The integrin ligand c(RGDf(NMe)Nal) reduces neointimal hyperplasia in a polymer-free drug-eluting stent system

Article abstract of DOI:10.1002/cmdc.201400078

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

Full text of DOI:10.1002/cmdc.201400078

CHEMMEDCHEM
FULL PAPERS
DOI: 10.1002/cmdc.201400078
The Integrin Ligand c(RGDf(NMe)Nal) Reduces Neointimal
Hyperplasia in a Polymer-Free Drug-Eluting Stent System
Florian Rechenmacher,[a] Kristin Steigerwald,[b] Burkhardt Laufer,[a] Stefanie Neubauer,[a]
Tobias G. Kapp,[a] Liang Li,[b] Carlos Mas-Moruno,[a, c] Michael Joner,[b, d] and Horst Kessler*[a, e]
The use of highly active and selective integrin ligands in com-
bination with stent implantation is emerging as a promising al-
ternative to the release of classical immunosuppressive drugs
by current drug-eluting stents (DES), which has been associat-
ed 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-prolifer-
ative molecule that targets coronary artery smooth muscle
cells (CASMCs). This peptide showed an antagonistic activity
for avb3 and avb5 in the low-nanomolar range, and selectivity
against the platelet receptor aIIbb3. In vitro, it efficiently inhib-
ited 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 success-
fully decrease in-stent restenosis in the absence of delayed
vascular healing.
Introduction
The development of drug-eluting stents (DES) was a major
breakthrough in the interventional treatment of myocardial in-
farctions and coronary artery disease, as it significantly de-
creased the risk of restenosis, the most significant limitation of
percutaneous coronary intervention using bare metal stents
(BMS).[1] The principle of DES is the deferred release of anti-pro-
liferative drugs such as Rapamycin (sirolimus) or Taxol (paclitax-
el) to avoid re-narrowing of the vessel (Figure 1). In this regard,
the released drug limits proliferation and migration of smooth
muscle cells (SMCs) and thus tissue growth of the newly built
intimal layer, the so-called neointima, an important contributor
[a] Dr. F. Rechenmacher,+ Dr. B. Laufer,+ Dr. S. Neubauer, T. G. Kapp,
Dr. C. Mas-Moruno, Prof. Dr. H. Kessler
Institute for Advanced Study at the Department of Chemistry
Technische Universitꢀt Mꢁnchen
Lichtenbergstraße 4, 85748 Garching (Germany)
E-mail: Kessler@tum.de
[b] Dr. K. Steigerwald,+ L. Li, Dr. M. Joner
Department of Cardiology, Deutsches Herzzentrum Mꢁnchen
Lazarettstraße 36, 80636 Mꢁnchen (Germany)
[c] Dr. C. Mas-Moruno
Biomaterials, Biomechanics and Tissue Engineering Group
Department of Materials Science and Metallurgical Engineering
Technical University of Catalonia (UPC)
Av. Diagonal 647, 08028 Barcelona (Spain)
[d] Dr. M. Joner
CVPath Institute Inc.
19 Firstfield Road, Gaithersburg, MD 20878 (USA)
[e] Prof. Dr. H. Kessler
Faculty of Science, King Abdulaziz University
P.O. Box 80203, Jeddah 21589 (Saudi Arabia)
[+] These authors contributed equally to this work.
Figure 1. Schematic presentation of a drug-eluting stent in a blood vessel.
The released drug (cyan) targets VSMCs to decrease their proliferation in
order to prevent restenosis.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201400078.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2014, 9, 1413 – 1418 1413

CHEMMEDCHEM
FULL PAPERS
www.chemmedchem.org
of in-stent restenosis.[2] However, the major drawback of this
technology is the unspecific inhibition of various cell types. In
particular, most drugs in current use also adversely affect en-
dothelial cells that are necessary to maintain anti-thrombotic
properties and vasomotor function of the artery,[2,3] thus im-
pairing stent re-endothelialization and vascular healing. The
endothelial layer represents the physiological layer of the inner
vessel wall, and has important functions such as regulating
thrombosis, inflammation, and vessel tonus.
geting this subtype with a highly avb3-active peptide released
from a DES. Furthermore, a compound that can be used in
a polymer-free stent system would be of high interest, because
of the above-mentioned side effects of polymers applied in
this context.
