Development of phospholipid-based nanotherapeutics for treating abdominal aortic aneurysm

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PROJECT SUMMARY/ABSTRACT Abdominal aortic aneurysm (AAA) is defined as a permanent, localized dilatation of the abdominal aorta with the potentially fatal consequence of aortic rupture. The only effective treatment for AAA is open or endovascular surgical repair when AAA patients with symptomatic or large AAA. The vast majority of AAA are below the threshold for surgical repair and 50-70% of small AAAs eventually progress to a stage requiring surgical repair. Currently, there is no effective medical therapy for these patients to reduce aneurysm growth and reduce the risk of rupture, highlighting an urgent need to develop effective medical treatments to prevent aneurysm growth and reduce the risk of rupture. Chronic inflammation and vascular smooth muscle (VSMC) dysfunction have been well documented in AAA pathogenesis in both AAA patients and animal models. Our study and others have shown that macrophage infiltration and VSMC dysfunction can be noted at a very early stage of AAA induction. Inhibition of inflammatory activation effectively reduces development and progression of AAA in animal models. However, several clinical trials have reported no efficacy of several drugs with anti- inflammatory properties to limit AAA progression, indicating a need of new strategies by targeting AAA lesions and suppressing inflammatory responses and preserving VSMC function to prevent and treat AAA. We have been developing nanoparticles (NP) to treat cardiovascular disease since 2014, in which small size NP and/or encapsulated with active therapeutic agents can be precisely applied to the target sites, such as atherosclerotic plaques and AAA lesions. Recently, we generated a novel phospholipid NP (PLN), miNano (Michigan Nanoparticle), which could accumulate in AAA lesions. Our previous studies have demonstrated that Krüppel-like factor 14 (KLF14) has strong anti-inflammatory effects by directly suppressing the nuclear factor- κB p65 expression. Recently, we found that KLF14 play an important role in maintaining VSMC function. Our preliminary studies found that nitro-oleic acid (OA-NO2), a compound currently in Phase 2 clinical trials, could induce KLF14 expression and shows VSMC protective effects in a KLF14-dependent manner. Administration of OA-NO2 protects against AAA formation and progression in mouse model. Based on these findings, we propose the central hypothesis that PLN-mediated delivery OA-NO2, a KLF14 inducer, protects against AAA pathogenesis by maintaining VSMC function and inhibiting vascular inflammation. Aim 1. Define that OA-NO2- KLF14 is a protective pathway in AAA pathogenesis. Aim 2. Develop PLN as an efficient AAA drug delivery system. Aim 3. Determine the ability of PLN-OA-NO2 to reduce AAA dissection and rupture in vivo. This study will promote the development of novel pharmacological therapies for AAA by PLN-mediated targeted drug delivery for highly efficient, more feasible and less side effects.