Multiscale Approaches to Treatment for Atherosclerotic Cardiovascular Disease 4 views

Atherosclerotic cardiovascular disease remains a leading cause of morbidity and mortality, with a complex, multifactorial pathogenesis involving endothelial dysfunction, lipid accumulation, inflammation, oxidative stress, maladaptive vascular remodeling, and plaque progression. Because these disease processes occur across biological pathways and anatomic sites, no single therapeutic modality is likely adequate to fully address disease progression. This dissertation therefore investigates multiscale approaches to the treatment of atherosclerotic cardiovascular disease, spanning nanoscale therapeutic delivery systems to endovascular plaque-directed intervention. First, a review of the emerging role of nanotherapeutics in atherosclerosis, with emphasis on lipid-targeting, inflammation-modulating, and multimodal nanoparticle platforms informs the development of a VCAM-1-targeted peptide amphiphile nanoparticle that localizes to atherosclerotic plaque and establishes a foundation for site-directed vascular therapy. Building upon that platform, this dissertation then evaluates estrogen-loaded targeted nanoparticles as a therapeutic strategy and demonstrates reduced plaque burden in selected in vivo settings, with a particular focus on modeling treatment response in a hormone-depleted rodent model of atherosclerosis. Bridging nanoscale targeted treatment with endovascular intervention, this dissertation next examines a nitric oxide-releasing peptide amphiphile nanofiber in a rat model of arterial injury with concomitant renal failure, showing inhibition of neointimal hyperplasia in a clinically relevant comorbid environment. Finally, this work evaluates a novel endovascular enzymatic plaque-debulking approach in a swine model of atherosclerosis, demonstrating acute plaque reduction while preserving vessel architecture. Taken together, these studies support a central conclusion: the complexity of atherosclerotic cardiovascular disease necessitates treatment strategies across multiple scales. Nanoscale therapeutics offer preventative opportunities for biologically precise targeting and controlled drug delivery, whereas endovascular approaches remain important for directly addressing established, clinically significant plaque burden. This dissertation advances a broader therapeutic framework in which complementary strategies, both pharmacologic and surgical, are used to improve the treatment of atherosclerotic cardiovascular disease.

PHD (Doctor of Philosophy)

atherosclerosis; nanomedicine; cardiovascular disease; peptide amphiphile; plaque

English

2026-04-22