药学学报

Nanoparticle class	Classification
Lipid-based NP	Liposomes, solid lipid NP, nanoemulsions
Polymeric NP	Dendrimers, lactic-co-glycolic acid NP, polystyrene NP, poly (β-amino ester) NP, polyanhydride NP, chitosan NP, polycaprolactone NP
Inorganic NP	Gold NP, carbon nanotubes NP, mesoporous silica NP
Biological NP	Exosomes, microvesicles, apoptotic bodies

Nanoparticle class	Classification
Lipid-based NP	Liposomes, solid lipid NP, nanoemulsions
Polymeric NP	Dendrimers, lactic-co-glycolic acid NP, polystyrene NP, poly (β-amino ester) NP, polyanhydride NP, chitosan NP, polycaprolactone NP
Inorganic NP	Gold NP, carbon nanotubes NP, mesoporous silica NP
Biological NP	Exosomes, microvesicles, apoptotic bodies

Type	Classification
Cell-penetrating peptides	Angiopep-2, HIV-1, TAT, cyclic cell-penetrating peptide, glucose transporter, SynB peptide, penetratin
Cell-targeting peptides	Somatostatin mimicking peptide, arginine-glycine-aspartate peptide, gonadotropin releasing hormone peptide

Type	Classification
Cell-penetrating peptides	Angiopep-2, HIV-1, TAT, cyclic cell-penetrating peptide, glucose transporter, SynB peptide, penetratin
Cell-targeting peptides	Somatostatin mimicking peptide, arginine-glycine-aspartate peptide, gonadotropin releasing hormone peptide

Type	Characteristic	Strength	Weakness
Liposomes	30-2 500 nm; spherical vesicle system consisting of lipid bilayer surrounding water nucleus	Amphipathy; biocompatibility; degradable	Rapid elimination from bloodstream; CARPA
Exosomes	30-150 nm; released by multivesicular body; formed by the inward budding of the cell plasma	Biocompatibility; payload flexibility; low toxicity and low immunogenicity; stability	Rapid elimination from bloodstream; complex purification process
Apoptotic bodies	> 1 000 nm; formed by the outward budding of the cell plasma during cellular apoptosis	High stability; biocompatibility; long circulation time; stealth capacity	Uneven size distribution; complex composition
Cell-penetrating peptides	Oligopeptides consisting of hydrophobic and/or positively charged side chains	Potential for surface modification; low immunogenicity	Lack of cell specificity; poor internal stability
Cell-targeting peptides	Cell/tissue-specific binding activity	Biocompatibility; reduce peripheral side effects and drug resistance	Short half-life period

Type	Characteristic	Strength	Weakness
Liposomes	30-2 500 nm; spherical vesicle system consisting of lipid bilayer surrounding water nucleus	Amphipathy; biocompatibility; degradable	Rapid elimination from bloodstream; CARPA
Exosomes	30-150 nm; released by multivesicular body; formed by the inward budding of the cell plasma	Biocompatibility; payload flexibility; low toxicity and low immunogenicity; stability	Rapid elimination from bloodstream; complex purification process
Apoptotic bodies	> 1 000 nm; formed by the outward budding of the cell plasma during cellular apoptosis	High stability; biocompatibility; long circulation time; stealth capacity	Uneven size distribution; complex composition
Cell-penetrating peptides	Oligopeptides consisting of hydrophobic and/or positively charged side chains	Potential for surface modification; low immunogenicity	Lack of cell specificity; poor internal stability
Cell-targeting peptides	Cell/tissue-specific binding activity	Biocompatibility; reduce peripheral side effects and drug resistance	Short half-life period

跨血脑屏障药物载体的研究进展

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曹婉昕 ¹ , 杨艺辉 ¹ , 杨红 ¹ , 张森 ¹ , 张宜之 ¹ , 许芳 ¹ , 李婉 ¹ , 郝悦 ¹ , 李晓雪 ¹^,² , 张旭 ¹ , 杜冠华 ¹ , 王金华 ¹^,^*

药学学报 | 综述 2024,59(12): 3222-3231

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药学学报 | 综述 2024, 59(12): 3222-3231

跨血脑屏障药物载体的研究进展

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曹婉昕¹, 杨艺辉¹, 杨红¹, 张森¹, 张宜之¹, 许芳¹, 李婉¹, 郝悦¹, 李晓雪¹^,², 张旭¹, 杜冠华¹, 王金华¹^,^*

作者信息

1.中国医学科学院、北京协和医学院药物研究所, 北京市药物靶点研究与新药筛选重点实验室, 北京 100050

2.沈阳药科大学, 辽宁沈阳 117004

通讯作者:

^*王金华, Tel: 13810230480, E-mail: wjh@imm.ac.cn

Research progress in drug carriers across the blood-brain barrier

Wan-xin CAO¹, Yi-hui YANG¹, Hong YANG¹, Sen ZHANG¹, Yi-zhi ZHANG¹, Fang XU¹, Wan LI¹, Yue HAO¹, Xiao-xue LI¹^,², Xu ZHANG¹, Guan-hua DU¹, Jin-hua WANG¹^,^*

