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Research Article

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

View ORCID ProfileOscar 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, and Vladimir R. Muzykantov
PNAS first published January 31, 2020 https://doi.org/10.1073/pnas.1912012117
Oscar A. Marcos-Contreras
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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  • ORCID record for Oscar A. Marcos-Contreras
  • For correspondence: oscarmar@pennmedicine.upenn.edu coling@med.umich.edu muzykant@mail.med.upenn.edu
Colin F. Greineder
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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  • For correspondence: oscarmar@pennmedicine.upenn.edu coling@med.umich.edu muzykant@mail.med.upenn.edu
Raisa Yu Kiseleva
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Hamideh Parhiz
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Landis R. Walsh
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Viviana Zuluaga-Ramirez
bDepartment of Pathology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
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Jacob W. Myerson
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Elizabeth D. Hood
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Carlos H. Villa
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Istvan Tombacz
cInfectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Norbert Pardi
cInfectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Alecia Seliga
bDepartment of Pathology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
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Barbara L. Mui
dAcuitas Therapeutics, Vancouver, BC V6L 2A1, Canada;
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Ying K. Tam
dAcuitas Therapeutics, Vancouver, BC V6L 2A1, Canada;
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Patrick M. Glassman
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Vladimir V. Shuvaev
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;eCenter for Translational Targeted Therapeutics and Nanomedicine, University of Pennsylvania, Philadelphia, PA 19140;
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Jia Nong
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Jacob S. Brenner
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;eCenter for Translational Targeted Therapeutics and Nanomedicine, University of Pennsylvania, Philadelphia, PA 19140;fPulmonary and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Makan Khoshnejad
gThe Wistar Institute, Philadelphia, PA 19104
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Tom Madden
dAcuitas Therapeutics, Vancouver, BC V6L 2A1, Canada;
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Drew Weissmann
cInfectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Yuri Persidsky
bDepartment of Pathology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
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Vladimir R. Muzykantov
aDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;eCenter for Translational Targeted Therapeutics and Nanomedicine, University of Pennsylvania, Philadelphia, PA 19140;
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  • For correspondence: oscarmar@pennmedicine.upenn.edu coling@med.umich.edu muzykant@mail.med.upenn.edu
  1. 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.

  • blood–brain barrier
  • cerebrovascular drug targeting
  • drug delivery to brain
  • mRNA therapy
  • VCAM-1

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.

Published under the PNAS license.

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Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood–brain barrier
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
Proceedings of the National Academy of Sciences Jan 2020, 201912012; DOI: 10.1073/pnas.1912012117

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Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood–brain barrier
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
Proceedings of the National Academy of Sciences Jan 2020, 201912012; DOI: 10.1073/pnas.1912012117
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