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(ε-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.

• Authors: Xiaohua Yu, Toshio Takayama, Shakti A Goel, Xudong Shi, Yifan Zhou, K Craig Kent, William L Murphy, Lian-Wang Guo
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 191 Pg. 47-53 (Oct 10 2014) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 24852098 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Cardiovascular Agents
• Delayed-Action Preparations
• Drug Carriers
• Polyesters
• polycaprolactone
• Sirolimus

Topics

• Animals
• Cardiovascular Agents (administration & dosage, chemistry)
• Carotid Artery Injuries (drug therapy, pathology)
• Carotid Stenosis (pathology, prevention & control)
• Cell Proliferation (drug effects)
• Chemistry, Pharmaceutical
• Delayed-Action Preparations
• Disease Models, Animal
• Drug Carriers
• Hyperplasia
• Kinetics
• Linear Models
• Male
• Neointima
• Polyesters (chemistry)
• Rats
• Rats, Sprague-Dawley
• Sirolimus (administration & dosage, chemistry)
• Solubility
• Technology, Pharmaceutical (methods)