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A rapamycin-releasing perivascular polymeric sheath produces highly effective inhibition of intimal hyperplasia.

ABSTRACT: Intimal hyperplasia produces restenosis (re-narrowing) of the vessel lumen following vascular intervention. Drugs that inhibit intimal hyperplasia have been developed, however there is currently no clinical method of perivascular drug-delivery to prevent restenosis following open surgical procedures. Here we report a poly(?-caprolactone) (PCL) sheath that is highly effective in preventing intimal hyperplasia through perivascular delivery of rapamycin. We first screened a series of bioresorbable polymers, i.e., poly(lactide-co-glycolide) (PLGA), poly(lactic acid) (PLLA), PCL, and their blends, to identify desired release kinetics and sheath physical properties. Both PLGA and PLLA sheaths produced minimal (<30%) rapamycin release within 50days in PBS buffer. In contrast, PCL sheaths exhibited more rapid and near-linear release kinetics, as well as durable integrity (>90days) as evidenced in both scanning electron microscopy and subcutaneous embedding experiments. Moreover, a PCL sheath deployed around balloon-injured rat carotid arteries was associated with a minimum rate of thrombosis compared to PLGA and PLLA. Morphometric analysis and immunohistochemistry revealed that rapamycin-loaded perivascular PCL sheaths produced pronounced (85%) inhibition of intimal hyperplasia (0.15±0.05 vs 1.01±0.16), without impairment of the luminal endothelium, the vessel's anti-thrombotic layer. Our data collectively show that a rapamycin-loaded PCL delivery system produces substantial mitigation of neointima, likely due to its favorable physical properties leading to a stable yet flexible perivascular sheath and steady and prolonged release kinetics. Thus, a PCL sheath may provide useful scaffolding for devising effective perivascular drug delivery particularly suited for preventing restenosis following open vascular surgery.

SUBMITTER: Yu X

PROVIDER: S-EPMC4156896 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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A rapamycin-releasing perivascular polymeric sheath produces highly effective inhibition of intimal hyperplasia.

Yu Xiaohua X Takayama Toshio T Goel Shakti A SA Shi Xudong X Zhou Yifan Y Kent K Craig KC Murphy William L WL Guo Lian-Wang LW

Journal of controlled release : official journal of the Controlled Release Society 20140520

Intimal hyperplasia produces restenosis (re-narrowing) of the vessel lumen following vascular intervention. Drugs that inhibit intimal hyperplasia have been developed, however there is currently no clinical method of perivascular drug-delivery to prevent restenosis following open surgical procedures. Here we report a poly(ε-caprolactone) (PCL) sheath that is highly effective in preventing intimal hyperplasia through perivascular delivery of rapamycin. We first screened a series of bioresorbable ...[more]

PMID: 24852098

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Project description:Currently available interventions for vascular occlusive diseases suffer from high failure rates due to re-occlusive vascular wall adaptations, a process called intimal hyperplasia (IH). Naturally occurring hydrogen sulfide (H2S) works as a vasculoprotective gasotransmitter in vivo. However, given its reactive and hazardous nature, H2S is difficult to administer systemically. Here, we developed a hydrogel capable of localized slow release of precise amounts of H2S and tested its benefits on IH. The H2S-releasing hydrogel was prepared from a short peptide attached to an S-aroylthiooxime H2S donor. Upon dissolution in aqueous buffer, the peptide self-assembled into nanofibers, which formed a gel in the presence of calcium. This new hydrogel delivered H2S over the course of several hours, in contrast with fast-releasing NaHS. The H2S-releasing peptide/gel inhibited proliferation and migration of primary human vascular smooth muscle cells (VSMCs), while promoting proliferation and migration of human umbilical endothelial cells (ECs). Both NaHS and the H2S-releasing gel limited IH in human great saphenous vein segments obtained from vascular patients undergoing bypass surgery, with the H2S-releasing gel showing efficacy at a 5x lower dose than NaHS. These results suggest local perivascular H2S release as a new strategy to limit VSMC proliferation and IH while promoting EC proliferation, hence re-endothelialization. STATEMENT OF SIGNIFICANCE: Arterial occlusive disease is the leading cause of death in Western countries, yet current therapies suffer from high failure rates due to intimal hyperplasia (IH), a thickening of the vascular wall leading to secondary vessel occlusion. Hydrogen sulfide (H2S) is a gasotransmitter with vasculoprotective properties. Here we designed and synthesized a peptide-based H2S-releasing hydrogel and found that local application of the gel reduced IH in human vein segments obtained from patients undergoing bypass surgery. This work provides the first evidence of H2S efficacy against IH in human tissue, and the results show that the gel is more effective than NaHS, a common instantaneous H2S donor.

Dataset Information

A rapamycin-releasing perivascular polymeric sheath produces highly effective inhibition of intimal hyperplasia.

Publications

A rapamycin-releasing perivascular polymeric sheath produces highly effective inhibition of intimal hyperplasia.

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