In this work, we designed and synthesized the avb3 integrin
ligand c(RGDf(NMe)Nal) as an anti-proliferative molecule
(Scheme 1) and evaluated its biological potency when released
from a polymer-free DES in a rabbit iliac artery model. The
peptide, which is a derivative of the anti-angiogenic drug can-
didate cilengitide,[15] was first assessed in vitro regarding its
anti-proliferative potential to inhibit coronary artery smooth
muscle cell (CASMC) proliferation. In a further experiment, the
integrin ligand was loaded onto a microporous BMS using
a previously established customizable spray-coating technolo-
gy.[7a] Following implantation of these novel DES in healthy
iliac arteries of New Zealand white rabbits, histopathological
assessment was performed at follow-up of 28 days relative to
BMS as well as to the FDA-approved Cypher DES.
Furthermore, most of the currently approved DES use per-
manent polymers to facilitate drug coating and modulate drug
release kinetics. This represents another potential issue, be-
cause it has been reported that the permanent presence of
these polymers is associated with inflammatory and hypersen-
sitivity reactions, important drivers of delayed vascular heal-
ing.[4] Delayed arterial healing has been identified as the key
risk factor for late stent thrombosis, an often fatal event in pa-
tients,[5] and new evidence has emerged that this may also be
the underlying cause for late restenotic events owing to pre-
mature neoatherosclerotic changes in patients treated with
DES.[6] For these reasons, current research has focused on the
improvement of polymer-free or biodegradable DES systems
to enhance and accelerate vessel wall healing.[7]
Results and Discussion
In our study, we aimed at targeting the avb3 integrin known
to play an important role in VSMC proliferation, but in a poly-
mer-free approach, in contrast to previously reported studies.
Starting with the drug candidate cilengitide c(RGDf(NMe)V),
which is active for avb3 in the sub-nanomolar range and for
avb5 and a5b1 in the low-nanomolar range,[15b] we tried to in-
troduce lipophilic amino acids without affecting its biological
properties. Lipophilicity is an important criterion for this pre-
clinical application, as the compound must be slowly eluted
from the polymer-free surface of a microporous BMS. In this
context, enhanced hydrophilicity of the drug would lead to
rapid elution from the stent during blood passage. On the
other hand, very high lipophilicity often leads to excessive
serum binding, thus lowering the biological activity.
Integrins are of crucial relevance for the interaction between
vascular cells and the extracellular matrix (ECM) during the
process of neointima formation after coronary interventions.
Especially integrins avb3, avb5, and a5b1 are key players in
migration, proliferation, and survival of cells.[8] The fact that in-
tegrins are promising targets for blocking proliferation, and as
a consequence angiogenesis, has stimulated the development
of integrin ligands in medicinal chemistry.[9] One of the most
prominent binding motifs in ECM proteins is the RGD se-
quence,[10] which is recognized by nearly half of the 24 hetero-
dimers known to date, including all av integrins binding to vi-
tronectin, the fibronectin binding integrin a5b1, and the plate-
let integrin aIIbb3. Thus, mimicking the RGD binding motif
with peptides or peptidomimetics possessing defined integrin
subtype-selectivity profiles is a powerful approach to target
these integrins.[11] However, the interplay of integrins during
vascular development is very complex, and it has not yet been
fully elucidated which integrin subtype plays the most impor-
tant role in this context.[12] The levels of different integrin sub-
types, such as avb3, avb5, or a5b1, expressed on vascular
smooth muscle cells (VSMCs) as well as on endothelial cells
may vary during the process of neointima formation, leading
to a dynamically changing integrin pattern.
