Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries

Abstract

Aim:The use of currently marketed drug-eluting stents (DES) presents safety concerns, including an increased risk for late thrombosis in the range of 0.6% per year in patients, including acute coronary syndrome, which is thought to result from delayed endothelial healing effects. A new DES system targeting vascular smooth muscle cells without adverse effects on endothelial cells is therefore needed. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of restenosis; therefore, we hypothesized that imatinib mesylate (PDGF receptor tyrosine kinase inhibitor) encapsulated bioabsorbable polymeric nanoparticle (NP)-eluting stent attenuates in-stent neointima formation. Methods: Effects of imatinib-incorporated NP-eluting stent on neointima formation and endothelial healing were examined in a pig coronary artery stent model. Effects of imatinib-NP were also examined in cultured cells. Results: In a cultured cell study, imatinib-NP attenuated the proliferation of vascular smooth muscle cells associated with inhibition of the target molecule (phosphorylation of PDGF receptor-), but showed no effect on endothelial proliferation. In a pig coronary artery stent model, imatinib-NPeluting stent markedly attenuated in-stent neointima formation and stenosis by approximately 50% as assessed by angiographic, histopathological, and intravascular ultrasound imaging analyses. Imatinib-NP-eluting stent also attenuated MAP kinase activity, but did not affect inflammation and re-endothelialization. Conclusion: These data suggest that suppression of neointima formation by a imatinib-NP-eluting stent holds promise as a molecular-targeting NP delivery system for preventing in-stent restenosis.

Pitavastatin-Incorporated Nanoparticle-Eluting Stents Attenuate In-Stent Stenosis without Delayed Endothelial Healing Effects in a Porcine Coronary Artery Model

“…The results are expressed as a percentage of the total surface area above or between struts or the total and percentage area lacking coverage at each repeated crown along the longitudinal axis from the proximal to the distal orientation. Endothelial cells were identified as sheets of spindle-or polygonal-shaped monolayers in close apposition, a distinguishing feature from other cell types in en face preparations 24) . By contrast, intimal smooth muscle cells showed elongated processes and were generally stacked in disorganized or haphazard layers 24) .…”

“…Endothelial cells were identified as sheets of spindle-or polygonal-shaped monolayers in close apposition, a distinguishing feature from other cell types in en face preparations 24) . By contrast, intimal smooth muscle cells showed elongated processes and were generally stacked in disorganized or haphazard layers 24) . Other adherent cells present on stent surfaces included platelets, characteristically 1 to 2 μm in size with an irregular discoid appearance, and inflammatory cells, which were round and varied from 7 to 10 μm in diameter with a ruffled surface.…”

Cardiovascular therapy through nanotechnology – how far are we still from bedside?

“…Another approach was tested by Tsukie et al (107), who utilized a novel bioabsorbable polymeric nanoparticle-eluting stent (NES) that provides more sustained delivery of therapeutic agents than the common dip-coated DES (108). For this purpose, nanoparticles were produced containing pitavastatin.…”

Anti-inflammatory Nanoparticle for Prevention of Atherosclerotic Vascular Diseases

“…By coating stents with PLGA-NPs containing anti-proliferative or anti-inflammatory drugs, these stents can be used to prevent restenosis after vascular intervention. We have reported a novel method to coat metal stents electrically and demonstrated the in vivo efficacy of stents coated with nanoparticles incorporated with imatinib mesylate, a tyrosine kinase inhibitor of PDGF receptor (ImatinibNPs), or Pitava-NPs 46,47) . After implantation of these stents in injured vasculatures, drugs coated on the stents surface are released and delivered to the surrounding vascular walls.…”