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Nanocarriers Targeting Intercellular Adhesion Molecule Enhance Delivery to the Inflamed Brain
Author(s) -
g Jia,
MarcosContreras Oscar,
Glassman Patrick,
Brenner Jacob,
Muzykantov Vladimir
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03172
Subject(s) - tumor necrosis factor alpha , icam 1 , neuroinflammation , cell adhesion molecule , extravasation , medicine , intercellular adhesion molecule 1 , flow cytometry , pharmacology , blood–brain barrier , dexamethasone , chemistry , pathology , immunology , inflammation , central nervous system
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.