Research progress of blood-brain barrier crossing strategies and brain-targeted drug delivery mediated by nano-delivery system
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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。
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.
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脑科学是当前国际科技前沿的热点领域和重要方向，“十四五”国家规划将“脑科学与类脑研究”列入七大“科技前沿领域攻关项目”，涵盖了脑重大疾病机制与干预研究等核心攻关难题。药学是支撑“脑计划”研究的关键领域，然而目前有关脑部疾病的药物开发陷入疗效低、临床转化率低的困境，这主要源于特殊生理屏障（血-脑脊液屏障/血脑屏障）的阻碍。精准可控的脑内药物递送技术与创新治疗策略的开发是突破脑重大疾病治疗瓶颈的关键举措。本专栏聚焦脑内药物递送技术，展开对现有脑病治疗策略的讨论，全面总结现阶段临床脑病用药前沿研究，以期为脑病治疗提供新启发、开辟新道路。
1. 脑内药物递送技术研究
脑部疾病的治疗药物前期研发困难、后期临床转化率低，主要原因在于血脑屏障（blood brain barrier，BBB）的阻碍。BBB作为大脑的天然保护屏障，对保护大脑免受外部有害物质的攻击起着至关重要的作用。此外，BBB也限制了药物分子入脑，显著影响了脑部疾病的用药疗效。因此，克服BBB是改善脑重大疾病治疗的关键。
迄今为止，研究人员开发了多种药物跨BBB递送策略，涉及候选药物分子修饰以增强BBB渗透性、干扰BBB紧密连接排布或表达、抑制药物中枢外排系统，以及利用载体偶联药物递送入脑等。这些方法旨在提高药物生物利用度，继而实现药物在特定病灶脑区的精准递释。虽然多种脑病用药已进入临床试验，但其临床转化率仅有8.2%。针对药物入脑较低、疗效不佳的挑战，优选给药路径绕过BBB，或者设计新型递药系统增强BBB渗透活性是提高药物入脑效率和临床转化率的重要研究方向。本期专题中由加拿大曼尼托巴大学顾晓晨联合中国药科大学丁杨团队撰写的《脑病用药递送策略及临床研究进展》一文从脑病用药在临床研究中存在的关键问题出发，分别从优化给药途径和开发新型递药系统两方面综述了脑病治疗药物的开发策略。在优效给药途径方面，非侵入性给药如鼻黏膜给药、口腔黏膜给药、吸入给药和经皮给药等策略应用广泛。这些给药途径能够避免肝脏首过效应，提高药物的生物利用度，并且可以直接或间接地将药物递送至脑内。其中，鼻黏膜给药利用鼻腔的独特生理结构，通过嗅神经和三叉神经绕过BBB直接递送药物入脑，显著提高药物的脑内富集。口腔黏膜给药则通过颊黏膜和舌下黏膜丰富的毛细血管，使药物快速进入体循环或直接跨越BBB入脑。吸入给药和经皮给药也因其独特的优势为众多临床脑病治疗药物所青睐。侵入性局部给药能够实现药物在脑内高效富集及物脑内精准递送，具有极高临床应用前景。新型递药系统的研究则集中在如何提高药物跨BBB效率。文章介绍了基于受体介导转胞吞递药系统、基于细胞归巢的跨膜递药系统和基于超声可逆打开BBB递药系统等策略，通过利用脑内天然转运机制或物理手段，显著提高药物的入脑效率。例如，受体介导转胞吞递药系统利用BBB上的特定受体，促进药物的胞吞和转运入脑。细胞归巢策略则利用免疫细胞的天然BBB渗透能力，将药物直接递送至脑内炎症区域。超声技术则通过物理手段短暂可逆打开BBB，为药物提供穿越的通道，为治疗脑病的大分子药物提供高效的开发策略。
