Stent-Based Delivery of Sirolimus Reduces Neointimal Formation in a Porcine Coronary Model

Abstract

Background-The purpose of this study was to determine the efficacy of stent-based delivery of sirolimus (SRL) alone or in combination with dexamethasone (DEX) to reduce in-stent neointimal hyperplasia. SRL is a potent immunosuppressive agent that inhibits SMC proliferation by blocking cell cycle progression. Methods and Results-Stents were coated with a nonerodable polymer containing 185 g SRL, 350 g DEX, or 185 g SRL and 350 g DEX. Polymer biocompatibility studies in the porcine and canine models showed acceptable tissue response at 60 days. Forty-seven stents (metal, nϭ13; SRL, nϭ13; DEX, nϭ13; SRL and DEX, nϭ8) were implanted in the coronary arteries of 16 pigs. The tissue level of SRL was 97Ϯ13 ng/artery, with a stent content of 71Ϯ10 g at 3 days. At 7 days, proliferating cell nuclear antigen and retinoblastoma protein expression were reduced 60% and 50%, respectively, by the SRL stents. After 28 days, the mean neointimal area was 2.47Ϯ1.04 mm 2 for the SRL alone and 2.42Ϯ1.04 mm 2 for the combination of SRL and DEX compared with the metal (5.06Ϯ1.88 mm 2 , PϽ0.0001) or DEX-coated stents (4.31Ϯ3.21 mm 2 , PϽ0.001), resulting in a 50% reduction of percent in-stent stenosis. Conclusions-Stent-based delivery of SRL via a nonerodable polymer matrix is feasible and effectively reduces in-stent neointimal hyperplasia by inhibiting cellular proliferation.

Downstream coronary effects of drug-eluting stents

“…[3][4][5] Mechanical disruption of the endothelium and media appears to trigger intimal and vascular smooth muscle proliferation around the stent surface, and borrowing from the oncologic armamentarium, cell-cycle inhibition has been shown to inhibit this process. 6,7 Coating stents with antiproliferative agents allows targeted delivery to the region of local trauma. 8 A few studies have also shown similar reductions in in-stent restenosis with systemic administration of cell-cycle inhibitors.…”

Dose-dependent Inhibition of Myointimal Hyperplasia by Orally Administered Rapamycin

“…33 Previous studies of rapamycin-or everolimusimpregnated stents in animal models have shown that, compared to controls, local drug delivery inhibited within-stent stenosis or intimal hyperplasia by approximately 50%, but not much more. [34][35][36] Clinical trials with rapamycin-impregnated coronary stents have found within-stent restenosis to be nearly completely eliminated, indicating that atherosclerotic lesions may be more sensitive to rapamycin than normal animal arteries. 37 Human leukocytes are more sensitive to the antiproliferative effect of rapamycin than porcine leukocytes, 38 and the clearance of systemic rapamycin is slower in humans than in other species.…”

Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent

“…Recently, studies using coated stents that release rapamycin and paclitaxel have reported substantial decreases in the extent of in-stent restenosis during animal studies [8][9][10] and the initial phases of clinical trials. 11,12 However, coated stents could also be used to deliver genetic material to the cells of the vessel wall by diffusion from the polymer coating.…”