Echogenic Targeted Liposomes: Transfection/Drug Delivery

PROJECT SUMMARY/ABSTRACT Atherosclerotic peripheral arterial disease affects 202 million people worldwide and leads to serious health complications, including limb amputation. Peripheral arterial stent implantation ameliorates flow, but ~15% of patients lose patency within a year following treatment due to in-stent and peri-stent restenosis Traditional means to treat arterial disease are hampered by their inability to direct therapeutics to local atheroma components. Direct delivery results in high local bioavailability with decreased dose and toxicity. Pioglitazone is a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist that reduces pro- inflammatory cytokines and generates anti-inflammatory and anti-arteriosclerotic effects. We have developed a novel methodology for local delivery of pioglitazone loaded into fibrin-targeted echogenic liposomes (Atheroglitatide). We are able conjugate a fibrin-targeting peptide to the outer surface of the lipid bilayer, encapsulate octafluoropropane to provide echogenic properties, and include pioglitazone in sufficient quantities to stabilize the stented artery and attenuate the surrounding peri-stent neoatheroma. The use of ultrasonic catheters (EKOS™ Endovascular System (Boston Scientific, Corp., USA)) provides a localized source for therapeutic delivery and ultrasonic penetration to augment atheroma stabilization in the arterial bed at the time of intervention. We have previously demonstrated that therapeutic efficacy was concomitant with ultrasound (US)-mediated bubble activity, or cavitation. We have developed an atheroma stabilization strategy using pretreatment with nitroglycerin followed by infusion of fibrin-targeted pioglitazone-loaded ELIP into stented peripheral arteries using clinically translatable compounds. We demonstrated sustained cavitation nucleated by atheroglitatide infused through the EKOS™ catheter driven with the endovascular system, an FDA-approved ultrasonic delivery system. In these studies, we will complete final product determination and demonstration of effective cavitation nucleation for tissue penetration without causing local tissue damage. Together, these results will provide IND-enabling studies and translation to first in human trials.