Affiliations

1. Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

2. Shenyang Pharmaceutical University, Shenyang 117004, China

出版时间: 2024-12-12 doi: 10.16438/j.0513-4870.2024-0732

文章导航

摘要

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血脑屏障(blood brain barrier, BBB) 在维持大脑内环境稳态的同时, 也给中枢神经系统疾病的治疗带来困难。药物载体可以帮助药物穿过血脑屏障发挥药效。本文对药物跨血脑屏障的途径、药物载体入脑后的命运调控及药物载体分类进行了介绍, 重点阐述了脂质体、外泌体、凋亡小体、细胞穿透肽和细胞靶向肽的特点及应用, 并对跨血脑屏障药物递送领域的研究前景及所面临的挑战进行了分析。

关键词

药物载体 / 血脑屏障 / 脑内命运 / 脂质体 / 外泌体 / 凋亡小体 / 细胞穿透肽 / 细胞靶向肽

Abstract

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The blood-brain barrier (BBB) plays a crucial role in maintaining the homeostasis of the brain's internal environment, which poses challenges to the treatment of central nervous system diseases. Drug carriers can aid in the delivery of therapeutic agents across the BBB to exert their pharmacological effects. The article reviewed the pathways for drug delivery across the BBB, the intracerebral fate and the classification of drug carriers and focuses on the functions and characteristics of liposomes, exosomes, apoptotic bodies, cell-penetrating peptides, and cell-targeting peptides. The review will provide an outlook on the future and challenge of research in the field of drug delivery across the BBB.

Key words

drug carrier / blood-brain barrier / intracerebral fate / liposome / exosome / apoptotic body / cell-penetrating peptide / cell-targeting peptide

引用本文

曹婉昕, 杨艺辉, 杨红, 张森, 张宜之, 许芳, 李婉, 郝悦, 李晓雪, 张旭, 杜冠华, 王金华. 跨血脑屏障药物载体的研究进展. 药学学报, 2024 , 59 (12) : 3222 -3231 . DOI: 10.16438/j.0513-4870.2024-0732

Wan-xin CAO, Yi-hui YANG, Hong YANG, Sen ZHANG, Yi-zhi ZHANG, Fang XU, Wan LI, Yue HAO, Xiao-xue LI, Xu ZHANG, Guan-hua DU, Jin-hua WANG. Research progress in drug carriers across the blood-brain barrier[J]. Acta Pharmaceutica Sinica, 2024 , 59 (12) : 3222 -3231 . DOI: 10.16438/j.0513-4870.2024-0732

正文

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血脑屏障(blood brain barrier, BBB) 主要由脑微血管内皮细胞、星形胶质细胞、周细胞和基膜构成。其中, 脑微血管内皮水平的血脑屏障是血液-中枢神经系统交换的主要部位^[1]。相邻的血管内皮细胞之间存在复杂的紧密连接, 可以限制细胞旁通透性, 并使内皮具有顶端-基底极性^[2]。紧密连接在阻止有毒物质穿过血脑屏障以维持大脑内环境稳态的同时, 也使得亲水性药物和多肽等大分子药物难以递送到中枢神经系统发挥药理作用。除了以紧密连接为基础的物理屏障之外, 血脑屏障的功能还包括以外排转运体为基础的代谢屏障^[3], 常见的外排转运蛋白包括P-糖蛋白(P-glycoprotein, P-gp)、有机阴离子转运多肽(organic anion transporting polypeptide, OATP)、ABC转运蛋白(ATP-binding cassette transporter, ABC transporter) 等, 它们可以把一些药物从内皮细胞泵回血液循环, 使脑-血药物比大大降低, 从而给中枢神经系统疾病的治疗带来困难^[4-6]。

中枢神经系统疾病主要有阿尔茨海默病、帕金森病、癫痫、脑肿瘤、脑卒中、脑膜炎等^[7]。上述疾病状态下的血脑屏障通常可出现病理性开放, 不同脑部疾病的血脑屏障处渗漏间隙的开放程度不同。因此, 需针对各种脑部疾病的血脑屏障特性研发高效的药物递送系统。

脑部药物输送途径主要分为侵入性技术和非侵入性技术两种。侵入性技术可使药物绕过血脑屏障直接入脑, 主要包括脑深部刺激、脑内移植、直接脑注射、鞘内脑输送等^[8]。但侵入性技术存在潜在的安全性问题, 可能会造成中枢神经系统毒性, 从而导致中枢神经系统功能障碍或脑损伤^[9]。且高侵入性方式不利于重复给药, 使其应用存在局限性。非侵入性技术主要包括药物载体、外排泵抑制剂、病毒载体和鼻内/鞘内给药。非侵入性技术可以帮助药物穿透血脑屏障而不造成物理破坏, 是一种相对安全、无创的中枢神经系统给药途径^[10-12], 其中, 跨血脑屏障的药物载体是非侵入性技术的重要组成部分。

本综述介绍了药物穿过血脑屏障的不同途径、药物载体入脑后的命运调控以及药物载体的系统分类, 并对其中研究较多的药物载体进行了详细阐述。

1 药物穿过血脑屏障的不同途径

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药物穿过血脑屏障的途径包括细胞旁通路(paracellular pathway) 和跨细胞途径(transcellular pathway)。其中, 跨细胞途径包括被动跨膜扩散、外排泵介导的药物递送途径和受体/载体/吸附/细胞介导的胞吞作用^[13] (图 1)。

