Precise Regulation of Inflammation and Oxidative Stress by ROS-Responsive Prodrug Coated Balloon for Preventing Vascular Restenosis

Abstract

Vascular restenosis after balloon dilation is largely caused by the over-proliferation of smooth muscle cells, which is triggered and exacerbated by local excessive inflammation and oxidative stress. The excessive inflammatory and oxidative stress cause tissue/cell damage, hamper endothelial functions, and worsen intimal hyperplasia and restenosis. A high level of reactive oxygen species (ROS) overproduction is regarded as the main culprit. Therefore, efficiently inhibiting ROS over-production or weightily depleting them is of great significance. Herein, a “ROS-responsive/scavenging prodrug” is introduced into balloon coating for the treatment of vascular restenosis. A reversible phenylboronic ester-bearing caffeic acid (CA) macromolecular prodrug (PBC) is designed for the controlled and on-demand dual-drug release triggered by the local high ROS level; the released CA and 4-hydroxybenzyl alcohol exhibit efficient antioxidant and anti-inflammatory effects by scavenging ROS, thereby regulating vascular microenvironment and protecting endothelium functions. To accelerate endothelium regeneration, pro-endothelial microRNA-126 is further introduced. The ROS-responsive/scavenging prodrug/miRNA balloon coating efficiently prevents intimal hyperplasia, alleviates local inflammation, and improves endothelium healing in a rat abdominal aorta restenosis model, which may provide applicative perspectives for next-generation drug-coated balloons and other cardiovascular diseases treatment.