The integrin ligand c(RGDf(NMe)Nal) reduces neointimal hyperplasia in a polymer-free drug-eluting stent system.
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.
Institute for Advanced Study at the Department of Chemistry, Technische Universität München, Lichtenbergstraße 4, 85748 Garching (Germany).
Florian
F
Rechenmacher
Kristin
K
Steigerwald
Burkhardt
B
Laufer
Stefanie
S
Neubauer
Tobias G
TG
Kapp
Liang
L
Li
Carlos
C
Mas-Moruno
Michael
M
Joner
Horst
H
Kessler
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D054855:Drug-Eluting Stents; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology; D016023:Integrins / Q000737:chemistry* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D011817:Rabbits; D012910:Snake Venoms / Q000737:chemistry* / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
D007166:Immunosuppressive Agents; D016023:Integrins; D009842:Oligopeptides; D011108:Polymers; D012910:Snake Venoms; C422910:Cilengitide; C047981:arginyl-glycyl-aspartic acid
RGD; drug-eluting stents; integrin ligands; myocardial infarction; peptides; smooth muscle cells