2. Academic Validation
  3. Targeted drug delivery to the brain endothelium dominates over passive delivery via vascular leak in experimental intracerebral hemorrhage

Targeted drug delivery to the brain endothelium dominates over passive delivery via vascular leak in experimental intracerebral hemorrhage

  • J Control Release. 2023 Apr:356:185-195. doi: 10.1016/j.jconrel.2023.02.037.
Sahily Reyes-Esteves 1,  Jia Nong 2,  Patrick M Glassman 3,  Serena Omo-Lamai 2,  Sarah Ohashi 4,  Jacob W Myerson 2,  Marco E Zamora 2,  Xiaonan Ma 2,  Scott E Kasner 1,  Lauren Sansing 4,  Vladimir R Muzykantov 2,  Oscar A Marcos-Contreras 5,  Jacob S Brenner 6
Affiliations

Affiliations

  • 1 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
  • 2 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
  • 3 Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, United States of America.
  • 4 Department of Neurology, Yale School of Medicine, New Haven, CT, United States of America.
  • 5 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America. Electronic address: oscarmar@pennmedicine.upenn.edu.
  • 6 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America; Division of Pulmonary Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America. Electronic address: jacob.brenner@pennmedicine.upenn.edu.
PMID: 36868517 DOI: 10.1016/j.jconrel.2023.02.037
Abstract

Intracerebral hemorrhage (ICH) is one of the most common causes of fatal stroke, yet has no specific drug therapies. Many attempts at passive intravenous (IV) delivery in ICH have failed to deliver drugs to the salvageable area around the hemorrhage. The passive delivery method assumes vascular leak through the ruptured blood-brain barrier will allow drug accumulation in the brain. Here we tested this assumption using intrastriatal injection of collagenase, a well-established experimental model of ICH. Fitting with hematoma expansion in clinical ICH, we showed that collagenase-induced blood leak drops significantly by 4 h after ICH onset and is gone by 24 h. We observed passive-leak brain accumulation also declines rapidly over ∼4 h for 3 model IV therapeutics (non-targeted IgG; a protein therapeutic; PEGylated nanoparticles). We compared these passive leak results with targeted brain delivery by IV monoclonal antibodies (mAbs) that actively bind vascular endothelium (anti-VCAM, anti-PECAM, anti-ICAM). Even at early time points after ICH induction, where there is high vascular leak, brain accumulation via passive leak is dwarfed by brain accumulation of endothelial-targeted agents: At 4 h after injury, anti-PECAM mAbs accumulate at 8-fold higher levels in the brain vs. non-immune IgG; anti-VCAM nanoparticles (NPs) deliver a protein therapeutic (superoxide dismutase, SOD) at 4.5-fold higher levels than the carrier-free therapeutic at 24 h after injury. These data suggest that relying on passive vascular leak provides inefficient delivery of therapeutics even at early time points after ICH, and that a better strategy might be targeted delivery to the brain endothelium, which serves as the gateway for the immune attack on the peri-hemorrhage inflamed brain region.

Keywords

Brain drug delivery; Endothelial inflammation; Hemorrhagic stroke; Intracerebral hemorrhage; Targeted nanoparticles; Vascular leakage.

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