1.1 细胞旁通路和被动跨膜扩散

不同特性的药物分子跨越血脑屏障的途径不同。药物经细胞旁通路扩散时受脑内皮细胞间紧密连接的限制, 只有水、氧气和一些亲水的小分子能通过细胞旁通路穿过血脑屏障^[13]。被动扩散则允许大多数亲脂小分子穿过血脑屏障。易通过被动扩散向血脑屏障渗透的分子通常有以下特征: 小分子量(< 500 Da)、弱氢键(少于6个氢键)、亲脂性(logP > 2)、缺乏自由可旋转键、极性表面积(polar surface area, PSA) < 60 Å^[14]。

1.2 外排泵介导的药物递送途径

血脑屏障中存在外排泵, 可将紫杉醇、多柔比星、甲氨蝶呤和长春花碱等抗癌药物泵回血液, 使其无法在脑内达到有效浓度。为了减小药物与外排泵的相互作用, 可以将药物与外排泵抑制剂合用或对药物进行化学修饰以减小外排转运体对药物的亲和力^[13]。P-gp泵的外排作用是血脑屏障和肠道的主要保护机制, P-gp泵在避免毒性外来物和内源性代谢物进入大脑和血液系统方面发挥着重要作用, 在全身范围内使用P-gp抑制剂会导致外周不良反应的发生。Wang等^[15]构建出的FSCON纳米颗粒(nanoparticles, NP) 能在低功率近红外激光照射下主动靶向肿瘤组织, 实现P-gp抑制剂和化疗药物的精确控释, 减少外周不良反应的发生。此外, Zhang等^[16]研究发现血脑屏障通透性存在昼夜节律, 外排泵的活动受Mg²⁺调节。夜间细胞内Mg²⁺浓度低, 细胞外排活动减少。因此, 夜间给予苯妥英治疗可以增加药物在脑组织的积累, 有效发挥抗癫痫效果。

1.3 胞吞作用

胞吞作用是指细胞通过质膜内陷形成囊泡, 将胞外药物载体摄取到细胞内的过程。随后, 囊泡经胞内运输、分选后与血脑屏障管腔膜发生融合, 使囊泡内容物进入脑实质发挥药理作用^[10]。胞吞作用可由受体/载体/吸附/细胞介导。

1.3.1 受体介导的胞吞作用

受体介导的胞吞作用是细胞借助特异性受体选择性地摄入特定大分子的过程^[17]。囊泡表面配体可与脑微血管和毛细血管内皮细胞管腔膜上的同源受体结合。Andreone等^[18]研究发现, 相比外周内皮细胞, 脑内皮细胞的囊泡转运率异常低, 这可能与血管内皮细胞的脂质组成有关。

目前研究最多的血脑屏障靶标有转铁蛋白受体(transferrin receptor, TfR)、胰岛素受体和胰岛素样生长因子1/2受体、低密度脂蛋白受体(low-density lipoprotein receptor, LDLR)、低密度脂蛋白受体相关蛋白1/2、黑素转铁蛋白、CD98hc、瘦素受体、葡萄糖转运蛋白-1 (glucose transporter type 1, GLUT-1)、烟碱乙酰胆碱受体(nicotinic acetylcholine receptors, nAchR) 等^{[17, 19]}。然而, 这些受体在外周组织中也有表达, 靶向受体策略也会增加骨髓、肝脏和脾脏等外周腔室的药物暴露, 导致脱靶效应^[20]。TfR在网织红细胞中高表达, 给予小鼠治疗性TfR抗体后, 小鼠出现了网织红细胞减少的不良反应。为减少这一不良反应的发生, Couch等^[21]设计出了TfR/BACE1双特异性抗体。相比TfR抗体, TfR/BACE1双特异性抗体与TfR的结合亲和力更低, 从而明显降低了TfR抗体的外周暴露量, 使用药安全性显著提升。Giugliani等^[22]研究发现, 胰岛素受体介导的脑内药物递送可能会引起短暂性低血糖, 而向胰岛素受体靶向系统中输注葡萄糖或使用低剂量高亲和力的抗体则可有效降低低血糖风险。

Tylawsky等^[23]将维莫德吉包裹于岩藻多糖-纳米颗粒中用于治疗患有SHH型髓母细胞瘤的小鼠, 该纳米颗粒可靶向血管内皮细胞表面的P-选择素(P-selectin)。在放疗(radiotherapy, RT) 条件下, 血管内皮细胞上P-选择素的表达增加, 使纳米颗粒可以通过P-选择素和caveolin-1介导的胞吞作用实现跨内皮转运(图 2)。

1.3.2 载体介导的胞吞作用

常见的血脑屏障载体包括GLUT、大氨基酸转运蛋白1(large amino acid transporter 1, LAT1)、阳离子氨基酸转运蛋白1、单羧酸转运蛋白1、浓缩核苷转运蛋白2等^[24]。其中, 由于GLUT对D-葡萄糖有立体异构专一性, 而大脑表达GLUT1、GLUT3、GLUT6、GLUT8、GLUT13基因, 所以将D-葡萄糖与药物偶联设计出的葡萄糖模拟药物可借助GLUT载体穿过血脑屏障^[25]。

