Periadventitial drug delivery for the prevention of intimal hyperplasia following open surgery

Abstract

Background Intimal hyperplasia (IH) remains a major cause of poor patient outcomes after surgical revascularization to treat atherosclerosis. A multitude of drugs have been shown to prevent the development of IH. Moreover, endovascular drug delivery following angioplasty and stenting has been achieved with a marked diminution in the incidence of restenosis. Despite advances in endovascular drug delivery, there is currently no clinically available method of periadventitial drug delivery suitable for open vascular reconstructions. Herein we provide an overview of the recent literature regarding innovative polymer platforms for periadventitial drug delivery in preclinical models of IH as well as insights about barriers to clinical translation. Methods A comprehensive PubMed search confined to the past 15 years was performed for studies of periadventitial drug delivery. Additional searches were performed for relevant clinical trials, patents, meeting abstracts, and awards of NIH funding. Results Most of the research involving direct periadventitial delivery without a drug carrier was published prior to 2000. Over the past 15 years there have been a surge of reports utilizing periadventitial drug-releasing polymer platforms, most commonly bioresorbable hydrogels and wraps. These methods proved to be effective for the inhibition of IH in various animal models (e.g. balloon angioplasty, wire injury, and vein graft), but very few have advanced to clinical trials. There are a number of barriers that may account for this lack of translation. Promising new approaches including the use of nanoparticles will be described. Conclusions No periadventitial drug delivery system has reached clinical application. For periadventitial delivery, polymer hydrogels, wraps, and nanoparticles exhibit overlapping and complementary properties. The ideal periadventitial delivery platform would allow for sustained drug release yet exert minimal mechanical and inflammatory stresses to the vessel wall. A clinically applicable strategy for periadventital drug delivery would benefit thousands of patients undergoing open vascular reconstruction each year.

Heparin-functionalized polymer graft surface eluting MK2 inhibitory peptide to improve hemocompatibility and anti-neointimal activity

“…To prevent these adverse clinical outcomes, various approaches combining with potent therapeutic agents ( e.g. , simple drug-coating/blending, hydrogel coating, nanoparticles) have been explored so far [12]. However, there is still an unmet need in terms of long-term drug delivery because burst release at the early stage of drug elusion limits their endovascular delivery and anti-hyperplasia effects.…”

“…When a vascular graft is implanted, the mechanical and biochemical stresses ( e.g., transforming growth factor-beta; TGF-β, platelet-derived growth factor; PDGF) triggered by vascular injury result in pathologic remodeling including intimal thickening and graft stenosis/occlusion, ultimately leading to graft failure [11]. Various drugs that can inhibit abnormal activities of VSMCs were employed to prevent development of intimal hyperplasia [12]. In particular, we have been studying potent inhibitory effects of a cell-penetrating peptide inhibitor of Mitogen Activated Protein Kinase II (MK2i) on neointimal hyperplasia, fibrosis and inflammation [7, 13].…”

Unimolecular Micelle-Based Hybrid System for Perivascular Drug Delivery Produces Long-Term Efficacy for Neointima Attenuation in Rats

“…2 Thus, there is a great clinical need for drug delivery methods that can be applied concomitantly with these open surgical procedures, 8 as the treated artery or bypass conduit is readily accessible at this time, making perivascular drug administration achievable. 2 …”

“…2,9 In the past decade, various materials and platforms have been tried for perivascular drug delivery and shown efficacy in animal models, 9–16 but none has reached clinical application. 2,8,17 (Re)stenosis in humans is progressive; thus, it demands sustained drug release for treatment. Unfortunately, the majority of the animal tests on perivascular drug delivery were short-term (2–4 weeks).…”

“…Unfortunately, the majority of the animal tests on perivascular drug delivery were short-term (2–4 weeks). 2 To our knowledge, long-term tests extending to 3 months or longer have been extremely rare.…”