近年来，纳米技术的飞速发展为脑内药物递送提供了新途径。在提高药物入脑效率的基础上，纳米技术通过调控药物的靶向性和释放特性，降低药物对正常脑组织的毒性。此外，多功能的纳米载体对融合诊断和治疗的“诊疗一体化”策略具有重要意义。本期专题中由中国药科大学药学院张华清团队撰写的《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》一文介绍了BBB的生理结构与转运机制，总结了不同基材的纳米颗粒跨BBB递送药物的研究案例及最新进展。以中枢系统疾病为线索，详细阐述了BBB在不同病理条件下的病变特征以及定制化药物递送途径。如阿尔茨海默病（Alzheimer’s disease，AD）病变过程中，BBB呈现出脑内胶质细胞激活、脑微血管内皮细胞覆盖减少、紧密连接中断等病理变化，进而诱发BBB渗透性增强、外周免疫细胞浸润增多等级联反应。干细胞疗法巧妙借用了AD病理环境下BBB的高渗透特性，高效入脑发挥疗效。同时，AD患者BBB上的转运受体表达异常，如：承担Aβ由血入脑的晚期糖基化终末产物（RAGE）转运体表达上调，而运输Aβ出脑入血的低密度脂蛋白受体相关蛋白1（LRP1）转运体则表达下调，二者“联手”加剧了脑内Aβ的异常蓄积。RAGE和LRP1受体表达变化启发研究者开发RAGE转运体底物及其模拟物，进而通过靶向修饰增效药物递送入脑。而在帕金森病中，脑微血管内皮细胞的显著增加导致多种转运蛋白均表达上调，为药物渗透入脑提供了靶向条件。此外，脑胶质瘤治疗药物递送面临BBB与血-肿瘤屏障（BBTB）的双重障碍，其治疗手段需实现多重渗透与靶向；创伤性脑损伤的BBB开放程度则呈现时间依赖性，药物递送需重点考虑BBB的有效开放时间窗。虽然不同脑部疾病背景下的BBB特性和病理变化各不相同，但均为脑内药物递送及不同脑部疾病跨BBB药物递送策略的开发提供了新的方向；针对不同疾病病理下BBB变化特征，设计新型药物递送系统，有望为不同中枢疾病的脑内药物递送策略和纳米递送系统设计提供思路。
2. 脑病治疗策略研究
脑病治疗难点在于病程长、预后恢复较差、致残率和致死率高，但与之相对应的是极低的药物疗效与临床转化成功率。开发新型药物递送策略是增强中枢疾病药物疗效的主要途径之一，本期专题分析了多种脑部疾病药物递送困难，介绍并讨论了其临床新型脑部递药策略。如偏头痛、癫痫等的治疗注重快速缓解症状、发病时给药便捷。因此，能够将药物快速递送入脑的鼻黏膜给药、吸入给药在临床治疗中广为实践。而脑肿瘤和某些神经退行性疾病的疗效优化关键点在于增强药物的BBB渗透效率，故直接将药物递送至脑内或脑脊液中的侵入性局部给药途径因其递送效率高而更为合适。但考虑到侵入性给药的低顺应性与安全性，近年来经皮给药凭借其持续药物释放特性与高生物利用度被更多地用于开发临床神经退行性疾病治疗。
AD是一种进行性的神经退行性疾病，以记忆力减退、认知功能障碍和行为改变为主要临床表现。根据《中国阿尔茨海默病报告2024》，2021年中国AD及其他痴呆患者人数已达将近
1700 万例，且患病率随年龄的增加而不断上升。与高患病率不对等的是AD低治疗水平，两者间的不平衡迫切需要AD新药研发。但是，AD药物的临床失败率极高，主要原因就是复杂的病理机制，且不同病理之间存在相互串扰。小胶质细胞作为中枢神经系统（central nervous system，CNS）的主要免疫细胞，在AD神经保护和修复中扮演着“双刃剑”角色。它们在维持脑内微环境稳定、保护神经元和清除AD毒性蛋白（Aβ或Tau）方面发挥着重要作用，但功能失调的小胶质细胞也会诱发脑内炎性风暴，加剧AD病理过程。因此，调节小胶质细胞的状态和功能是AD治疗的途径之一。目前，基于小胶质细胞的AD治疗策略在多项研究中取得进展，美国食品药品监督管理局（FDA）批准上市的3款Aβ单抗均依赖于小胶质细胞对Aβ清除活性而发挥疗效。