The 15th Annual Meeting 2009 Japan Society of Gene Therapy : Date July 9–11, 2009 Venue Osaka University Convention Center 1-1, Yamada–oka, Suita–city 565-0871, Osaka JSGT Home–page URL: http://jsgt.jp

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 793 KB
• Volume: 12
• Category: Article
• ISSN: 1099-498X
• DOI: 10.1002/jgm.1532

✦ Synopsis

Background: Drug-eluting stents (DES) have been highly successful in reducing in-stent restenosis; however, current DES are associated with increased late stent thrombosis, an often catastrophic complication. Late stent thrombosis is likely due to long-term antiproliferative effects of the current ''anti-healing'' drugs used to coat stents, which impair healing of the stented arterial wall. Polymers used in the construction of DES may also impair healing. These ''anti-healing'' drugs are used in most of newer generation of DES, which would continue to create similar safety concerns till proven otherwise. The use of ''pro-healing'' approach, that accelerates re-endothelialization, protects against thrombosis, and decreases restenosis, would be warranted. The current methods used to construct DES involve dip or spray techniques that are useful for strongly lipophilic drugs (rapamycin, paclitaxel etc). Biodegradable polymeric nanoparticle (NP)-eluting stent capable of releasing watersoluble drugs, including oligonucleotides, may be highly advantageous.

Methods and Results:

The current study shows promising preliminary data that such a NP-mediated stent drug delivery platforms is feasible. As one of the ''pro-healing'' candidate drugs for NP-mediated delivery, we selected HMG-CoA reductase inhibitors, so-called statins, because statins have multiple vasculoprotective effects. Statins reportedly promote endothelial regeneration, inhibit VSMC proliferation and attenuate in-stent stenosis in animals. In contrast, clinical studies in humans have reported no definite effects of statins within the clinical dose range on indices of restenosis. Therefore, we hypothesized that statin-NP-eluting stent can deliver adequate therapeutic dosage of statin to the artery and thus be an innovative ''pro-healing'' strategy for treating in-stent stenosis in vivo. To implicate NP-eluting stent design, we firstly compared effects of commercially marketed 6 statins on ''pro-healing'' states and VSMC proliferation, and found pitavastatin a most appropriate statin for this purpose. Importantly, pitavastatin inhibited thrombin-induced tissue factor expression in human endothelial cells, whereas rapamycin enhanced the tissue factor expression. We then formulated pitavastatin-NP-eluting stent (20 µg Pitava per stent). In pig coronary artery model, Pitava-NP-eluting stent attenuated in-stent stenosis as effective as polymer-coated sirolimus-eluting stent (SES). In SES sites, anti-healing effects such as impaired endothelilal cell coverage on stent sites as well as increased inflammation and fibrin deposition, were observed. In contrast, the opposite pro-healing effects such as normal endothelial coverage and minor inflammation and fibrin deposition, were observed in Pitava-NP-eluting stent sites. Conclusion: Pitava-NP-eluting stents attenuated in-stent stenosis as effective as SES with pro-healing effects seen with SES and elicited pro-healing effects in porcine coronary artery model. This approach may provide the optimal prohealing strategy: inhibition of VSMC proliferation to decrease restenosis and promotion of re-endothelialization to protect from late stent thrombosis.