Abstract 16198: Targeting Lipid Nanoparticles to the Blood Brain Barrier to Ameliorate Acute Ischemic Stroke

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There are more than 7.6 million new cases of ischemic strokes annually. Despite numerous unsuccessful drug trials for acute ischemic stroke (AIS), one common reason for their failure is the limited concentration of drugs reaching the at-risk penumbra. To address this issue, we have utilized nanotechnology to significantly enhance drug concentrations in the blood-brain barrier (BBB) of the penumbra. The increased BBB permeability during AIS is believed to be detrimental to neurons due to exposure to toxic plasma proteins. To develop drug-loaded nanocarriers targeted to the BBB, we have conjugated them with antibodies that bind to various cell adhesion molecules (CAMs) on the BBB endothelium. In a mouse model of AIS induced by transient middle cerebral artery occlusion, we compared the accessibility of nanocarriers targeting platelet endothelial CAM (PECAM), intercellular CAM (ICAM), and vascular CAM (VCAM), including liposomes and lipid nanoparticles (LNP). VCAM-targeted liposomes exhibited significantly higher uptake in the ipsilateral hemisphere compared to the contralateral counterpart, and superior targeting with a 2.5-fold higher uptake than ICAM, 1.9-fold higher than PECAM, and 20-fold higher than the untargeted control IgG counterpart (A). Similarly, VCAM-targeted LNP displayed a 3.4-fold, 2.4-fold, and 12.2-fold higher uptake than ICAM, PECAM, and IgG, respectively (B). Flow cytometry analysis revealed that VCAM-targeted liposomes were primarily associated with endothelial cells and leukocytes (C). In a therapeutic study, VCAM-targeted dexamethasone-loaded liposomes or IL-10 mRNA-loaded LNP reduced the infarct volume by 35% and 73%, respectively (D). VCAM/IL-10 mRNA LNP also achieved a 100% survival rate (E) and elevated plasma levels of IL-10. In conclusion, VCAM-targeted lipid nanoparticles provide a novel platform for effectively concentrating drugs within the compromised BBB of the penumbra, thereby improving the outcomes of AIS.