Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood-brain barrier.

Abstract

Drug targeting to inflammatory brain pathologies such as stroke and traumatic brain injury remains an elusive goal. Using a mouse model of acute brain inflammation induced by local tumor necrosis factor alpha (TNFα), we found that uptake of intravenously injected antibody to vascular cell adhesion molecule 1 (anti-VCAM) in the inflamed brain is >10-fold greater than antibodies to transferrin receptor-1 and intercellular adhesion molecule 1 (TfR-1 and ICAM-1). Furthermore, uptake of anti-VCAM/liposomes exceeded that of anti-TfR and anti-ICAM counterparts by ∼27- and ∼8-fold, respectively, achieving brain/blood ratio >300-fold higher than that of immunoglobulin G/liposomes. Single-photon emission computed tomography imaging affirmed specific anti-VCAM/liposome targeting to inflamed brain in mice. Intravital microscopy via cranial window and flow cytometry showed that in the inflamed brain anti-VCAM/liposomes bind to endothelium, not to leukocytes. Anti-VCAM/LNP selectively accumulated in the inflamed brain, providing de novo expression of proteins encoded by cargo messenger RNA (mRNA). Anti-VCAM/LNP-mRNA mediated expression of thrombomodulin (a natural endothelial inhibitor of thrombosis, inflammation, and vascular leakage) and alleviated TNFα-induced brain edema. Thus VCAM-directed nanocarriers provide a platform for cerebrovascular targeting to inflamed brain, with the goal of normalizing the integrity of the blood-brain barrier, thus benefiting numerous brain pathologies.

• Authors: Oscar A Marcos-Contreras, Colin F Greineder, Raisa Yu Kiseleva, Hamideh Parhiz, Landis R Walsh, Viviana Zuluaga-Ramirez, Jacob W Myerson, Elizabeth D Hood, Carlos H Villa, Istvan Tombacz, Norbert Pardi, Alecia Seliga, Barbara L Mui, Ying K Tam, Patrick M Glassman, Vladimir V Shuvaev, Jia Nong, Jacob S Brenner, Makan Khoshnejad, Tom Madden, Drew Weissmann, Yuri Persidsky, Vladimir R Muzykantov
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 7 Pg. 3405-3414 (02 18 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32005712 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Receptors, Transferrin
• Tfrc protein, mouse
• Thrombomodulin
• Tumor Necrosis Factor-alpha
• Vascular Cell Adhesion Molecule-1
• Intercellular Adhesion Molecule-1

Topics

• Animals
• Antibodies (administration & dosage)
• Blood-Brain Barrier (drug effects, immunology)
• Encephalitis (drug therapy, genetics, immunology)
• Endothelium, Vascular (drug effects, immunology)
• Humans
• Intercellular Adhesion Molecule-1 (genetics, immunology)
• Mice
• Nanomedicine (methods)
• Receptors, Transferrin (genetics, immunology)
• Thrombomodulin (genetics, immunology)
• Tumor Necrosis Factor-alpha (genetics, immunology)
• Vascular Cell Adhesion Molecule-1 (genetics, immunology)