Sustained Efficacy and Arterial Drug Retention by a Fast Drug Eluting Cross-Linked Fatty Acid Coronary Stent Coating

Abstract

The long held assumption that sustained drug elution from stent coatings over weeks to months is imperative for clinical efficacy has limited the choice for stent coating materials. We developed and evaluated an omega-3 fatty acid (O3FA) based stent coating that is 85% absorbed and elutes 97% of its Sirolimus analog (Corolimus) load within 8d of implantation. O3FA coated stents sustained drug levels in porcine coronary arteries similarly to those achieved by slow-eluting durable coated Cypher Select Plus Stents and with significantly lower levels of granuloma formation and luminal stenosis. Computational modeling confirmed that diffusion and binding constants of Corolimus and Sirolimus are identical and explained that the sustained retention of Corolimus was facilitated by binding to high affinity intracellular receptors (FKBP12). First in man outcomes were positive—unlike Cypher stents where late lumen loss drops over 6 month, there was a stable effect without diminution in the presence of O3FA. These results speak to a new paradigm whereby the safety of drug eluting stents can be optimized through the use of resorbable biocompatible coating materials with resorption kinetics that coincide with the dissociation and tissue elimination of receptor-bound drug.

In vitro Cas9-assisted editing of modular polyketide synthase genes to produce desired natural product derivatives

“…The chemical structure of compound 16 was further confirmed by NMR analysis (Supplementary Data 71 – 77 ). Compound 16 was chemically synthesised from rapamycin via reduction of the ketone at the C-32 27 , and have been tried clinical application of coronary stent therapy 28 .…”

Combining mathematical modelling with in vitro experiments to predict in vivo drug-eluting stent performance

“…This idea has previously been adopted in a one-layer model in the literature (e.g. [26]). Equation 11represents continuity of concentration of drug across the interface.…”

“…We note that estimates of all of the parameters in the arterial wall are either available in the literature, or have been estimated from the experiments in this study prior to using the mathematical model to make predictions ( Table 1: A summary of the parameter values used in the simulations. All parameters taken from [26] except those marked , which were estimated in this study prior to using the mathematical model to make predictions.…”

“…Secondly, rather than explicitly model blood flow, we (as have others [26]) have accounted for drug being lost to the blood stream through a modification of the flux boundary condition at the stent/arterial wall interface. The fraction of drug delivered to the wall (α) is likely to be dependent on the stent platform in question, in particular the geometry (i.e.…”

Endovascular Drug Delivery and Drug Elution Systems

“…We hypothesized that naturally derived coating compositions which degrade rapidly can deliver controlled volumes of drug without loss of biological effect and at reduced periods of tissue vulnerability. To examine this hypothesis, cobalt chromium stents were conformally coated with a novel cross-linked omega-3 fatty acid (O3FA) based coating(20) that is 85% absorbed (Figure 6A) and elutes 97% of its Sirolimus analog (Corolimus) load within 8 days of implantation (Figure 6B). Evaluation in pig coronary arteries revealed sustained efficacious drug levels that were similar to those achieved by slow eluting durable coated Sirolimus-eluting stents (Figure 6C) and resulted in superior efficacy and more benign tissue response.…”