Vascular Lesion-Specific Drug Delivery Systems: JACC State-of-the-Art Review

Abstract

Drug delivery is central to modern cardiovascular care, where drug-eluting stents, bioresorbable scaffolds, and drug-coated balloons all aim to restore perfusion while inhibiting exuberant healing. The promise and enthusiasm of these devices has in some cases exceeded demonstration of efficacy and even understanding of driving mechanisms. The authors review the means of drug delivery in each device, outlining how the technologies affect vascular behavior. They focus on how drug retention and response are governed by lesion morphology: lipid displacing drug-specific binding sites, calcium inhibiting diffusion, blocking thrombi or promoting luminal washout, and vascular healing steering hyperplastic developments. In this regard, the authors outline the fundamental impact of vascular structure on drug delivery and review the development of contemporary and future devices for coronary and peripheral intervention. They look toward a future where incorporating information on lesion distribution is central to therapeutic success and envision a transition toward lesion-specific treatment for improved interventional outcomes.

Keywords: atherosclerosis; drug delivery; endovascular therapy; lesion morphology; lesion-specific treatment.

FIGURE 1. Impact of Atherosclerotic Characteristics on Drug Delivery

Extracts from seminal work, showcasing the impact of vascular and atherosclerotic structure on drug retention. (A) En face microscopy of paclitaxel (PTX) delivery after drug-eluting stent (DES) implantation in ex vivo bovine carotids, clearly showing how drug delivery is governed by stent position and design (115) (reprinted with permission from the American Heart Association). (B) Equilibrium distribution of dextran (DXT), sirolimus (SRL), and PTX in ex vivo calf carotids, showing variations in transluminal tissue-binding (12) (reprinted with permission from the National Academy of Sciences). (C) Transluminal distribution of PTX in atheromatous vs. healthy control rabbits, showing definite effect of lesion complexity (19). (D) Transluminal distribution of SRL in atheromatous vs. healthy control rabbits, showing less effect of lesion complexity (19). (E) Vascular drug retention as a function of lipid content (evaluated in a rabbit model), showing how increasing lipid content reduces drug uptake (19) (C to E reprinted with permission from Elsevier). (F) Drug absorption as a function of calcium content (evaluated in cadaveric postmortem specimens), showing reduced permeation with increasing calcium (24) (reprinted with permission from Elsevier). (G) The presence of stent-induced thrombi (immediately adjacent to the stent strut) blocks transluminal diffusion and reduces uptake compared with control vessel (31) (reprinted with permission from the American Heart Association).

FIGURE 2. Plaque Morphologies and Related Lesion-Specific Approaches

Characteristic plaque morphologies defined according to the modified American Heart Association (AHA) classification, associated interventional obstacles relating to drug delivery, and potential implications of lesion-specific approach (note that these are posed as future perspectives and would have to be validated in randomized controlled trials). DCB = drug-containing balloon; DES = drug-eluting stent.

CENTRAL ILLUSTRATION. Influence of Vascular Biology and Intervention on Drug Delivery

Vascular, atherosclerotic, and device-induced aspects affecting local drug delivery. (A) In the healthy artery, the intima, media, and adventitia present with different levels of permeation blockage, as well as specific and nonspecific binding sites for delivered drug. In the diseased lesion, calcium, lipid, fibrous, and hemorrhagic entities all modify uptake and retention. (B) Device-induced aspects such as endothelial denudation, elastic lamina rupture, mechanical compression, and thrombus also influence the delivery of drug. mTOR = mammalian target of rapamycin; SMC = smooth muscle cell.