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Targeting lipid nanoparticles to the blood brain barrier to ameliorate acute ischemic stroke
Preprint   Open access

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

Jia Nong, Patrick M. Glassman, Sahily Reyes-Esteves, Helene C. Descamps, Vladimir V. Shuvaev, Raisa Y. Kiseleva, Tyler E. Papp, Mohamad-Gabriel Alameh, Ying K. Tam, Barbara L. Mui, …
bioRxiv
13 Jun 2023
DOI: https://doi.org/10.1101/2023.06.12.544645
url
https://doi.org/10.1101/2023.06.12.544645View
Preprint (Author's original)Open Access (License Unspecified),  Open

Abstract

After more than 100 failed drug trials for acute ischemic stroke (AIS), one of the most commonly cited reasons for the failure has been that drugs achieve very low concentrations in the at-risk penumbra. To address this problem, here we employ nanotechnology to significantly enhance drug concentration in the penumbra’s blood-brain barrier (BBB), whose increased permeability in AIS has long been hypothesized to kill neurons by exposing them to toxic plasma proteins. To devise drug-loaded nanocarriers targeted to the BBB, we conjugated them with antibodies that bind to various cell adhesion molecules on the BBB endothelium. In the transient middle cerebral artery occlusion (tMCAO) mouse model, nanocarriers targeted with VCAM antibodies achieved the highest level of brain delivery, nearly 2 orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles loaded with either a small molecule drug (dexamethasone) or mRNA (encoding IL-10) reduced cerebral infarct volume by 35% or 73%, respectively, and both significantly lowered mortality rates. In contrast, the drugs delivered without the nanocarriers had no effect on AIS outcomes. Thus, VCAM-targeted lipid nanoparticles represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS.

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