Abstract 11635: Device and Formulation Optimization for MK2 Inhibition and Restenosis Prevention at Sites of Peripheral Angioplasty

Abstract

Introduction: Peripheral angioplasty often fails due to intimal hyperplasia (IH), where contractile smooth muscle cells (SMCs) de-differentiate into proliferative, migratory, and pro-inflammatory synthetic SMCs, leading to restenosis. We have formerly shown that potentiation of an MK2 inhibitory peptide (MK2i) via delivery with poly(propyl acrylic acid) (PPAA) can block SMC phenotype switching and neointima formation in a transplant model. This work develops strategies for targeted in vivo MK2i+PPAA delivery to the site of angioplasty. Hypothesis: MK2i+PPAA can be effectively delivered into and retained within the arterial wall using either convective delivery or a coated angioplasty balloon. Methods: These studies have utilized isolated rat aortae as a model tissue. Aortae were balloon damaged and subjected to convective or coated balloon treatment. Delivery and retention of MK2i was determined with confocal microscopy and flow cytometry. MK2i activity was measured using IHC and western blots for pCREB, a downstream substrate of MK2. Results: Convective delivery studies have shown substantial MK2i delivery into the vascular wall, with pre-formed MK2i nanopolyplexes (NPs) having significantly more cell uptake than free MK2i or sequentially delivered PPAA and MK2i. Additionally, we have created a method for layered coating of MK2i+PPAA onto an angioplasty balloon that shows rapid release and successful arterial wall delivery. In efficacy studies, convective delivery of MK2i-NPs and balloon delivery of MK2i+PPAA with 50 mg/mL lactosucrose excipient significantly decreased levels of pCREB downstream of MK2 after balloon damage. Ongoing studies show that both delivery strategies block cellular proliferation in balloon damaged arteries after 7d in a flow loop bioreactor. Conclusions: Convective and coated balloon delivery show promise as strategies for on-target delivery of MK2i+PPAA to peripheral arteries after angioplasty to prevent restenosis.