1.3.3 吸附介导的胞吞作用

血管内皮细胞表面和血脑屏障的基底膜处带有阴离子电荷, 带正电的底物可与带负电的细胞膜发生静电相互作用, 穿过血脑屏障并进入脑间质^[26]。细胞穿透肽大多为净电荷在+5以上的阳离子肽^[27], 主要经AMT途径跨越血脑屏障^[28]。此外, 将蛋白质阳离子化可以使其具有通过AMT途径穿过血脑屏障的能力。将蛋白质阳离子化的最简单方法是将蛋白质上的羧基末端基团或谷氨酸和天冬氨酸的侧链基团酰胺化为带正电荷的胺, 这样蛋白质不依赖于细胞穿透肽也可实现经AMT的跨血脑屏障递送^[29]。

1.3.4 细胞介导的胞吞作用

细胞介导的胞吞作用又被称为特洛伊木马策略。由于载体细胞在体内停留时间长, 与其他跨细胞途径相比, 细胞介导的胞吞作用能更显著地延长药物在体内的循环时间。常见的细胞载体有白细胞、中性粒细胞和单核细胞^[13]。Yu等^[30]构建了一种靶向外周单核细胞样髓源抑制细胞的药物递送系统, 使其负载分泌型PD-L1质粒。该系统易于制备, 且注射1次即可使PD-L1蛋白在荷瘤小鼠瘤内维持长达3~5天的高水平表达。此外, 特洛伊木马策略还可与纳米载体联合应用, Liu等^[31]开发了一种基于特洛伊木马策略的仿生纳米载体, 将载有多柔比星的纳米颗粒用MDA-MB-231/Br细胞膜包裹形成核壳纳米结构, 有效减缓了脑转移性乳腺癌的进展。

2 药物载体入脑后的命运调控

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目前大量研究停留在药物载体靶向脑的递送过程, 而对载体入脑后的命运调控研究较少。区别于前述的药物递送途径, 命运调控主要关注药物载体入脑后的事件, 尤其是载体的清除过程。

脑实质中的物质清除依赖于脑脊液循环系统、血管循环系统和淋巴系统, 任一途径的功能障碍都可能导致药物在脑内的异常积累^[32]。纳米材料在大脑中异常积累后可能通过氧化应激、DNA损伤、溶酶体功能障碍、炎症级联反应、细胞凋亡、遗传毒性等机制诱导神经毒性, 从而导致神经退行性疾病进展^[33]。因此, 了解药物载体入脑后的命运调控过程对评价其安全性至关重要。

Gao等^[34]对无机纳米颗粒的脑内命运进行了研究, 发现无机纳米颗粒可以通过抑制ERK1/2信号传导干扰小胶质细胞产生细胞外囊泡, 从而导致无机纳米颗粒在小胶质细胞中过度积累, 进一步破坏小胶质细胞介导的血管旁清除途径。而应用ERK1/2激活剂可促进纳米颗粒从小胶质细胞外排, 并通过淋巴系统清除。

此外, 采用放射或荧光标记药物载体可实现药物的体内示踪。放射标记需要在特殊的实验室进行, 因而目前荧光染料标记的应用范围更广^[35]。荧光共振能量转移是目前评估纳米药物生物分布的主要方法, 但其检测成本相对较高。Click3D^[36]是一种使用点击化学对包括大脑在内的全组织器官进行高效荧光染色的方法。炔烃标记的缺氧探针可实现缺氧状态下的全脑成像。对药物载体进行荧光探针标记后可收集不同时间的大脑样本进行Click3D检测, 从而实现对药物载体脑内时空命运的研究。此外, LC-MS/MS^[37]也可以作为一种新型生物测定方法, 通过检测聚乙二醇而间接监测代谢产物为PEG1000的D-α-生育酚基聚乙二醇1000琥珀酸酯, 从而实现对该药体内命运的监测。

3 药物载体

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可携带药物穿过血脑屏障的药物载体主要可分为纳米颗粒和细胞传递肽(cell-penetrating peptides, CPPs) 两大类(表 1、2)。

纳米颗粒是粒径在10~1 000 nm内的颗粒状分散体或固体颗粒, 可以封装、携带和输送各种治疗药物穿过血脑屏障。纳米颗粒的特点是体积小、毒性低、易于被修饰、物理和化学稳定性高、能够延长药物释放时间^[38-40]。纳米颗粒分为合成纳米颗粒和生物纳米颗粒。其中, 脂质体、外泌体、凋亡小体是近几年研究较为火热的领域。

细胞传递肽包括细胞穿透肽和细胞靶向肽, 二者均可与药物偶联形成肽-药物偶联物(peptide-drug conjugates, PDCs) 介导跨血脑屏障的药物递送^[41]。PDCs是通过特殊的连接物与具有特定功能的肽序列共价连接的药物。区别于脂质体通过包裹药物以提高其体内稳定性, PDCs的原理是通过对药物共价修饰以暂时限制其活性, 是一种前药策略^[42]。

