Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke

Jia Nong; Patrick M Glassman; Vladimir V Shuvaev; Sahily Reyes-Esteves; Helene C Descamps; Raisa Y Kiseleva; Tyler E Papp; Mohamad-Gabriel Alameh; Ying K Tam; Barbara L Mui; Serena Omo-Lamai; Marco E Zamora; Tea Shuvaeva; Evguenia Arguiri; Xijing Gong; Taylor V Brysgel; Ai Wen Tan; Ashley G Woolfork; Aalim Weljie; Christoph A Thaiss; Jacob W Myerson; Drew Weissman; Scott E Kasner; Hamideh Parhiz; Vladimir R Muzykantov; Jacob S Brenner; Oscar A Marcos-Contreras

doi:10.1016/j.ymthe.2024.03.004

Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke

Mol Ther. 2024 Mar 7:S1525-0016(24)00145-X. doi: 10.1016/j.ymthe.2024.03.004. Online ahead of print.

Authors

Jia Nong¹, Patrick M Glassman², Vladimir V Shuvaev¹, Sahily Reyes-Esteves³, Helene C Descamps⁴, Raisa Y Kiseleva¹, Tyler E Papp⁵, Mohamad-Gabriel Alameh⁵, Ying K Tam⁶, Barbara L Mui⁶, Serena Omo-Lamai⁷, Marco E Zamora¹, Tea Shuvaeva¹, Evguenia Arguiri¹, Xijing Gong⁷, Taylor V Brysgel¹, Ai Wen Tan¹, Ashley G Woolfork¹, Aalim Weljie¹, Christoph A Thaiss⁸, Jacob W Myerson¹, Drew Weissman⁵, Scott E Kasner³, Hamideh Parhiz⁹, Vladimir R Muzykantov¹⁰, Jacob S Brenner¹¹, Oscar A Marcos-Contreras¹²

Affiliations

¹ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, USA.
³ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Acuitas Therapeutics, Vancouver, British Columbia V6T 1Z3, Canada.
⁷ Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: hamideh.parhiz@pennmedicine.upenn.edu.
¹⁰ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: muzykant@pennmedicine.upenn.edu.
¹¹ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Pulmonary Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: jacob.brenner@pennmedicine.upenn.edu.
¹² Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: oscarmar@pennmedicine.upenn.edu.

PMID: 38454606
DOI: 10.1016/j.ymthe.2024.03.004

Abstract

Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke (AIS). To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and an increase in the infarct volume. To enable targeted delivery to the inflamed BBB, we conjugated lipid nanocarriers (NCs) with antibodies that bind cell adhesion molecules expressed at the BBB. In the transient middle cerebral artery occlusion mouse model, NCs targeted to vascular cellular adhesion molecule-1 (VCAM) achieved the highest level of brain delivery, nearly two orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles with luciferase-encoding mRNA and Cre-recombinase showed selective expression in the ischemic brain. Anti-inflammatory drugs administered intravenously after ischemic stroke reduced cerebral infarct volume by 62% (interleukin-10 mRNA) or 35% (dexamethasone) only when they were encapsulated in VCAM-targeted NCs. Thus, VCAM-targeted lipid NCs represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS.

Keywords: drug delivery; drug targeting; ischemic stroke; lipid nanoparticles; neurovascular inflammation.