Abstract 4526: Stabilization of Aortic Aneurysms via Delivery of Ascorbic Acid and Retinoic Acid Through Polymeric Nanoparticles
OBJECTIVES: Medical therapies have not proven to be effective in halting or reversing the progressive dilation of aneurysms. Further, no therapy exists for small aortic aneurysms due to the significant risks of surgical repair. Smooth muscle cells (SMCs) have the ability to produce extracellular matrix (ECM) that is destroyed in the vessel wall during aneurysm formation. We hypothesized that polymeric nanoparticles bearing ascorbic acid (AA) and retinoic acid (RA) will be effective in reducing inflammation and promoting SMC synthesis of the ECM proteins, collagen and elastin, thus inhibiting aneurysm formation in vivo.
METHODS and RESULTS: Block co-polymer nanoparticles made of polyethylene oxide (PEO) and poly(ϵ-caprolactone) (PCL) capable of bearing both hydrophilic (AA) and hydrophobic (RA) drugs were fabricated by the formation of an organic/aqueous bi-phase stable emulsion. The particles were analyzed to ensure proper spherical morphology, nano diameter, and entrapment of drug prior to in vitro and in vivo testing. Mouse aortic smooth muscle cells (SMCs) demonstrated elevated expression of elastin and collagen type 1α1 relative to control cells within 7 days post treatment with drug-bearing nanoparticles. A PEO/PCL nanofiber matrix was prepared by electrospinning and used to deliver AA/RA loaded nanoparticles to mouse abdominal aortas in vivo immediately following perfusion with elastase to induce an aneurysm. Implantation of the nanofiber matrix prevented aneurysm formation in 83% (5/6) of animals at 14 days, while control animals perfused with elastase uniformly developed aneurysms at 14 days.
CONCLUSIONS: Treatment of SMCs with biodegradable nanoparticles bearing RA and AA increases expression of collagen and elastin, the principle matrix proteins responsible for the mechanical integrity of blood vessels. PEO/PCL nanofibers allow for rapid delivery of nanoparticles to the site of interest and can be effective in preventing experimental aneurysm formation. This novel treatment may eliminate the need for insertion of permanent grafts or stents and may be an effective therapy for patients with small aneurysms.