本文选取目前研究较多的脂质体、外泌体、凋亡小体、细胞传递肽4类药物载体进行阐述(图 3), 并对4类药物载体的优缺点进行了总结(表 3)。

3.1 脂质体

脂质体是粒径在30~2 500 nm内, 由围绕水核的脂质双分子层组成的球形囊泡系统^[43]。脂质体具有两亲性, 亲水/亲脂性的药物或其他小分子可通过主动或被动方式进入脂质体的亲水性核心或疏水性双层中, 也可通过化学偶联附着在磷脂双分子层表面, 随脂质体跨血脑屏障入脑^[44]。常用的化学键有二硫键、酯键和腙键, 它们分别可以在还原条件、酯酶或低pH条件下介导药物释放^[43]。

脂质体的特点还包括好的生物相容性和可降解性, 对脂质体表面进行修饰可以改变体循环时间, 实现药物的靶向递送, 有利于药物的生物分布, 并可以降低药物的脱靶毒性。载药浓度是影响药物释放速度和整体疗效的主要因素, 目前脂质体领域主要的研究热点在于提高脂质体的药物载量、靶向性和整体疗效。脂质体囊泡的大小和膜层厚度会影响药物的包封效率和在体内循环的时间^[45]。对脂质体的磷脂组成进行调整可以制造出多层或多泡脂质体, 使用多泡脂质体包裹药物可以防止药物在生理环境中被降解, 使药物在体内能够长时间维持有效血浆浓度, 并减少给药频率、增加依从性^[46]。

脂质体可以通过受体介导的胞吞作用携带药物跨过血脑屏障。LAT1在血脑屏障和胶质瘤细胞上均过表达, LAT1介导的双靶向给药系统可携带药物穿透血脑屏障并靶向胶质瘤细胞。装载多西紫杉醇且经LAT1修饰的脂质体的细胞毒性、血脑屏障穿透性及递送效率均高于未修饰脂质体^[47]。Angiopep-2的融合肽修饰的负载多柔比星的工程化人工囊泡也兼具良好的血脑屏障穿透力和胶质母细胞瘤靶向能力, 且不良反应较少^[48]。

脂质体引起的补体激活相关的假性过敏反应(complement activation-related pseudo-allergic reactions, CARPA) 已成为其临床应用的阻碍, 其发生与脂质体的大小、组成、表面电荷、形态学特性以及静脉给药的输注速度有关^[49]。

转铁蛋白修饰的脑靶向脂质体可促进单克隆抗体穿过血脑屏障进入神经元, 提高脑细胞中单克隆抗体的浓度, 从而减少α-突触核蛋白的异常聚集和神经炎症的发生^[50]。脂质体被聚乙二醇层或杂化细胞膜包裹后可被网状内皮系统屏蔽, 成为“隐形”脂质体, 其在体内的循环时间显著延长^{[44, 51]}。冰片可以增加血脑屏障的通透性, 将冰片和黄芩苷一起包裹在脂质体中静脉注射能显著延长黄芩苷在体内的循环时间^[52]。与PVAP肽结合的血小板膜杂化脂质体在脑转移性三阴性乳腺癌中显示出良好的靶向能力和治疗效果^[53]。Zhang等^[54]研发出了磷脂酶A2-磷脂酰丝氨酸混合脂质体, 磷脂酶A2具有开放血脑屏障的能力, 该系统中的磷脂酰丝氨酸与几滴磷脂酶A2液滴结合后即可选择性开放血脑屏障。相比对脂质体表面进行化学修饰, 该系统结构更为简单。Kuo等^[55]发现向脂质体中加入心磷脂和磷脂酸后脂质体对tau蛋白过度磷酸化的抑制作用增强, 有利于治疗神经退行性疾病。此外, 脂质体与反式转录激活因子(transactivator, TAT) 肽结合后穿透血脑屏障的能力也有所提升。

传递体(transfersome, TFS) 是由天然生物相容性磷脂和边缘活化剂组成的一种特殊类型脂质体, 具有超可变形性、两亲性、生物相容性、可生物降解性^[56]。现有TFS多采取鼻内给药, 通过嗅觉和三叉神经通路将药物输送至大脑^[57]。John等^[58]研发出一种由脂质阴离子磷脂、胆固醇和非离子洗涤剂Span 80组成的具有变形能力的跨血脑屏障纳米级递送媒介物(delivery nanoscale vector, DNV)。其中, 胆固醇为膜调节剂、Span 80为边缘活化剂, 二者共同为纳米粒子的脂质双层增加了可变形性。该DNV无毒且大小可调, 可封装包括小分子、蛋白质、RNA和DNA在内的各类药物, 也可帮助一些亲水性及疏水性药物跨血脑屏障递送。然而, TFS也有发生药物泄漏和氧化降解的可能性^[56], 制剂的稳定性稍差。

3.2 外泌体

外泌体起源于内吞途径, 由多泡体释放, 是从质膜表面向外出芽形成的直径为30~150 nm的囊泡^[59-61]。外泌体属于天然的纳米载体, 可以将蛋白质、脂质、核酸转运到靶细胞, 在多种生物过程中发挥重要作用^[62]。与人工合成纳米载体相比, 外泌体的生物相容性更好、毒性更低, 且药物传递效率更高, 载药能力更强^[59]。此外, 外泌体具有低免疫原性、先天靶向特性、稳定性和肿瘤归巢能力, 其在体内的血液循环半衰期也较长, 是一种理想的脑部药物递送载体^[63]。

