Abstract 192: Controlled Delivery Of Redox Responsive Polyurethane-polyurea Nanoparticles To Aortic Endothelium And Atherosclerotic Lesions

Objective: Aortic endothelial cell dysfunction is an early trigger of atherosclerosis, the major cause of cardiovascular disease. Nanomedicines targeting vascular endothelium and lesions hold great promise as therapeutic solutions to vascular disorders. The objective of the present study is to investigate macrovascular targeting efficacy of a redox-responsive degradable polyurethane-polyurea nanocapsule (Puua-NC). Approach and Results: Red fluorescent lipophilic cationic indocarbocyanine dye, with DiI as cargo, was encapsulated into Puua-NCs of variable sizes (20, 175, 255 nm in diameter) at a concentration of 8.60, 6.54, and 6.91ng/mg NCs, respectively. In vitro cellular uptake studies with human aortic endothelial cells (HAECs) indicated these different sized Puua-NCs were efficiently taken up by cells, and the cellular uptake of NCs was positively correlated with concentration and incubation time. Exposure of HAECs to dithiothreitol (DTT, a thiol reducing reagent) or diamide (a thiol oxidizing reagent) altered intracellular thiol redox status and broke disulfide bonds on the Puua-NC shell, triggering cell disassembly and release of the encapsulated fluorescent cargo DiI, as evidenced by the loss of bright punctuate red fluorescence and appearance of the weak diffused signals of DiI. Using ApoE deficient mice fed a Western-type diet, a mouse model of atherosclerosis, we showed that intravenously administrated Puua-NCs were efficiently taken up by aortic endothelium and atherosclerotic lesions in vivo . Importantly, internalized Puua-NCs in vascular cells and lesions were rapidly disassembled to release DiI in response to DTT treatment. Conclusions: Puua-NCs demonstrate remarkable affinity to aortic endothelium and atherosclerotic lesions, with disassembly well controlled by redox status. Puua-NCs may be used as a novel redox-responsive degradable nanodevice to deliver drugs and gene materials to the cardiovascular system.