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The Integrin Ligand c (RGDf( N Me)Nal) Reduces Neointimal Hyperplasia in a Polymer‐Free Drug‐Eluting Stent System
Author(s) -
Rechenmacher Florian,
Steigerwald Kristin,
Laufer Burkhardt,
Neubauer Stefanie,
Kapp Tobias G.,
Li Liang,
MasMoruno Carlos,
Joner Michael,
Kessler Horst
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201400078
Subject(s) - restenosis , neointimal hyperplasia , stent , integrin , in vivo , pharmacology , ligand (biochemistry) , neointima , peptide , vascular smooth muscle , medicine , chemistry , cancer research , receptor , biochemistry , biology , microbiology and biotechnology , smooth muscle
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( N Me)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.