外泌体主要通过受体介导的胞吞作用穿透血脑屏障。利用配体、磁性材料等对外泌体进行表面修饰可增强其对血脑屏障的穿透能力, 并提升其靶向性。如用抗EGFRvIII抗体修饰外泌体有助于增强外泌体对胶质母细胞瘤的靶向性^[64]。此外, 外泌体还可调节脂质代谢, 介导脂质代谢重编程和肿瘤微环境中的细胞间通讯, 影响肿瘤的发生及进展^[65]。

转运必需内体分选复合体(endosomal sorting complex required for transport, ESCRT) 独立/依赖性途径分别参与外泌体的生成和运输。细胞来源不同, 所产生外泌体的靶向能力、细胞内化和治疗效果不同。免疫细胞来源的外泌体可以杀伤癌细胞并促进细胞凋亡, 与抗肿瘤药协同发挥更强的抗肿瘤免疫治疗作用^[66]。肿瘤来源的外泌体表面含有免疫抑制生物分子, 会影响免疫检查点阻断疗法的效果, 导致耐药性。而利用工程化的抗病毒肽可以破坏肿瘤源性外泌体的膜, 帮助CD8⁺ T细胞恢复正常功能, 重塑肿瘤微环境, 从而增强免疫治疗效果^{[67, 68]}。此外, 干细胞、巨噬细胞和神经来源的外泌体的穿透血脑屏障的能力较强^{[63, 69]}。

3.3 凋亡小体

凋亡小体是在细胞凋亡的最后阶段, 通过发芽脱落或自噬体形成机制裂解释放出的直径大于1 000 nm的细胞外囊泡^{[70, 71]}。凋亡小体具有高度稳定性、生物相容性和免疫原性^[70], 且具有体积小、循环时间长、隐身能力强的优点^[72]。

凋亡小体的产生过程是细胞凋亡的自然过程, 通过标准化操作可以完全控制细胞凋亡过程。活细胞产生凋亡小体的效率比产生外泌体的效率要高。此外, 凋亡小体会主动释放出以磷脂酰丝氨酸为代表的“eat-me”信号, 引导小胶质细胞将其吞噬, 从而实现靶向药物递送^[72]。

凋亡小体可以由癌细胞、干细胞、免疫细胞、成纤维细胞、内皮细胞和上皮细胞等多种细胞产生, 凋亡小体的特性与其细胞来源有关^[73]。与脂质体、纳米颗粒等需要与特定基团修饰才能获得靶向能力的药物载体不同, 凋亡小体依靠其来源细胞就可获得靶向能力。如黑色素瘤细胞表面表达的CD44v6蛋白能够特异性地与血脑屏障上的多糖结合, 使黑色素瘤细胞所释放的凋亡小体也相应具有较强的血脑屏障穿透能力^[72]。

肿瘤免疫治疗在近几年得到迅猛发展^{[74, 75]}, 各种免疫检查点抑制剂层出不穷。然而, 由于免疫治疗对低免疫原性的肿瘤微环境影响不大, 仅有小部分患者能从免疫治疗中获益^[76]。胶质瘤属于“冷肿瘤”, 其免疫系统处于抑制状态。cGAMP可以激活Ⅰ型干扰素驱动的炎症反应, 使“冷”肿瘤向“热”肿瘤转化。cGAMP不易穿过细胞膜且易发生酶溶解, 被凋亡小体包被后可被抗原呈递细胞吞噬, 绕过肿瘤细胞的内吞作用并跨越血脑屏障, 从而实现靶向递送^[77]。

3.4 细胞穿透肽

细胞穿透肽是由疏水和/或带正电的侧链组成的寡肽, 易于合成和修饰, 免疫原性和成本较低, 通常由5~30个氨基酸组成, 根据氨基酸的类型和排列可分为阳离子肽、疏水性肽和两性肽^[28]。

可跨越血脑屏障的细胞穿透肽包括angiopep-2、1型人类免疫缺陷病毒转录激活因子(HIV-1 TAT)、环细胞穿透肽、SynB、转运蛋白10 (transportan 10, TP10)、穿透素、GLUT等^{[78, 79]}。

CPPs进入细胞的途径包括能量依赖的内吞作用途径和能量独立的直接穿透途径。pH、浓度、温度均会影响细胞摄取CPPs的途径^[28]。CPPs在较高浓度下经膜渗透进入细胞, 在较低浓度下经内吞作用进入细胞^[80]。大多数CPPs是阳离子肽, 易与细胞膜表面的阴离子基团发生静电相互作用, 从而经吸附介导的胞吞作用非特异性地进入细胞^[27]。

CPPs与载体或特定修饰基团偶联可以提升靶向性。组氨酸修饰的CPPs可用于pH敏感性药物递送, 过表达酶修饰的CPPs可用于酶反应性药物递送^[81]。Angiopep-2可以结合脑内皮细胞顶膜上的LRP-1, 通过受体介导的胞吞作用穿过血脑屏障, 同时靶向胶质母细胞瘤^[82]。将angiopep-2与吗啡-6-葡萄糖醛酸盐偶联可显著改善血脑屏障渗透, 有效发挥镇痛作用, 同时减少外周不良反应的发生^[83]。此外, 血脑屏障穿梭肽PB5-3与重组腺相关病毒特异性结合后转胞吞效率显著提升^[84]。细胞穿透肽SynB3还可以与MMP-2敏感肽结合形成双功能肽, 与紫杉醇偶联后组成药物-肽纳米复合物, 对裸鼠脑胶质瘤的抑制作用较强^[78]。