It has been shown that the valine residue of cilengitide can
be easily substituted with other amino acids without a notable
loss in activity, offering a suitable position for functionalization
purposes.[16] Thus, a series of lipophilic residues were intro-
duced in such position leading to a small library of cilengitide
derivatives with increased lipophilicity (peptides 1–5,
Scheme 1). In preliminary cell proliferation assays (data not
shown), compounds 1–3 showed excellent and similar anti-
proliferative properties; however, whereas in peptide 1 the l-2-
naphthylalanine building block could be incorporated directly
on solid phase (Scheme 1), the functionalization of 2 and 3 re-
quired an extra synthetic step in solution. Peptide 4 failed to
reproduce the same biological activity due to insufficient load-
ing onto the stent surface, and 5 was insoluble in water as
a consequence of the high lipophilicity of its acyl chains. For
these reasons, peptide 1 c(RGDf(NMe)Nal) was chosen as
promising candidate and evaluated in a solid-phase integrin
binding assay regarding its biological activity (Scheme 1). The
binding affinity for integrins avb3 and avb5 was retained
almost completely relative to cilengitide. Furthermore,
1 showed no activity for the blood platelet integrin aIIbb3
Owing to the shortcomings of first-generation DES, alterna-
tive coating strategies of coronary stents were focused on
a more specific disruption of neointimal growth without caus-
ing excess collateral damage including delayed vascular heal-
ing. In this regard, combining stent therapy with systemic in-
tegrin inhibitors or direct stent coating with integrin ligands
was reported to result in a more favorable reduction of neoin-
timal growth relative to contemporary DES releasing immuno-
suppressive drugs.[13] Because RGD peptides can interact with
integrins in a potent manner and block cell proliferation, and
as SMCs strongly express the avb3 subtype,[14] we aimed at tar-
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2014, 9, 1413 – 1418 1414

CHEMMEDCHEM
FULL PAPERS
www.chemmedchem.org
Scheme 1. Fmoc-based, solid-phase peptide synthesis of 1, structures of peptides 1–5, and activities of 1 for the integrin subtypes avb3 and avb5 relative to
cilengitide. a) piperidine/DMF (1:4); b) Fmoc-Gly-OH, HATU, HOAt, DIEA, DMF; c) piperidine/DMF (1:4); d) Fmoc-Arg(Pbf)-OH, HATU, HOAt, DIEA, DMF; e) piperi-
dine/DMF (1:4); f) Fmoc-Nal-OH, HATU, HOAt, DIEA, DMF; g) piperidine/DMF (1:4); h) NBS-Cl, collidine, NMP; i) Ph3P, MeOH, DIAD, THF; j) HS(CH2)2OH, DBU,
NMP; k) Fmoc-d-Phe-OH, HATU, HOAt, DIEA, DMF; l) piperidine/DMF (1:4); m) HFIP/CH2Cl2 (1:4); n) DPPA, NaHCO3, DMF; o) TFA/CH2Cl2/H2O/TIS (60:35:2.5:2.5).
Fmoc: 9-fluorenylmethoxycarbonyl, DMF: N,N-dimethylformamide, HATU: O-(7-azabenzotriazol-1-yl)-tetramethyluronium hexafluorophosphate, HOAt: 1-hy-
droxy-7-azabenzotriazole, DIEA: ethyldiisopropylamine, NBS-Cl: nitrobenzylsulfonyl chloride, NMP: N-methyl-2-pyrrolidone, DIAD: diisopropylazodicarboxylate,
DBU: 1,5-diazabicyclo[5.4.0]undec-5-ene, HFIP: hexafluoroisopropanol, DPPA: diphenylphosphorylazide, TFA: trifluoroacetic acid, TIS: triisopropylsilane.
(IC50 >1000 nm), which is necessary for both preclinical and
clinical applications.
solution of 1 as previously reported,[7a] resulting in a total sur-
face load of 100 mg per stent. To examine the inhibitory effect
of 1 in vitro, RGD-peptide-coated stents (+RGD) were placed
in sterile cell culture media in the absence of additives for 1, 7,
and 14 days. The supernatant was subsequently incubated
with CASMCs, and cell proliferation assessed after 0, 24, and
72 h (Figure 3). The control groups consisted of supernatant
media derived from coated stents with the same coating solu-
tion but without RGD peptide (ÀRGD) and of untreated cell
culture medium (untreated). Treatment of CASMCs with super-
natant media from RGD-peptide-coated stents (days 1 and 7)
To further evaluate the inhibitory activity of 1, we performed
a cell proliferation assay with CASMCs (Figure 2). After seeding,
CASMCs were incubated with 1 or cilengitide for 72 h in con-
centrations ranging from 10 nm to 100 mm. Proliferation was
clearly inhibited at a concentration of ꢀ10 mm and ꢀ100 mm
for 1 and cilengitide, respectively. Surprisingly, 1 clearly inhibit-
ed CASMCs at a concentration of 10 mm, while cilengitide re-
mained less effective, thus giving striking evidence for the su-
perior anti-proliferative properties of the lipophilic derivative
(Figure 2).
revealed
a sustained anti-proliferative effect up to 72 h
In a follow-up experiment, RGD-peptide-coated stents were
tested for their release kinetic profile of 1 and were examined
in vitro regarding their potential to inhibit CASMC proliferation.
