Rechenmacher Florian, Steigerwald Kristin, Laufer Burkhardt, Neubauer Stefanie, Kapp Tobias G, Li Liang, Mas-Moruno Carlos, Joner Michael, Kessler Horst
Institute for Advanced Study at the Department of Chemistry, Technische Universität München, Lichtenbergstraße 4, 85748 Garching (Germany).
ChemMedChem. 2014 Jul;9(7):1413-8. doi: 10.1002/cmdc.201400078. Epub 2014 Apr 6.
The use of highly active and selective integrin ligands in combination with stent implantation is emerging as a promising alternative to the release of classical immunosuppressive drugs by current drug-eluting stents (DES), which has been associated with delayed vascular healing and late stent thrombosis. Herein we present the development and biological evaluation of the integrin ligand c(RGDf(NMe)Nal) as a potent anti-proliferative molecule that targets coronary artery smooth muscle cells (CASMCs). This peptide showed an antagonistic activity for αvβ3 and αvβ5 in the low-nanomolar range, and selectivity against the platelet receptor αIIbβ3. In vitro, it efficiently inhibited the proliferation of CASMCs, displaying higher potency than the anti-tumor drug candidate cilengitide. This peptide was then loaded into a polymer-free bare metal stent (BMS), and its release studied at different time points. Up to seven days of elution, the peptide-coated stents retained high anti-proliferative activity toward CASMCs. Finally, the peptide was examined in vivo in a polymer-free DES system in a rabbit iliac artery model. After 28 days of implantation, histopathological analysis revealed that the peptide clearly decreased neointimal growth and improved vessel healing and re-endothelialization compared with the FDA-approved Cypher DES. Our study shows that this type of lipophilic integrin ligand, when eluted from a polymer-free stent system, has the potential to successfully decrease in-stent restenosis in the absence of delayed vascular healing.
将高活性和选择性的整合素配体与支架植入相结合，正逐渐成为一种有前景的替代方案，以取代目前药物洗脱支架（DES）释放经典免疫抑制药物的方式，后者与血管愈合延迟和晚期支架血栓形成有关。在此，我们展示了整合素配体c(RGDf(NMe)Nal)作为一种靶向冠状动脉平滑肌细胞（CASMCs）的有效抗增殖分子的研发及生物学评估。该肽在低纳摩尔范围内对αvβ3和αvβ5表现出拮抗活性，且对血小板受体αIIbβ3具有选择性。在体外，它能有效抑制CASMCs的增殖，其效力高于抗肿瘤候选药物西仑吉肽。然后将该肽加载到无聚合物的裸金属支架（BMS）中，并在不同时间点研究其释放情况。在长达七天的洗脱过程中，肽涂层支架对CASMCs保持着高抗增殖活性。最后，在兔髂动脉模型的无聚合物DES系统中对该肽进行体内研究。植入28天后，组织病理学分析显示，与FDA批准的Cypher DES相比，该肽明显减少了新生内膜生长，改善了血管愈合和再内皮化。我们的研究表明，这种亲脂性整合素配体从无聚合物支架系统洗脱时，有潜力在不导致血管愈合延迟的情况下成功减少支架内再狭窄。
