Sunday, May 11, 2025
5/11/2025
Targeted drug delivery for the treatment of cardiovascular disease and its clinical complications - Cardiovascular disease is the leading cause of death world-wide. Two main reasons for this are atherosclerosis, which narrows major arteries, and thrombosis, which results in occlusive blood clots. Despite the ongoing health burden, the translation of experimental therapies has stalled. A common challenge for therapies addressing atherosclerosis and thrombosis is their poor localization in sites of disease such as atherosclerotic plaque and thrombi. Thus, there is a pressing clinical need to develop novel targeting strategies to improve therapeutic accumulation in these sites. I hypothesize that cell-mediated delivery of nanoparticle-encapsulated therapies will improve site-specific therapeutic accumulation to treat atherosclerosis and thrombosis. To test this, I will employ next-generation nanoparticle synthesis technologies (Flash NanoPrecipitation (FNP) and inverse FNP) coupled with cell-mediated delivery for the directed delivery of therapies to atherosclerotic plaque and thrombi. FNP and iFNP are new polymeric nanoparticle synthesis technologies that uniquely address challenges related to scalability for manufacturing. To direct these nanoparticles to sites of vascular injury, I will employ cell-mediated delivery. In this method, nanoparticles can be either loaded into cells ex vivo or decorated with ligands to exploit interactions with internalization receptors specifically expressed on pertinent cells in vivo. Atherosclerosis and venous thrombosis are two disease settings characterized by immunological cell infiltration; as such, they are uniquely suited for the application of cell-mediated delivery of nano-encapsulated therapies. With respect to atherosclerosis, circulating activated monocytes infiltrate into the inflamed arterial wall and differentiate into macrophages, which are centrally important to atherogenesis. Notably, these cells over-express an internalization receptor for folic acid: folate receptor-beta. Herein, I will develop therapeutic-carrying nanoparticles conjugated to folic acid, with the goal of being specifically internalized by activated monocytes/macrophages thereby employing these immune cells as delivery vehicles for the localization of drug to atherosclerotic plaque. As oxidative stress is a key driver of atherosclerotic progression, I will focus on delivering antioxidant interventions. An equally innovative strategy using exogenous neutrophils can be used to treat thrombosis. A key challenge in our treatment of thrombosis is a time-dependent decrease in treatment efficacy, as aging thrombi become increasingly difficult for clot-dissolving (thrombolytic) enzymes to penetrate. Moreover, high doses of thrombolytic enzymes can lead to dangerous bleeding. I propose to address this penetration issue by utilizing neutrophils as cell carriers of thrombolytic proteins encapsulated in polymeric nanoparticles. Neutrophils actively infiltrate thrombi, and can be rapidly loaded ex vivo with polymeric nanoparticles. Employing neutrophils as a delivery vehicle would address the issue of clot penetration and could circumvent the problem of bleeding. Overall, my project aims to develop novel cell-mediated therapeutic delivery platforms with the goal of preventing atherosclerotic plaque progression and treatment of thrombosis.
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