPCDs）	作为一种多功能β-sheet结构破坏剂通过靶向Aβ治疗AD	[30]
羰基纳米颗粒	多壁碳纳米管（MWCNTs）	通过刺激中枢神经系统释放一氧化氮来调节血压	[31]
无机金属纳米颗粒	靶向紧密连接的金纳米颗粒（Au NPs）	一种提高无机金属纳米颗粒跨BBB转运能力的策略	[32]
	利用Opca蛋白表面修饰并包载MTX的MnO2 NPs（MTX@MnO2-Opca）	一种能有效克服BBB并治疗GBM的仿生纳米递送系统	[33]

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