Local perivascular delivery of anti-restenotic agents from a drug-eluting poly(epsilon-caprolactone) stent cuff.
The introduction of drug-eluting stents (DES) to prevent in-stent restenosis is one of the major advances in interventional cardiology. Currently many types of DES are under evaluation for effectiveness and safety, a time-consuming and difficult procedure in humans. An animal model that allows rapid evaluation of the present and upcoming therapeutic approaches to prevent in-stent restenosis is most valuable and still lacking. Here, a perivascular cuff to induce restenosis was constructed of a poly(epsilon-caprolactone) (PCL) formulation suitable for the controlled delivery of drugs. Placing the PCL cuff around the femoral artery, in vivo, resulted in reproducible restenosis-like lesions containing predominantly smooth muscle-actin positive cells. Loading the cuff with the anti-restenotic compounds paclitaxel and rapamycin resulted, in vitro, in a sustained and dose-dependent release for at least 3 weeks. Paclitaxel- and rapamycin-eluting PCL cuffs placed around the femoral artery of mice in vivo significantly reduced intimal thickening by 76 +/- 2% and 75 +/- 6%, respectively, at 21 days. Perivascular sustained release of both anti-restenotic agents is restricted to the cuffed vessel segment with no systemic adverse effects or effect on cuffed contralateral femoral arteries. Drug-eluting PCL cuffs provide an easy and rapid tool to evaluate anti-restenotic agents to be used in combination with the DES strategies.
Pires
Nuno M M
NM
TNO-Quality of Life, Gaubius Laboratory, CK Leiden, The Netherlands.
van der Hoeven
Barend L
BL
de Vries
Margreet R
MR
Havekes
Louis M
LM
van Vlijmen
Bart J
BJ
Hennink
Wim E
WE
Quax
Paul H A
PH
Jukema
J Wouter
JW
D000818:Animals; D001807:Blood Vessel Prosthesis / Q000009:adverse effects*; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage / Q000737:chemistry; D004058:Diffusion; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D004343:Drug Implants / Q000008:administration & dosage* / Q000737:chemistry*; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry; D008297:Male; D008422:Materials Testing; D051379:Mice; D008810:Mice, Inbred C57BL; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry*; D020123:Sirolimus / Q000008:administration & dosage / Q000737:chemistry; D015607:Stents / Q000009:adverse effects
D020099:Coated Materials, Biocompatible; D004337:Drug Carriers; D004343:Drug Implants; D007166:Immunosuppressive Agents; D011091:Polyesters; C016240:polycaprolactone; D017239:Paclitaxel; D020123:Sirolimus