3.5 细胞靶向肽

细胞靶向肽是指具有细胞或组织特异性结合活性的肽。药物与细胞靶向肽偶联可以增加药物在靶器官中的积累, 减少药物在无靶向受体的正常细胞中的富集, 从而降低外周不良反应, 减少耐药的发生^[85]。与细胞穿透肽不同, 细胞靶向肽经受体介导的胞吞作用跨越血脑屏障。

可跨越血脑屏障的细胞靶向肽包括靶向LRP-1、LRP-2、LDLR、TfR、EGFR的多肽、精氨酸-甘氨酸-天冬氨酸(arginine-glycine-aspartate, RGD) 肽、促性腺激素释放激素肽和生长抑素模拟肽等。

TfR1在血脑屏障内皮细胞和脑肿瘤细胞中均高表达, 其在癌细胞中的表达水平比在正常细胞中几乎高了一个数量级, 且TfR1还与脑肿瘤的病理分级相关。因此, TfR1是参与开发脑肿瘤相关药物的优秀靶标^[86]。T7肽(HAIYPRH) 是一种通过噬菌体技术筛选得到的短肽, 是TfR理想的外源靶向配体。其与内源性转铁蛋白无竞争作用, 且具有易合成、稳定性好、空间位阻小等优点^[87]。肿瘤靶向肽(tumor-targeting peptide, TPP) 还可以与细胞穿透肽联合用于递送紫杉醇(paclitaxel, PTX), 所形成的TPP-CPP-PTX偶联物对肿瘤细胞有较强的靶向能力, 也可减少PTX耐药性的发生^[88]。

4 结语与展望

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中枢神经系统疾病的有效治疗已成为制药科学的一个重大挑战, 血脑屏障的存在导致许多潜在有效的药物难以进入大脑内部发挥作用。因此, 开发新型药物递送系统是改善中枢神经系统疾病治疗困境的关键。脂质体、外泌体、凋亡小体、细胞穿透肽和细胞靶向肽等药物载体因其能够有效穿越血脑屏障而广泛应用于药物递送领域。

其中, 脂质体因其易于修饰且具有良好的生物相容性而在跨血脑屏障研究中占据主导地位。当前研究的突破方向包括增加药物载量、提高药物包封效率和延长药物在体内的循环时间。通过将外泌体和脂质体进行膜融合设计可制造出外泌体-脂质体杂化纳米囊泡, 从而使其同时具有外泌体的内源性靶向特性和人工脂质体的药物递送特性^{[89, 90]}。外泌体和凋亡小体的功能不仅限于药物递送, 还包括参与细胞间通讯, 显示出广阔的临床应用前景。

随着分子生物学和药理学研究的深入, 未来将发现更多与血脑屏障相关的靶点。对脑内皮细胞进行蛋白质组学分析可以帮助识别新的RMT靶点^[91], 这些靶点的发现将为药物设计提供新思路。精准医疗是医学科技发展的前沿方向, 基因组学、蛋白质组学和大数据分析的结合有助于开发出更加个性化的药物递送系统, 根据患者的疾病状态和遗传背景定制出个性化治疗方案。

尽管跨血脑屏障药物递送系统的开发取得了显著进展, 但仍面临一些挑战。目前该领域存在的最大挑战是临床转化困难。临床研究侧重安全性, 而药物载体经修饰或载药后的稳定性和毒性变化尚不清楚^[92]。

目前众多药物载体的研究仅停留在载体跨过血脑屏障的过程, 而很少研究其入脑后的内化过程、作用机制及在脑内的分布、蓄积情况。由于跨血脑屏障药物递送系统的药代动力学大多涉及游离药物、包封药物和空载体之间复杂的相互作用, 传统的药代动力学(pharmacokinetics, PK) 模型无法准确描述该递送系统的脑内过程。因此, 目前极缺乏可靠的分析方法预测药物载体的脑内行为, 对组织、细胞中的药物进行定量, 并对药物在靶细胞中释放的速率和效率进行测量, 以评价药物载体用于脑内给药的安全性和有效性。与传统的小分子药物不同, 外泌体、凋亡小体是由活细胞自然释放出的药物载体, 其大小具有异质性, 分离纯化是其大规模生产的难题。此外, 有效质量控制措施的缺乏也是其临床转化的一大阻碍。

跨血脑屏障药物递送领域的另一大挑战是血脑屏障模型的缺乏。由于动物与人类的同源性较差, 不同物种的血脑屏障转运体功能差异较大^[93], 因而许多在临床前研究中表现良好的药物递送系统在人体上的效果却并不理想甚至存在潜在毒性。血脑屏障的细胞模型缺乏细胞间的相互作用, 与血脑屏障的生理状态相关性较差, 仅适用于早期高通量筛选^[94]。而类器官模型缺乏功能性血管系统, 会影响各种细胞类型的分化和成熟^[95], 且价格比较昂贵。因此, 现有血脑屏障模型都不能准确反映人类血脑屏障的状态, 甚至体内外模型的评价结果还存在不一致的可能, 这极大地阻碍了跨血脑屏障药物递送系统的临床转化。为了更好地研发和测试新型药物递送系统, 需要开发更为精确的血脑屏障模型, 这些模型应更好地模拟人类血脑屏障的结构和功能, 以便评估药物递送系统的有效性和安全性。

