Drug deposition and distribution in healthy and atherosclerotic arteries and in models of atherosclerosis following bulk or stent-based drug delivery

Abstract

Drug eluting stents have revolutionized the practice of medicine and the landscape of medical devices. Yet, more than four years after introduction clinical trial data and clinical use have still not fully clarified what drives the safety and efficacy of these devices. The goal of this thesis was to help fill this void by describing the mechanisms by which stent-eluted drugs are distributed within healthy and atherosclerotic vascular models. In the first part of the thesis we investigated the effect of drug physicochemical properties on drug deposition, retention, and distribution in a healthy vascular model. We found that hydrophobic drugs are deposited to a far greater degree than hydrophilic drugs, with longer retention times, and distribution patterns that likely track with specific and general binding sites. The second part of the thesis investigated how arterial ultrastructure in health and disease modulates the arterial deposition and distribution of hydrophobic antiproliferative drugs used with drug-eluting stents. We tracked the distribution of radiolabeled and FITC-labeled compounds and demonstrated that macrostructural changes in arterial architecture led to profound changes in drug deposition. Paclitaxel in particular was sensitive to tissue state.

(cont.) This drug binds specifically to tubulin and to lesser extent in a general manner to elastic. Drug levels fell as paclitaxel, tubulin and elastin were displaced by lipid and collagen. These observations might well explain how drugs may partition within different arterial lesions as determined by lesion composition. Finally, we demonstrated that association with these binding sites was governed by association kinetics that reflects the different components of the arterial wall compartments. Slower release kinetics yielded up to 64% higher deposition of a drug from stents implanted in rabbit iliac arteries over a 28-day period. Mathematical modeling illustrates that the dependence of drug deposition on stent release kinetics is contingent on drug retention. Further model development is implicated for predicting drug deposition profiles for different types of drugs, arterial states, and stent release kinetics.