1. Academic Validation
  2. RGD-coated polymeric microbubbles promote ultrasound-mediated drug delivery in an inflamed endothelium-pericyte co-culture model of the blood-brain barrier

RGD-coated polymeric microbubbles promote ultrasound-mediated drug delivery in an inflamed endothelium-pericyte co-culture model of the blood-brain barrier

  • Drug Deliv Transl Res. 2024 Mar 18. doi: 10.1007/s13346-024-01561-6.
Christopher Hark 1 Junlin Chen 1 Julia Blöck 1 Eva Miriam Buhl 2 Harald Radermacher 1 Robert Pola 3 Michal Pechar 3 Tomáš Etrych 3 Quim Peña 1 Anne Rix 1 Natascha I Drude 4 Fabian Kiessling 1 Twan Lammers 5 Jan-Niklas May 6
Affiliations

Affiliations

  • 1 Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University, Aachen, Germany.
  • 2 Electron Microscopy Facility, Institute for Pathology, University Clinic RWTH Aachen, Aachen, Germany.
  • 3 Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.
  • 4 QUEST Center for Responsible Research, Berlin Institute of Health at Charité, Berlin, Germany.
  • 5 Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University, Aachen, Germany. tlammers@ukaachen.de.
  • 6 Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University, Aachen, Germany. jmay@ukaachen.de.
Abstract

Drug Delivery to central nervous pathologies is compromised by the blood-brain barrier (BBB). A clinically explored strategy to promote Drug Delivery across the BBB is sonopermeation, which relies on the combined use of ultrasound (US) and microbubbles (MB) to induce temporally and spatially controlled opening of the BBB. We developed an advanced in vitro BBB model to study the impact of sonopermeation on the delivery of the prototypic polymeric drug carrier pHPMA as a larger molecule and the small molecule Antiviral drug ribavirin. This was done under standard and under inflammatory conditions, employing both untargeted and RGD peptide-coated MB. The BBB model is based on human cerebral capillary endothelial cells and human placental pericytes, which are co-cultivated in transwell inserts and which present with proper transendothelial electrical resistance (TEER). Sonopermeation induced a significant decrease in TEER values and facilitated the trans-BBB delivery of fluorescently labeled pHPMA (Atto488-pHPMA). To study Drug Delivery under inflamed endothelial conditions, which are typical for e.g. tumors, neurodegenerative diseases and CNS infections, tumor necrosis factor (TNF) was employed to induce inflammation in the BBB model. RGD-coated MB bound to and permeabilized the inflamed endothelium-pericyte co-culture model, and potently improved Atto488-pHPMA and ribavirin delivery. Taken together, our work combines in vitro BBB bioengineering with MB-mediated Drug Delivery enhancement, thereby providing a framework for future studies on optimization of US-mediated Drug Delivery to the brain.

Keywords

Blood-brain barrier; Drug delivery; Microbubbles; Sonopermeation; Ultrasound.

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