An adventitial painting modality of local drug delivery to abate intimal hyperplasia

Abstract

A major medical problem is the persistent lack of approved therapeutic methods to prevent postoperative intimal hyperplasia (IH) which leads to high-rate failure of open vascular reconstructions such as bypass grafting. Hydrogel has been widely used in preclinical trials for perivascular drug administration to mitigate postoperative IH. However, bulky hydrogel is potentially pro-inflammatory, posing a significant hurdle to clinical translation. Here we developed a new modality of directly "painting" drug-loaded unimolecular micelles (UM) to the adventitia thus obviating the need for a hydrogel. To render tissue adhesion, we generated amine-reactive unimolecular micelles with N-hydroxysuccinimide ester (UM-NHS) terminal groups to form stable amide bonds with the adventitia. To test periadventitial application, we either soaked balloon-injured rat carotid arteries in crosslinked UM-NHS (Mode-1) or non-crosslinked UM-NHS (Mode-2), or painted the vessel surface with non-crosslinked UM-NHS (Mode-3). The UM-NHS were loaded with or without a model drug (rapamycin) known to be IH inhibitory. We found that Mode-1 produced a marked IH-mitigating drug effect but also caused severe tissue damage. Mode-2 resulted in lower tissue toxicity yet less drug effect on IH. However, the painting method, Mode-3, demonstrated a pronounced therapeutic effect (75% inhibition of IH) without obvious toxicity. In summary, we present a simple painting modality of periadventitial local drug delivery using tissue-adhesive UM. Given the robust IH-abating efficacy and low tissue toxicity, this prototype merits further development towards an effective anti-stenosis therapy suitable for open vascular reconstructions.

Keywords: Intima hyperplasia; Painting; Perivascular application; Tissue adhesive unimolecular micelle.