In vitro study of dual drug-eluting stents with locally focused sirolimus and atorvastatin release

Abstract

Within the context of novel stent designs we developed a dual drug-eluting stent (DDES) with an abluminally focussed release of the potent anti-proliferative drug sirolimus and a luminally focussed release of atorvastatin with stabilizing effect on atherosclerotic deposits and stimulating impact on endothelial function, both from biodegradable poly(L-lactide)-based stent coatings. With this concept we aim at simultaneous inhibition of in-stent restenosis as a result of disproportionally increased smooth muscle cell proliferation and migration as well as thrombosis due to failed or incomplete endothelialisation. The especially adapted spray-coating processes allowed the formation of smooth form-fit polymer coatings at the abluminal and luminal side with 70% respectively 90% of the drug/polymer solution being deposited at the intended stent surface. The impacts of tempering, sterilization, and layer composition on drug release are thoroughly discussed making use of a semi-empirical model. While tempering at 80 °C seems to be necessary for the achievement of adequate and sustained drug release, the coating sequence for DDES should be rather abluminal-luminal than luminal-abluminal, as reduction of the amount of sirolimus eluted luminally could then potentially minimize the provocation of endothelial dysfunction. In vitro proliferation and viability assays with smooth muscle and endothelial cells underline the high potential of the developed DDES.

Expression of OATP2B1 as determinant of drug effects in the microcompartment of the coronary artery

“…This is in part based on the localization of target and non-target cells in immediate vicinity of the drug delivery device and the use of compounds with high passive permeability. One of the approaches to enhance cell targeting may be the restricted loading on the drug delivery device, as previously reported, showing dual loading of stents with atorvastatin on the luminal side and sirolimus on the abluminal side [27]. In addition, derivatives of the lead compound sirolimus and their influence on smooth muscle cell proliferation and viability have been tested, showing a pronounced impact on proliferation without affecting cell viability compared to cells treated with paclitaxel, a compound demonstrating high cytotoxic effects [28,29].…”

Polymers for Cardiovascular Stent Coatings

“…The CHOICE trial might shed some light on this question [49]. Possibly, biocompatible, polymer-based abluminal or dual, and side-selective coatings as well as other innovative, polymer-free drug reservoirs might be applicable [14,50,51]. Common DES are summarized in Table 1.…”

Advanced Polymers in Medicine

“…In our own published studies, absorbable polymer stent coatings based on PLLA were developed. This research focused on the one hand on physicochemical characterization of the obtained coating with regard to morphology and the impact of processing parameters on polymer degradation [132] and on the other hand on the establishment of novel dual drug-eluting stents (DDES) with an abluminally focussed release of the potent anti-proliferative drug sirolimus and a luminally focussed release of atorvastatin with stabilizing effect on atherosclerotic deposits and stimulating impact on endothelial function [252]. During physicochemical characterization of established PLLA coatings, we observed that achieved structural integrity via a spray-coating process was maintained after crimping and full expansion of stent prototypes.…”