Long-term effect of stents eluting 6-mercaptopurine in porcine coronary arteries.

BACKGROUND: Drug-eluting stents (DES) have dramatically reduced restenosis rates compared to bare metal stents and are widely used in coronary artery angioplasty. The anti-proliferative nature of the drugs reduces smooth muscle cell (SMC) proliferation effectively, but unfortunately also negatively affects endothelialization of stent struts, necessitating prolonged dual anti-platelet therapy. Cell-type specific therapy may prevent this complication, giving rise to safer stents that do not require additional medication. 6-Mercaptopurine (6-MP) is a drug with demonstrated cell-type specific effects on vascular cells both in vitro and in vivo, inhibiting proliferation of SMCs while promoting survival of endothelial cells. In rabbits, we demonstrated that DES locally releasing 6-MP during 4 weeks reduced in-stent stenosis by inhibiting SMC proliferation and reducing inflammation, without negatively affecting endothelialization of the stent surface. The aim of the present study was to investigate whether 6-MP-eluting stents are similarly effective in preventing stenosis in porcine coronary arteries after 3 months, in order to assess the eligibility for human application. METHODS: 6-MP-eluting and polymer-only control stents (both n = 7) were implanted in porcine coronary arteries after local balloon injury to assess the effect of 6-MP on vascular lesion formation. Three months after implantation, stented coronary arteries were harvested and analyzed. RESULTS: Morphometric analyses revealed that stents were implanted reproducibly and with limited injury to the vessel wall. Unexpectedly, both in-stent stenosis (6-MP: 41.1 ± 10.3 %; control: 29.6 ± 5.9 %) and inflammation (6-MP: 2.14 ± 0.51; control: 1.43 ± 0.45) were similar between the groups after 3 months. CONCLUSION: In conclusion, although 6-MP was previously found to potently inhibit SMC proliferation, reduce inflammation and promote endothelial cell survival, thereby effectively reducing in-stent restenosis in rabbits, stents containing 300 µg 6-MP did not reduce stenosis and inflammation in porcine coronary arteries.

Stents Eluting 6-Mercaptopurine Reduce Neointima Formation and Inflammation while Enhancing Strut Coverage in Rabbits.

BACKGROUND: The introduction of drug-eluting stents (DES) has dramatically reduced restenosis rates compared with bare metal stents, but in-stent thrombosis remains a safety concern, necessitating prolonged dual anti-platelet therapy. The drug 6-Mercaptopurine (6-MP) has been shown to have beneficial effects in a cell-specific fashion on smooth muscle cells (SMC), endothelial cells and macrophages. We generated and analyzed a novel bioresorbable polymer coated DES, releasing 6-MP into the vessel wall, to reduce restenosis by inhibiting SMC proliferation and decreasing inflammation, without negatively affecting endothelialization of the stent surface. METHODS: Stents spray-coated with a bioresorbable polymer containing 0, 30 or 300 µg 6-MP were implanted in the iliac arteries of 17 male New Zealand White rabbits. Animals were euthanized for stent harvest 1 week after implantation for evaluation of cellular stent coverage and after 4 weeks for morphometric analyses of the lesions. RESULTS: Four weeks after implantation, the high dose of 6-MP attenuated restenosis with 16% compared to controls. Reduced neointima formation could at least partly be explained by an almost 2-fold induction of the cell cycle inhibiting kinase p27Kip1. Additionally, inflammation score, the quantification of RAM11-positive cells in the vessel wall, was significantly reduced in the high dose group with 23% compared to the control group. Evaluation with scanning electron microscopy showed 6-MP did not inhibit strut coverage 1 week after implantation. CONCLUSION: We demonstrate that novel stents coated with a bioresorbable polymer coating eluting 6-MP inhibit restenosis and attenuate inflammation, while stimulating endothelial coverage. The 6-MP-eluting stents demonstrate that inhibition of restenosis without leaving uncovered metal is feasible, bringing stents without risk of late thrombosis one step closer to the patient.

Effect of polymer composition on rheological and degradation properties of temperature-responsive gelling systems composed of acyl-capped PCLA-PEG-PCLA.

In this study, the ability to modulate the rheological and degradation properties of temperature-responsive gelling systems composed of acyl-capped poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide) (PCLA-PEG-PCLA) triblock copolymers was investigated. Eight polymers with varying molecular weight of PCLA, caproyl/lactoyl ratio (CL/LA) and capped with either acetyl- or propionyl-groups were synthesized by ring-opening polymerization of L-lactide and ε-caprolactone in toluene using PEG as initiator and tin(II) 2-ethylhexanoate as catalyst, and subsequently reacted in solution with an excess of acyl chloride to yield fully acyl-capped PCLA-PEG-PCLA. The microstructure of the polymers was determined by (1)H NMR, and the thermal properties and crystallinity of the polymers in dry state and in 25 wt % aqueous systems were studied by differential scanning calorimetry and X-ray diffraction. Rheological and degradation/dissolution properties of aqueous systems composed of the polymers in 25 wt % aqueous systems were studied. (1)H NMR analysis revealed that the monomer sequence in the PCLA blocks was not fully random, resulting in relatively long CL sequences, even though transesterification was demonstrated by the enrichment with lactoyl units and the presence of PEG-OH end groups. Except the most hydrophilic polymer composed of acetyl-capped PCLA1400-PEG1500-PCLA1400 having a CL/LA molar ratio of 2.5, the polymers at 25 wt % in buffer were sols below room temperature and transformed into gels between room temperature and 37 °C, which makes them suitable as temperature-responsive gelling systems for drug delivery. Over a period of weeks at 37 °C, the systems containing polymers with long CL sequences (~8 CL) and propionyl end-groups became semicrystalline as shown by X-ray diffraction analysis. Degradation of the gels by dissolution at 37 °C took 100-150 days for the amorphous gels and 250-300 days for the semicrystalline gels. In conclusion, this study shows that changes in the polymer composition allow an easy but significant modulation of rheological and degradation properties.