For that purpose, stents were spray-coated with a polymer-free
(Figure 3). This effect was decreased when supernatant from
the day-14 group was used. Notably, all supernatant media re-
sulted in decreased cell numbers at 72 h relative to control
(ÀRGD). To summarize, supernatant media from RGD-peptide-
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2014, 9, 1413 – 1418 1415

CHEMMEDCHEM
FULL PAPERS
www.chemmedchem.org
Figure 2. In vitro proliferation assay of CASMCs incubated with 1 or cilengi-
tide. Cell culture medium (without peptide) and serum-free medium served
as positive and negative controls, respectively.
Figure 4. Histopathological evaluation of the stent eluting 1. Upper panel:
Overview images of the RGD-, bare metal (BMS), and Cypher drug-eluting
stents at 40ꢁ magnification, Movats Pentachrome staining. Lower panel:
Images at 200ꢁ magnification, hematoxylin and eosin stain. Black arrows in-
dicate fibrin persistence; *p value not significant; **p<0.0001 for Cypher
versus others.
ing stent known to inhibit neointimal growth and display de-
layed arterial healing in the applied animal model.[17] The treat-
ed arteries were histopathologically evaluated 28 days after
stent deployment regarding neointimal growth and vessel
healing parameters. The assessment of percent luminal endo-
thelialization and degree of fibrin deposition in the neointimal
tissue were of special interest. Low percent endothelialization
and persisting fibrin deposition are indicators of delayed vessel
healing and important predictors of stent safety with regards
to thrombotic risk.[18]
Histopathological evaluation revealed the percentage of
stenosis was greatest in the BMS and lowest in Cypher, where-
as the RGD-peptide-coated stent showed an intermediate re-
duction in percent stenosis (Figure 4). Vascular healing was
completed in the RGD-coated stent and BMS at 28 days, as
markers of delayed healing were almost absent. In contrast,
Cypher DES showed evidence of delayed arterial healing dis-
played by incomplete endothelialization and persistence of
fibrin (Figure 4, black arrows). The peptide-eluting stent
showed an almost complete re-endothelialization (88.8%) and
low percentage of exposed struts. In contrast, after four weeks
almost 50% of the struts in the Cypher stents were uncovered,
and incomplete re-endothelialization (77.2%) was observed
(Figure 4). To date, incomplete re-endothelialization and ex-
posed stent struts were often reported as important factors
that increase the risk of late or very late stent thrombosis. Ad-
ditionally, Cypher showed greater delayed healing character-
ized by persistent fibrin accumulation, whereas the fibrin dep-
osition at strut level of the peptide-eluting stent was very low,
at 3.7%. Taken together, these results demonstrate that coat-
ing stents with c(RGDf(NMe)Nal) is feasible, safe, and at the
same time effective in terms of neointimal growth reduction.
Figure 3. Inhibitory effects of supernatant media derived from RGD-peptide-
coated stents. a) CASMC density and morphology 72 h after exposure to su-
pernatant media derived from coated stents incubated in media for 1 (left),
7 (middle), and 14 days (right). b) Quantification of cell proliferation at vari-
ous time points.
coated stents 1 resulted in sustained abolishment of SMC pro-
liferation up to 7 days in vitro.
Following successful in vitro testing, the RGD-peptide-
coated stents were evaluated in a proof-of-concept study in
vivo (Figure 4). Six healthy New Zealand white rabbits received
bilateral stent implantation in the external iliac arteries. Stents
(Yukon DES, Translumina, 3 mm ꢁ 12 mm) were either coated
with peptide 1 (RGD-coated stent) or remained uncoated
(BMS) to serve as control. Animals were randomized to three
different treatment groups consisting of the RGD-coated stent,
the BMS and the Cypher DES: an FDA-approved sirolimus-elut-
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2014, 9, 1413 – 1418 1416

CHEMMEDCHEM
FULL PAPERS
www.chemmedchem.org
Otsuka, M. Nakano, M. Vorpahl, S. K. Yazdani, E. Ladich, F. D. Kolodgie,
A. V. Finn, R. Virmani, J. Am. Coll. Cardiol. 2011, 57, 1314–1322.
[7] a) J. Hausleiter, A. Kastrati, R. Wessely, A. Dibra, J. Mehilli, T. Schrat-
zenstaller, I. Graf, M. Renke-Gluszko, B. Behnisch, J. Dirschinger, E. Win-
termantel, A. Schçmig, Eur. Heart J. 2005, 26, 1475–1481; b) N. Tada, R.
