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Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood–brain barrier
Edited by Kristi S. Anseth, University of Colorado Boulder, Boulder, CO, and approved December 31, 2019 (received for review July 15, 2019)

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Significance
Drug delivery to the brain is a challenging and elusive goal. Conjugating with ligands of target molecules including transferrin receptor modestly enhances cerebral accumulation of drugs and drug carriers. We found that conjugating with ligands of VCAM-1 provides order(s) of magnitude higher cerebral accumulation of nanocarriers, especially in the inflamed brain. VCAM-1 targeted nanocarriers loaded with messenger RNA encoding endothelial glycoprotein thrombomodulin cause expression of the transgene in the lumen of cerebral vasculature. This alleviates pathological permeability of the blood–brain barrier in mouse model of neurovascular inflammation. These results provide a basis for precise and effective molecular interventions in the cerebral vasculature.
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.
Footnotes
↵1O.A.M.-C., C.F.G., R.Yu.K., and H.P. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: oscarmar{at}pennmedicine.upenn.edu, coling{at}med.umich.edu, or muzykant{at}mail.med.upenn.edu.
↵3Present addresses: Department of Emergency Medicine and Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
Author contributions: V.R.M. conceived the study; V.R.M. directed the study; O.A.M.-C., C.F.G., R.Yu.K., L.R.W., P.M.G., J.N., J.S.B., D.W., Y.P., and V.R.M. designed research; O.A.M.-C., C.F.G., R.Yu.K., H.P., L.R.W., V.Z.-R., J.W.M., E.D.H., I.T., N.P., A.S., P.M.G., J.N., J.S.B., and M.K. performed research; V.R.M. organized the framework for the collaborative efforts; Y.K.T., T.M., D.W., and Y.P. directed part of the collaborative efforts; O.A.M.-C., R.Yu.K., H.P., V.Z.-R., J.W.M., E.D.H., C.H.V., I.T., N.P., B.L.M., Y.K.T., V.V.S., J.S.B., T.M., D.W., and Y.P. contributed new reagents/analytic tools; V.V.S. provided key knowledge; O.A.M.-C., C.F.G., R.Yu.K., L.R.W., V.Z.-R., J.W.M., C.H.V., P.M.G., Y.P., and V.R.M. analyzed data; B.L.M. and Y.K.T. provided a key reagent (LNPs); and O.A.M.-C., C.F.G., J.W.M., P.M.G., J.S.B., and V.R.M. wrote the paper.
Competing interest statement: O.A.M.-C., H.P., V.V.S., D.W., and V.R.M. are inventors on a patent filed on some aspects of this work. Those interests have been fully disclosed to the University of Pennsylvania.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1912012117/-/DCSupplemental.
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