期刊
JOURNAL OF CONTROLLED RELEASE
卷 191, 期 -, 页码 47-53出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2014.05.017
关键词
Intimal hyperplasia; Ploy(epsilon-caprolactone) (PCL) sheath; Rapamycin; Perivascular drug delivery; Open vascular surgery
资金
- NHLBI NIH HHS [R01HL093282, R01-HL-068673, R01 HL093282, R01 HL068673] Funding Source: Medline
- NIBIB NIH HHS [R21 EB016381] Funding Source: Medline
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(epsilon-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 50 days in PBS buffer. In contrast, PCL sheaths exhibited more rapid and near-linear release kinetics, as well as durable integrity (>90 days) 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. (C) 2014 Elsevier B.V. All rights reserved.
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