Virmani, G. Grant, L. Bartlett, A. Black, C. Clavijo, U. Christians, R. Betts,
D. Savage, S. H. Su, J. Shulze, S. Kar, Circ. Cardiovasc. Interv. 2010, 3,
174–183; c) L. Pendyala, X. Yin, J. Li, T. Shinke, Y. Xu, J. P. Chen, S. B.
King, K. Colley, T. Goodchild, N. Chronos, D. Hou, EuroIntervention 2010,
6, 126–133; d) T. Koppara, M. Joner, G. Bayer, K. Steigerwald, T. Diener,
E. Wittchow, Thromb. Haemostasis 2012, 107, 1161–1171.
Conclusions
In summary, we have demonstrated that coating of DES with
the lipophilic integrin targeting peptide c(RGDf(NMe)Nal) 1 is
a promising alternative to the FDA-approved medical devices
coated with immunosuppressive drugs such as Rapamycin.
This peptide clearly inhibited CASMC proliferation and migra-
tion in vitro and was successfully loaded onto microporous
stents without the need for a polymer. In a rabbit model,
stents coated with 1 clearly decreased neointimal growth and
improved vessel healing and re-endothelialization relative to
Cypher DES. The cyclic peptide was able to induce a substantial
decrease in neointimal growth in the novel DES group relative
to control, at the same time showing a favorable healing pro-
file compared with commercially available Cypher DES, thereby
giving striking evidence for its potential in the use of polymer-
free DES.
[8] C. J. Avraamides, B. Garmy-Susini, J. A. Varner, Nat. Rev. Cancer 2008, 8,
604–617.
ˇ
´
[9] a) D. Zimmermann, E. W. Guthçhrlein, M. Malesevic, K. Sewald, L.
Wobbe, C. Heggemann, N. Sewald, ChemBioChem 2005, 6, 272–276;
b) D. Heckmann, A. Meyer, L. Marinelli, G. Zahn, R. Stragies, H. Kessler,
Angew. Chem. Int. Ed. 2007, 46, 3571–3574; Angew. Chem. 2007, 119,
3641–3644; c) S. Urman, K. Gaus, Y. Yang, Y. U. Strijowski, N. Sewald, S.
De Pol, O. Reiser, Angew. Chem. Int. Ed. 2007, 46, 3976–3978; Angew.
Chem. 2007, 119, 4050–4053; d) L. Manzoni, L. Belvisi, D. Arosio, M.
Civera, M. Pilkington-Miksa, D. Potenza, A. Caprini, E. M. V. Araldi, E.
Monferini, M. Mancino, F. Podestꢃ, C. Scolastico, ChemMedChem 2009,
4, 615–632; e) A. Tolomelli, L. Gentilucci, E. Mosconi, A. Viola, S. D. Dat-
toli, M. Baiula, S. Spampinato, L. Belvisi, M. Civera, ChemMedChem 2011,
6, 2264–2272; f) L. Manzoni, L. Belvisi, D. Arosio, M. P. Bartolomeo, A.
Bianchi, C. Brioschi, F. Buonsanti, C. Cabella, C. Casagrande, M. Civera,
M. De Matteo, L. Fugazza, L. Lattuada, F. Maisano, L. Miragoli, C. Neira,
M. Pilkington-Miksa, C. Scolastico, ChemMedChem 2012, 7, 1084–1093;
g) F. Curnis, A. Cattaneo, R. Longhi, A. Sacchi, A. M. Gasparri, F. Pastori-
no, P. Di Matteo, C. Traversari, A. Bachi, M. Ponzoni, G. P. Rizzardi, A.
Corti, J. Biol. Chem. 2010, 285, 9114–9123; h) S. L. Goodman, M. Picard,
Trends Pharmacol. Sci. 2012, 33, 405–412.
Animal study
The study protocol was approved by the responsible authority
(Regierung von Oberbayern, AZ 55.2-1-54-2531-30-09) imple-
menting the German Animal Welfare Act. Animal housing and
care were in accordance with the Directive 2010/63/EU of the
European Parliament, compliant with the US National Institutes
of Health Guide for the Care and Use of Laboratory Animals.
