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

Abstract

Aim:The use of currently marketed drug-eluting stents presents safety concerns including increased late thrombosis, which is thought to result mainly from delayed endothelial healing effects (impaired re-endothelialization resulting in abnormal inflammation and fibrin deposition). We recently developed a bioabsorbable polymeric nanoparticle (NP)-eluting stent using a novel cationic electrodeposition technology. Statins are known to inhibit the proliferation of vascular smooth muscle cells (VSMC) and to promote vascular healing. We therefore hypothesized that statin-incorporated NPeluting stents would attenuate in-stent stenosis without delayed endothelial healing effects. Methods: Among six marketed statins, pitavastatin (Pitava) was found to have the most potent effects on VSMC proliferation and endothelial regeneration in vitro. We thus formulated a Pitava-NP-eluting stent (20 μg Pitava per stent). Results: In a pig coronary artery model, Pitava-NP-eluting stents attenuated in-stent stenosis as effectively as polymer-coated sirolimus-eluting stents (SES). At SES sites, delayed endothelial healing effects were noted, whereas no such effects were observed in Pitava-NP-eluting stent sites. Conclusion: Pitava-NP-eluting stents attenuated in-stent stenosis as effectively as SES without the delayed endothelial healing effects of SES in a porcine coronary artery model. This nanotechnology platform could be developed into a safer and more effective device in the future.

Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Left Ventricular Remodeling After Acute Myocardial Infarction by Inhibiting Monocyte-Mediated Inflammation

“…Because PLGA nanoparticles are delivered selectively to inflammatory cells (mainly monocytes) after intravenous administration, 21,22) it is suggested that monocyte-mediated inflammation plays an important role in the mechanism by which pitavastatin-NP exerted beneficial effects in these previous studies. [18][19][20][21] Therefore, in the present study, we used a mouse model of post-infarct LV remodeling and tested the hypothesis that 1) PLGA nanoparticles are selectively delivered to inflammatory cells (mainly activated monocytes) and 2) the nanoparticlemediated targeting of pitavastatin to these inflammatory cells after establishment of MI protects the heart from LV remodeling by inhibiting recruitment of inflammatory monocytes to the infarcted heart.…”

“…[14][15][16][17] We recently reported that nanoparticle-mediated delivery of pitavastatin showed significant therapeutic effects on pulmonary arterial hypertension, 18) restenosis, 19) ischemia-reperfusion injury, 20) and atherosclerosis 21) in animals by inhibiting the MCP1-CCR2 pathway. Because PLGA nanoparticles are delivered selectively to inflammatory cells (mainly monocytes) after intravenous administration, 21,22) it is suggested that monocyte-mediated inflammation plays an important role in the mechanism by which pitavastatin-NP exerted beneficial effects in these previous studies.…”

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.…”

Nanoparticle-Mediated Drug Delivery System for Cardiovascular Disease

“…Possible application of nano-DDS in other cardiovascular diseases may include pulmonary hypertension, 12,17) vein graft disease, 53) and therapeutic neovascularization for clinical limb ischemia 15,18,54) and coronary stents. 14,19) We have started a phase I/IIa investigator initiated clinical trial in Kyushu University Hospital to test the efficacy of PLGA nanoparticle-mediated delivery of pitavastatin in patients with critical limb ischemia (UMIN000008011). Future clinical trials conducted in the next decade may prove the safety and efficacy of nano-DDS for cardiovascular diseases.…”

“…[11][12][13][14][15][16][17][18][19][20] Dendrimers are highly branched macromole-cules with a controlled near monodisperse three-dimensional architecture emanating from a central core. Polymer growth starts from a central core molecule and growth occurs in an outward direction by a series of polymerization reactions, which determines the size of dendrimers starting from a few nanometers.…”