作者贡献: 曹婉昕负责论文的撰写、图片与表格的绘制; 杨艺辉、杨红、张森、张宜之、许芳、李婉、郝悦、李晓雪、张旭负责文献收集与分析; 王金华负责论文的选题、构思并指导文章的撰写; 王金华、杜冠华负责稿件的修改与校对。所有作者阅读并认可终稿。

利益冲突: 本文作者声明无利益冲突。

基金

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中国医学科学院创新工程基金(2021-12M-1-029)
中国医学科学院创新工程基金(2023-12M-2-006)

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2024年第59卷第12期

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doi: 10.16438/j.0513-4870.2024-0732

接收时间：2024-07-30
首发时间：2025-11-24
出版时间：2024-12-12

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收稿日期：2024-07-30
修回日期：2024-09-27

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中国医学科学院创新工程基金(2021-12M-1-029)

中国医学科学院创新工程基金(2023-12M-2-006)

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1.中国医学科学院、北京协和医学院药物研究所, 北京市药物靶点研究与新药筛选重点实验室, 北京 100050

2.沈阳药科大学, 辽宁沈阳 117004

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^*王金华, Tel: 13810230480, E-mail: wjh@imm.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Nanoparticle class	Classification
Lipid-based NP	Liposomes, solid lipid NP, nanoemulsions
Polymeric NP	Dendrimers, lactic-co-glycolic acid NP, polystyrene NP, poly (β-amino ester) NP, polyanhydride NP, chitosan NP, polycaprolactone NP
Inorganic NP	Gold NP, carbon nanotubes NP, mesoporous silica NP
Biological NP	Exosomes, microvesicles, apoptotic bodies

Nanoparticle class

Classification

Lipid-based NP

Liposomes, solid lipid NP, nanoemulsions

Polymeric NP

Dendrimers, lactic-co-glycolic acid NP, polystyrene NP, poly (β-amino ester) NP, polyanhydride NP, chitosan NP, polycaprolactone NP

Inorganic NP

Gold NP, carbon nanotubes NP, mesoporous silica NP

Biological NP

Exosomes, microvesicles, apoptotic bodies

Type	Classification
Cell-penetrating peptides	Angiopep-2, HIV-1, TAT, cyclic cell-penetrating peptide, glucose transporter, SynB peptide, penetratin
Cell-targeting peptides	Somatostatin mimicking peptide, arginine-glycine-aspartate peptide, gonadotropin releasing hormone peptide

Type

Classification

Cell-penetrating peptides

Angiopep-2, HIV-1, TAT, cyclic cell-penetrating peptide, glucose transporter, SynB peptide, penetratin

Cell-targeting peptides

Somatostatin mimicking peptide, arginine-glycine-aspartate peptide, gonadotropin releasing hormone peptide

Type	Characteristic	Strength	Weakness
Liposomes	30-2 500 nm; spherical vesicle system consisting of lipid bilayer surrounding water nucleus	Amphipathy; biocompatibility; degradable	Rapid elimination from bloodstream; CARPA
Exosomes	30-150 nm; released by multivesicular body; formed by the inward budding of the cell plasma	Biocompatibility; payload flexibility; low toxicity and low immunogenicity; stability	Rapid elimination from bloodstream; complex purification process
Apoptotic bodies	> 1 000 nm; formed by the outward budding of the cell plasma during cellular apoptosis	High stability; biocompatibility; long circulation time; stealth capacity	Uneven size distribution; complex composition
Cell-penetrating peptides	Oligopeptides consisting of hydrophobic and/or positively charged side chains	Potential for surface modification; low immunogenicity	Lack of cell specificity; poor internal stability
Cell-targeting peptides	Cell/tissue-specific binding activity	Biocompatibility; reduce peripheral side effects and drug resistance	Short half-life period

Type

Characteristic

Strength

Weakness

Liposomes

30-2 500 nm; spherical vesicle system consisting of lipid bilayer surrounding water nucleus

Amphipathy; biocompatibility; degradable

Rapid elimination from bloodstream; CARPA

Exosomes

30-150 nm; released by multivesicular body; formed by the inward budding of the cell plasma

Biocompatibility; payload flexibility; low toxicity and low immunogenicity; stability

Rapid elimination from bloodstream; complex purification process

Apoptotic bodies

> 1 000 nm; formed by the outward budding of the cell plasma during cellular apoptosis

High stability; biocompatibility; long circulation time; stealth capacity

Uneven size distribution; complex composition

Cell-penetrating peptides

Oligopeptides consisting of hydrophobic and/or positively charged side chains

Potential for surface modification; low immunogenicity

Lack of cell specificity; poor internal stability

Cell-targeting peptides

Cell/tissue-specific binding activity

Biocompatibility; reduce peripheral side effects and drug resistance

Short half-life period