[10] M. D. Pierschbacher, E. Ruoslahti, Nature 1984, 309, 30–33.
[11] a) J. M. Smallheer, C. A. Weigelt, F. J. Woerner, J. S. Wells, W. F. Daneker,
S. A. Mousa, R. R. Wexler, P. K. Jadhav, Bioorg. Med. Chem. Lett. 2004, 14,
383–387; b) R. Stragies, F. Osterkamp, G. Zischinsky, D. Vossmeyer, H.
Kalkhof, U. Reimer, G. Zahn, J. Med. Chem. 2007, 50, 3786–3794; c) L.
Gentilucci, G. Cardillo, S. Spampinato, A. Tolomelli, F. Squassabia, R. De
Marco, A. Bedini, M. Baiula, L. Belvisi, M. Civera, J. Med. Chem. 2010, 53,
106–118; d) C. Mas-Moruno, J. G. Beck, L. Doedens, A. O. Frank, L. Ma-
rinelli, S. Cosconati, E. Novellino, H. Kessler, Angew. Chem. Int. Ed. 2011,
50, 9496–9500; Angew. Chem. 2011, 123, 9668–9672; e) F. Rechenmach-
er, S. Neubauer, J. Polleux, C. Mas-Moruno, M. De Simone, E. A. Caval-
canti-Adam, J. P. Spatz, R. Fꢄssler, H. Kessler, Angew. Chem. Int. Ed. 2013,
52, 1572–1575; Angew. Chem. 2013, 125, 1612–1616; f) S. Neubauer, F.
Rechenmacher, A. J. Beer, F. Curnis, K. Pohle, C. D’Alessandria, H.-J.
Wester, U. Reuning, A. Corti, M. Schwaiger, H. Kessler, Angew. Chem. Int.
Ed. 2013, 52, 11656–11659; Angew. Chem. 2013, 125, 11870–11873;
g) S. Neubauer, F. Rechenmacher, R. Brimioulle, F. S. Di Leva, A. Bochen,
T. R. Sobahi, M. Schottelius, E. Novellino, C. Mas-Moruno, L. Marinelli, H.
Kessler, J. Med. Chem. 2014, DOI: 10.1021/jm500092w.
Acknowledgements
We thank the International Graduate School of Science and Engi-
neering (IGSSE), the Bund der Freunde der TU Mꢁnchen e.V., and
Materials Science of Complex Interfaces (CompInt) of the Elite
Network of Bavaria for funding, and the Institute for Advanced
Study (IAS) of Technische Universitꢀt Mꢁnchen and the Center for
Integrated Protein Science Munich (CIPSM) for financial support.
We thank Philipp Ganthaler for illustrating Figure 1.
Keywords: drug-eluting stents · integrin ligands · myocardial
infarction · peptides · RGD · smooth muscle cells
[12] A. van der Flier, K. Badu-Nkansah, C. A. Whittaker, D. Crowley, R. T. Bron-
son, A. Lacy-Hulbert, R. O. Hynes, Development 2010, 137, 2439–2449.
[13] a) S. S. Srivatsa, L. A. Fitzpatrick, P. W. Tsao, T. M. Reilly, D. R. Holmes, R. S.
Schwartz, S. A. Mousa, Cardiovasc. Res. 1997, 36, 408–428; b) R. Blindt,
F. Vogt, I. Astafieva, C. Fach, M. Hristov, N. Krott, B. Seitz, A. Kapurniotu,
C. Kwok, M. Dewor, A. K. Bosserhoff, J. Bernhagen, P. Hanrath, R. Hof-
mann, C. Weber, J. Am. Coll. Cardiol. 2006, 47, 1786–1795; c) S. R.
Meyers, D. J. Kenan, M. W. Grinstaff, ChemMedChem 2008, 3, 1645–
1648; d) A. Braun, L. Dofiles, S. Rousselle, L. Guerrero, J. Gunther, T. Yed-
nock, A. Stricker-Krongrad, E. Messersmith, PLoS One 2010, 5, e14314;
e) S. R. Meyers, D. J. Kenan, X. Khoo, M. W. Grinstaff, Biomacromolecules
2011, 12, 533–539; f) M. Joner, Q. Cheng, S. Schçnhofer-Merl, M. Lopez,
S. Neubauer, C. Mas-Moruno, B. Laufer, F. D. Kolodgie, H. Kessler, R. Vir-
mani, J. Biomed. Mater. Res. Part B 2012, 100B, 637–645; g) W. Zheng, Z.
