Abstract
Over 600,000 Americans suffer from ischemic stroke annually. Inflammatory consequences of ischemic stroke include upregulation of adhesion molecules (e.g. intercellular adhesion molecule -1, ICAM) by activated endothelial cells. However, drug delivery to the central nervous system remains an emerging challenge. Here we developed anti-ICAM monoclonal antibody conjugated nanocarriers (ICAM/NCs) to target activated endothelial cells in the pathologically-altered neurovasculature. In a mouse model similar to post-stroke neuroinflammation (intra-striatal injection of Tumor Necrosis Factor-alpha, TNF), ICAM/NCs injected intravenously 2 hrs-post TNF injury accumulated in lungs within 30 min (146.7±2.5 % injected dose per gram tissue (%ID/g)). Over 24 hrs, ICAM/NCs slowly accumulated in the brain, resulting in a >4-fold increase in brain uptake (0.22±0.02%ID/g) vs. 30 minutes (0.05±0.01%ID/g), and significant clearance from lungs (Panel A). In addition, dexamethasone (Dex)-loaded ICAM/NCs were protective against TNF induced brain edema, as measured by extravasation of radiolabeled albumin, while free Dex had no protective effects at the same dose (1.5mg/kg) (Panel B). Flow cytometry of single cell suspensions from lungs and brain in TNF mice revealed that ~80% of ICAM/NC-positive cells were leukocytes in the lungs 30 min-post injection (while in naïve animals, ~40% NC-positive cells were leukocytes), and that ~98% of ICAM/NC-positive cells were leukocytes in the brain 24 hr-post injection (Panel C). The flow cytometry data for the lungs and brain indicated that ICAM/NCs target not only endothelial cells but also leukocytes. Targeting to pulmonary leukocytes is further enhanced following pathological challenges. Altogether, our results suggest that delayed brain delivery of ICAM/NCs was partially due to pulmonary leukocytes ferrying NCs from lungs to brain over time. Future work will focus on elucidating the mechanism of brain delivery.
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