Enzymatic Release of a Surface‐Adsorbed RGD Therapeutic from a Cleavable Peptide Anchor

Abstract

Implantation of a polymeric, ceramic, or metallic implant will unavoidably activate a response from the surrounding tissue. [1] Means to attenuate this inflammatory response at the implant site are of significant interest and currently include strategies based on surface morphology, chemical modification, or drug delivery. This response is particularly evident at the site of stent deployment, where the overproliferation of smooth muscle cells can lead to restenosis-a re-narrowing of the lumen.[2] Drug-eluting stents (DES) were introduced to decrease the rate and severity of this neointimal formation through passive diffusion of a drug physically entrapped in a nondegradable polymer coating over a metal framework. However, recent studies have expressed concern over the widespread use of DES owing to their increased late-thrombotic potential of two to three times the rates for a traditional bare metal stent. [3] This clinical outcome is likely due to delayed healing and endothelium regeneration as a result of the polymer coating (e.g., poly(styrene-b-isobutyl-b-styrene)) and the delivery of non-phenotype-specific antimitotic/antiproliferative drugs (e.g., sirolimus and paclitaxel). With the goal of improving implant performance through appropriate interactions with the surrounding biology, we previously reported the use of implant-specific peptide coatings to prevent nonspecific surface biofouling and to promote a pro-healing response through increasing cell adhesion and spreading.[4] Herein we report a third approach whereby a surface-adsorbed therapeutic is enzymatically released, resulting in drug elution (Figure 1).Engineering of an enzymatic recognition site into a material is an elegant approach to promote active degradation and has been used successfully with hydrogels, microspheres, bioplexes, and interpenetrating networks, [5] as well as for evaluating enzyme kinetics in the degradation of peptides on surfaces. [6] The enzymatic release of an adsorbed or tethered therapeutic from an implant surface is an exciting idea which would likely be of interest for many medical devices, including stents. Current stenting applications rely on passive drug entrapment and diffusion, and a wide variety of therapeutics are under investigation.[7] Some of these low-molecular-weight therapeutics include dexamethasone, methylprednisolone, 17-b-estradiol, angiopeptin, paclitaxel, actinomycin D, sirolimus, and arginine-glycine-aspartic acid (RGD).[8] The last example is particularly interesting, as clinical trials have shown that elution or local delivery of RGD decreased neointimal hyperplasia through the recruitment of circulating endothelial progenitor cells to the site of implantation and promoted arterial re-endothelialization. [8h, 9] Building upon these observations, we designed a peptide-based coating that consists of three distinct peptide domains: an implant-adsorptive sequence, an enzymatically cleavable recognition site, and a therapeutic to be delivered (i.e., RGD). Medical devices such as stents coated w...

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