Wang, L. Song, Q. Zhao, J. Zhang, D. Li, S. Wang, J. Han, X.-L. Zheng, Z.
Yang, D. Kong, Biomaterials 2012, 33, 2880–2891; h) C. McNichols, J.
Wilkins, A. Kubota, Y. T. Shiu, S. M. Aouadi, P. Kohli, J. Biomed. Mater. Res.
Part A 2014, 102, 532–539.
[1] a) P. W. Serruys, M. J. B. Kutryk, A. T. L. Ong, N. Engl. J. Med. 2006, 354,
483–495; b) R. Tung, S. Kaul, G. A. Diamond, P. K. Shah, Ann. Intern.
Med. 2006, 144, 913–919.
[2] T. J. Parry, R. Brosius, R. Thyagarajan, D. Carter, D. Argentieri, R. Falotico,
J. Siekierka, Eur. J. Pharmacol. 2005, 524, 19–29.
[3] S. Fuke, K. Maekawa, K. Kawamoto, H. Saito, T. Sato, T. Hioka, Circ. J.
2007, 71, 220–225.
[4] a) R. Virmani, A. Farb, G. Guagliumi, F. D. Kolodgie, Coron. Artery Dis.
2004, 15, 313–318; b) R. A. Byrne, M. Joner, A. Kastrati, Minerva Cardi-
oangiol. 2009, 57, 567–584.
[5] a) J. R. Nebeker, R. Virmani, C. L. Bennett, J. M. Hoffman, M. H. Samore, J.
Alvarez, C. J. Davidson, J. M. McKoy, D. W. Raisch, B. K. Whisenant, P. R.
Yarnold, S. M. Belknap, D. P. West, J. E. Gage, R. E. Morse, G. Gligoric, L.
Davidson, M. D. Feldman, R. Virmani, J. Am. Coll. Cardiol. 2006, 47, 175–
181; b) M. Joner, A. V. Finn, A. Farb, E. K. Mont, F. D. Kolodgie, E. Ladich,
R. Kutys, K. Skorija, H. K. Gold, R. Virmani, J. Am. Coll. Cardiol. 2006, 48,
193–202; c) T. F. Lꢂscher, J. Steffel, F. R. Eberli, M. Joner, G. Nakazawa,
F. C. Tanner, R. Virmani, Circulation 2007, 115, 1051–1058.
[6] a) R. A. Byrne, R. Iijima, J. Mehilli, S. Pinieck, O. Bruskina, A. Schçmig, A.
Kastrati, JACC Cardiovasc. Interv. 2009, 2, 291–299; b) G. Nakazawa, F.
[14] M. P. Bendeck, C. Irvin, M. Reidy, L. Smith, D. Mulholland, M. Horton,
C. M. Giachelli, Arterioscler. Thromb. Vasc. Biol. 2000, 20, 1467–1472.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2014, 9, 1413 – 1418 1417

CHEMMEDCHEM
FULL PAPERS
www.chemmedchem.org
[15] a) M. A. Dechantsreiter, E. Planker, B. Mathꢄ, E. Lohof, G. Hçlzemann, A.
Jonczyk, S. L. Goodman, H. Kessler, J. Med. Chem. 1999, 42, 3033–3040;
b) C. Mas-Moruno, F. Rechenmacher, H. Kessler, Anti-Cancer Agents Med.
Chem. 2010, 10, 753–768.
[18] A. V. Finn, G. Nakazawa, M. Joner, F. D. Kolodgie, E. K. Mont, H. K. Gold,
R. Virmani, Arterioscler. Thromb. Vasc. Biol. 2007, 27, 1500–1510.
[16] R. Haubner, R. Gratias, B. Diefenbach, S. L. Goodman, A. Jonczyk, H.
Kessler, J. Am. Chem. Soc. 1996, 118, 7461–7472.
[17] M. C. John, R. Wessely, A. Kastrati, A. Schçmig, M. Joner, M. Uchihashi, J.
Crimins, S. Lajoie, F. D. Kolodgie, H. K. Gold, R. Virmani, A. V. Finn, JACC
Cardiovasc. Interv. 2008, 1, 535–544.
Received: January 31, 2014
Published online on April 6, 2014
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2014, 9, 1413 – 1418 1418