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阿尔茨海默病中跨越血脑屏障的药物递送策略:对三种有前景策略的全面综述

Drug delivery strategies to cross the blood-brain barrier in Alzheimer's disease: a comprehensive review on three promising strategies.

作者信息

de Koning Lotte A, Vazquez-Matias Daniel A, Beaino Wissam, Vugts Daniëlle J, van Dongen Guus A M S, van der Flier Wiesje M, Ries Mario, van Vuurden Dannis G, Vijverberg Everard G B, van de Giessen Elsmarieke

机构信息

Department of Radiology & Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, the Netherlands.

Department of Radiology & Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, the Netherlands.

出版信息

J Prev Alzheimers Dis. 2025 Aug;12(7):100204. doi: 10.1016/j.tjpad.2025.100204. Epub 2025 May 19.


DOI:10.1016/j.tjpad.2025.100204
PMID:40393907
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12321624/
Abstract

The field of Alzheimer's disease (AD) drug development is rapidly changing, with two anti-amyloid monoclonal antibodies (mAbs) having received Food and Drug Administration (FDA) approval, additionally many compounds are in the pipeline. A major obstacle for novel AD therapeutics is the blood-brain barrier (BBB), which restricts passage of particles larger than 400-500 Da. It is estimated that only ∼0.1 % of mAbs, being ∼150 kDa, passes the BBB, which greatly hampers the efficacy of treatment. To enhance treatment efficacy and to lower the drug dose needed, mechanisms that effectively increase drug delivery across the BBB are urgently sought for. This narrative review describes three promising strategies to enhance drug delivery across the BBB in AD: focused ultrasound (FUS) with microbubbles, receptor-mediated transcytosis (RMT) and delivery using nanoparticle carrier systems. FUS and RMT have shown promising preclinical results and are now being tested in humans whereas nanoparticle carrier systems still need further preclinical validation before clinical application in humans. Zr-Immuno-PET provides a unique opportunity to noninvasively monitor and quantitatively assess novel brain delivery methods.

摘要

阿尔茨海默病(AD)药物研发领域正在迅速变化,已有两种抗淀粉样蛋白单克隆抗体(mAb)获得美国食品药品监督管理局(FDA)批准,此外还有许多化合物正在研发中。新型AD治疗药物面临的一个主要障碍是血脑屏障(BBB),它限制大于400 - 500道尔顿的颗粒通过。据估计,分子量约为150 kDa的单克隆抗体只有约0.1%能够通过血脑屏障,这极大地阻碍了治疗效果。为了提高治疗效果并降低所需药物剂量,迫切需要能够有效增加药物通过血脑屏障递送的机制。这篇叙述性综述描述了三种在AD中增强药物通过血脑屏障递送的有前景的策略:联合微泡的聚焦超声(FUS)、受体介导的转胞吞作用(RMT)以及使用纳米颗粒载体系统进行递送。FUS和RMT已在临床前研究中显示出有前景的结果,目前正在进行人体试验,而纳米颗粒载体系统在应用于人体临床之前仍需要进一步的临床前验证。锆 - 免疫正电子发射断层扫描(Zr - Immuno - PET)为无创监测和定量评估新型脑递送方法提供了独特的机会。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3679/12321624/61923fff1be5/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3679/12321624/61923fff1be5/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3679/12321624/61923fff1be5/gr1.jpg

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引用本文的文献

[1]
Breaking Barriers: Delivering Therapeutics to the Brain in Alzheimer's Disease.

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本文引用的文献

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Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier.

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[2]
Microglia-targeted inhibition of miR-17 via mannose-coated lipid nanoparticles improves pathology and behavior in a mouse model of Alzheimer's disease.

Brain Behav Immun. 2024-7

[3]
Scanning ultrasound-mediated memory and functional improvements do not require amyloid-β reduction.

Mol Psychiatry. 2024-8

[4]
Cerebrospinal fluid proteomics in patients with Alzheimer's disease reveals five molecular subtypes with distinct genetic risk profiles.

Nat Aging. 2024-1

[5]
Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease.

N Engl J Med. 2024-1-4

[6]
Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease.

N Engl J Med. 2023-11-16

[7]
Bispecific antibody shuttles targeting CD98hc mediate efficient and long-lived brain delivery of IgGs.

Cell Chem Biol. 2024-2-15

[8]
Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans.

MAbs. 2023

[9]
Optimizing Absorption for Intranasal Delivery of Drugs Targeting the Central Nervous System Using Alkylsaccharide Permeation Enhancers.

Pharmaceutics. 2023-8-10

[10]
Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients.

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