Molecular therapy : the journal of the American Society of Gene Therapy · 2024
Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Nong Jia, Glassman Patrick M, Shuvaev Vladimir V, Reyes-Esteves Sahily, Descamps Helene C, Kiseleva Raisa Y, Papp Tyler E, Alameh Mohamad-Gabriel, Tam Ying K, Mui Barbara L, Omo-Lamai Serena, Zamora Marco E, Shuvaeva Tea, Arguiri Evguenia, Gong Xijing, Brysgel Taylor V, Tan Ai Wen, Woolfork Ashley G, Weljie Aalim, Thaiss Christoph A, Myerson Jacob W, Weissman Drew, Kasner Scott E, Parhiz Hamideh, Muzykantov Vladimir R, Brenner Jacob S, Marcos-Contreras Oscar A
Аннотация
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.