Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke

血脑屏障 缺血性中风 冲程(发动机) 医学 缺血 内科学 中枢神经系统 物理 热力学
作者
Jia Nong,Patrick M. Glassman,Vladimir V. Shuvaev,Sahily Reyes‐Esteves,Hélène C. Descamps,Raisa Y. Kiseleva,Tyler E. Papp,Mohamad‐Gabriel Alameh,Ying K. Tam,Barbara L. Mui,Serena Omo‐Lamai,Marco E. Zamora,Tea Shuvaeva,Evguenia Arguiri,Xijing Gong,Taylor V. Brysgel,Ai Wen Tan,Ashley G. Woolfork,Aalim M. Weljie,Christoph A. Thaiss,Jacob W. Myerson,Drew Weissman,Scott E. Kasner,Hamideh Parhiz,Vladimir R. Muzykantov,Jacob S. Brenner,Oscar A. Marcos‐Contreras
出处
期刊:Molecular Therapy [Elsevier]
卷期号:32 (5): 1344-1358 被引量:13
标识
DOI:10.1016/j.ymthe.2024.03.004
摘要

Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke (AIS). To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and an increase in the infarct volume. To enable targeted delivery to the inflamed BBB, we conjugated lipid nanocarriers (NCs) with antibodies that bind cell adhesion molecules expressed at the BBB. In the transient middle cerebral artery occlusion mouse model, NCs targeted to vascular cellular adhesion molecule-1 (VCAM) achieved the highest level of brain delivery, nearly two orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles with luciferase-encoding mRNA and Cre-recombinase showed selective expression in the ischemic brain. Anti-inflammatory drugs administered intravenously after ischemic stroke reduced cerebral infarct volume by 62% (interleukin-10 mRNA) or 35% (dexamethasone) only when they were encapsulated in VCAM-targeted NCs. Thus, VCAM-targeted lipid NCs represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS. Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke (AIS). To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and an increase in the infarct volume. To enable targeted delivery to the inflamed BBB, we conjugated lipid nanocarriers (NCs) with antibodies that bind cell adhesion molecules expressed at the BBB. In the transient middle cerebral artery occlusion mouse model, NCs targeted to vascular cellular adhesion molecule-1 (VCAM) achieved the highest level of brain delivery, nearly two orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles with luciferase-encoding mRNA and Cre-recombinase showed selective expression in the ischemic brain. Anti-inflammatory drugs administered intravenously after ischemic stroke reduced cerebral infarct volume by 62% (interleukin-10 mRNA) or 35% (dexamethasone) only when they were encapsulated in VCAM-targeted NCs. Thus, VCAM-targeted lipid NCs represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS.
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