本期专题中由中国药科大学药学院钱程根团队撰写的《调控小胶质细胞干预阿尔茨海默病的研究进展》一文中介绍了小胶质细胞的来源与其在AD发生发展中的重要作用，阐明小胶质细胞能够多通路、多机制发挥AD治疗效果。文章详细列举了小胶质细胞在AD病理干预中的研究进展：一方面高度参与Aβ识别、吞噬、降解和跨细胞传播过程，另一方面过度吞噬Aβ会激活小胶质细胞加剧神经炎症。因此，调控“最佳状态”的小胶质细胞是AD治疗的关键。近年AD研究表明，铁死亡是一种铁触发脂质过氧化的调节性细胞死亡过程，对AD病理进程作用极大。铁死亡特征主要有细胞内铁含量增加、脂质过氧化及其产物导致损伤修复抑制等。AD患者脑内铁代谢紊乱、氧化还原失衡和脂质过氧化物途径增强，提示“铁死亡假说”是AD主要发病机制之一。本期专题中由中国药科大学药学院周建平、程皓团队撰写的《基于铁死亡致病机制的抗阿尔茨海默病纳米药物递送系统研究进展》一文中介绍了以干预铁死亡为靶点的AD治疗策略：利用铁螯合剂清除蓄积铁、逆转脑内铁转运来调控铁代谢失衡，通过抑制铁死亡发挥神经保护作用，已经在动物模型中显示出良好AD疗效。此外，脂质过氧化及其产物蓄积诱发的氧化还原稳态失衡亦是神经元铁死亡的直接诱因，通过重建氧化还原稳态抵抗铁死亡也是AD治疗的重要策略。
脑胶质瘤（glioblastoma，GBM）是中枢原发性恶性肿瘤，尽管治疗技术随着时代不断进步，但由于GBM病理复杂性和侵袭性，临床治疗仍然是一个严峻的挑战。手术是GBM临床治疗的主要方法，但由于GBM表现出弥漫性浸润边界，手术难以完全切除。为此，通常在术后配合放射治疗以杀灭或抑制肿瘤细胞，延长患者生存期。但常规放射疗法对正常脑组织造成损伤，且放射耐受性导致术后恢复和患者生活质量下降。本期专题中由复旦大学药学院孙涛团队撰写的《药物递送系统介导的脑胶质瘤放疗增敏》一文中基于放射治疗GBM机制，阐明放疗产生的内在耐受性以及肿瘤微环境介导的耐受性。解除放疗耐受性，实现放疗增敏药物的脑靶向递送，提高跨BBB递送能力及延长瘤内滞留是临床GBM术后放疗疗效关键。文章重点介绍了无机、有机、仿生3种类别的纳米递药系统，在实现精准靶向的同时，兼具肿瘤病灶的药物精准控释，甚至整合荧光探针以辅助精准放疗，为高效消除GBM、避免术后复发提供了新策略。
3. 展 望
脑内疾病的病理机制复杂多变，BBB作为生理屏障限制了药物入脑效率，是阻碍脑病用药疗效的关键因素。随着医药科技的发展，BBB结构的深入了解和纳米技术的进步推动着脑内药物递送系统的革新。针对脑病“定制”的纳米载体能够响应特定的生理或病理信号，实现药物在病变脑区的靶向释放，减少对正常脑组织的不良反应。而多种非侵入性给药方式为长周期的慢病管理提供了高顺应性的创新治疗方案。尽管跨BBB策略已被充分运用于各类脑病治疗中以提高药物疗效，但其具体效率仍有待量化。此外，如何平衡不同纳米载体的安全性与高效性是药物递送系统后续临床转化的潜在难题。
目前针对不同脑重大疾病，研究者已开发了相应的治疗策略对症下药。如AD小胶质细胞调控与铁死亡抑制策略，脑胶质瘤的放疗增敏策略等。但由于脑部疾病病征复杂性，控制单一病因往往无法达到理想的治疗效果，后续可考虑联合多种病理机制建立综合方案，以期实现脑部疾病的系统性治疗。随着脑机接口和神经调控技术的发展，未来将为脑病诊断和治疗提供新手段，从而实现脑内药物递送技术及脑病治疗策略的多元化、个性化和精准化。
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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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