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,
• MeSH
• Antiviral Agents administration & dosage   chemistry   pharmacology   pharmacokinetics   MeSH
• Endothelial Cells * drug effects   metabolism   MeSH
• Blood-Brain Barrier * metabolism   MeSH
• Coculture Techniques * MeSH
• Drug Delivery Systems methods   MeSH
• Humans MeSH
• Microbubbles * MeSH
• Oligopeptides * chemistry   administration & dosage   pharmacokinetics   MeSH
• Pericytes * metabolism   drug effects   MeSH
• Polymers chemistry   administration & dosage   MeSH
• Ribavirin administration & dosage   chemistry   pharmacokinetics   MeSH
• Ultrasonic Waves MeSH
• Inflammation drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antiviral Agents MeSH
• arginyl-glycyl-aspartic acid MeSH Browser
• Oligopeptides * MeSH
• Polymers MeSH
• Ribavirin MeSH