RESUMO
Both paclitaxel and zotarolimus are currently employed in vascular interventional therapies, such as drug-eluting stents, and are under investigation for use in other novel drug-device combination products. Paclitaxel is a microtubule-stabilizing compound with potent antiproliferative properties and antimigration effects, whereas zotarolimus is a potent mammalian target of rapamycin inhibitor with antiproliferative and antiinflammatory properties. This study was intended to compare paclitaxel and zotarolimus for intravascular applications in which drug exposure time may be reduced, such as in drug-coated balloons. These applications are generally aimed at reducing neointimal hyperplasia by limiting smooth muscle cell (SMC) proliferation and inflammatory cell recruitment, while minimally interfering with vessel reendothelialization after balloon denudation. In the cellular models described in this study, transient exposure of zotarolimus resulted in the sustained inhibition of SMC proliferation and reduced endothelial cell (EC) proinflammatory cytokine expression, while not affecting EC migration and viability. Transient exposure of paclitaxel inhibited SMC proliferation, EC migration, and overall cell viability, with no effect on expression of the proinflammatory biomarkers studied.
Assuntos
Fármacos Cardiovasculares/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Paclitaxel/farmacologia , Sirolimo/análogos & derivados , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/imunologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Relação Dose-Resposta a Droga , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Necrose , Sirolimo/farmacologia , Fatores de TempoRESUMO
This study compares the effects of two polymers currently being marketed on commercially available drug-eluting stents, PVDF-HFP fluorinated copolymer (FP) and phosphorylcholine polymer (PC), on re-endothelialization, acute thrombogenicity, and monocyte adhesion and activity. Rabbit iliac arteries were implanted with cobalt-chromium stents coated with FP or PC polymer (without drug) and assessed for endothelialization at 14 days by confocal and scanning electron microscopy (SEM). Endothelialization was equivalent and near complete for FP and PC polymer-coated stents (>80% by SEM). Acute thrombogenicity was assessed in a Chandler loop model using porcine blood. Thrombus adherence was similar for both polymers as assessed by clot weight, thrombin-antithrombin III complex, and lactate dehydrogenase expression. In vitro cell adhesion assays were performed on FP and PC polymer-coated glass coupon surfaces using HUVECs, HCAECs, and THP-1 monocytes. The number of ECs adhered to FP and control surfaces were equivalent and significantly greater than on PC surfaces (p<0.05). There were no differences in THP-1 monocyte adhesion and cytokine (MCP-1, RANTES, IL-6, MIP-1alpha, MIP-1beta, G-CSF) expression. The data suggests that biological responses to both FP and PC polymer are similar, with no mechanistic indication that these polymers would be causative factors for delayed vessel healing in an acute timeframe.