Assessing the targeting and fate of cathepsin k antibody-modified nanoparticles in a rat abdominal aortic aneurysm model

Abstract

Abdominal aortic aneurysms (AAAs), a prototypic proteolytic cardiovascular disorder, are localized expansions of the aortal wall. Chronically upregulated and overexpressed proteases irreversibly degrade and disrupt the elastic matrix, which provides stretch and recoil properties to the aortal wall. Adult vascular smooth muscle cells are inherently unable to produce sufficient elastin to form new elastic fibers to naturally repair the aortal wall and the AAA continues to grow until fatal rupture. Surgical intervention is reserved for AAAs with a high risk of rupture, but there is currently no treatment for small, still growing AAAs. We have previously developed matrix regenerative PEG-PLGA nanoparticles (NPs) with pro-elastogenic and anti-proteolytic properties that act synergistically with a released therapeutic. However, strategies are required to effectively deliver these NPs to the disease site to avail of these benefits. We have identified cathepsin K, a protease overexpressed in AAA tissue, as a potential substrate for antibody based active targeting. We sought to assess the safety and biocompatibility of NPs with anti-cathepsin K antibodies conjugated to the NP surface (cat K Ab-NPs) and then assess their biodistribution and retention in both the targeted aorta and non-target organs in a rat AAA model. In this work, we show that cat K Ab-NPs can selectively target the aneurysmal aorta in a rat AAA model. However, there is unwanted NP uptake and retention in non-target organs that can be addressed in future work. Still, cathepsin K is a viable target for active delivery of NPs in an AAA model. Statement of SignificanceWe have previously developed elastic matrix regenerative polymer nanoparticles (NPs), but require strategies to efficiently target the disease site. Antibodies against cathepsin K, an overexpressed protease in abdominal aortic aneurysms, have been conjugated to the NP surface to act as a targeting moiety. In this work, we assessed NP safety and in vivo biodistribution in an aneurysmal rat model and demonstrated positive targeting and retention for up to 2 weeks within the aortal wall.