Abstract
Background:
Clinical outcome of surgical revascularization using autologous vein graft is limited by vein graft failure attributable to neointima formation. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of vein graft failure. Therefore, we hypothesized that nanoparticle (NP)-mediated drug delivery system of PDGF-receptor (PDGF-R) tyrosine kinase inhibitor (imatinib mesylate: STI571) could be an innovative therapeutic strategy.
Methods and results:
Uptake of STI571-NP normalized PDGF-induced cell proliferation and migration. Excised rabbit jugular vein was treated ex vivo with PBS, STI571 only, FITC-NP, or STI571-NP, then interposed back into the carotid artery position. NP was detected in many cells in the neointima and media at 7 and 28 days after grafting. Significant neointima was formed 28 days after grafting in the PBS group; this neointima formation was suppressed in the STI571-NP group. STI571-NP treatment inhibited cell proliferation and phosphorylation of the PDGF-R-beta but did not affect inflammation and endothelial regeneration.
Conclusions:
STI571-NP-induced suppression of vein graft neointima formation holds promise as a strategy for preventing vein graft failure.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aorta / cytology
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Aorta / metabolism
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Benzamides
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured
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Coronary Vessels / cytology
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Coronary Vessels / metabolism
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Drug Delivery Systems*
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Humans
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Imatinib Mesylate
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In Vitro Techniques
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Intracellular Membranes / metabolism
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Jugular Veins / drug effects
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Jugular Veins / transplantation*
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Male
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Muscle, Smooth, Vascular / cytology
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Myocytes, Smooth Muscle / cytology
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Myocytes, Smooth Muscle / metabolism
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Myocytes, Smooth Muscle / physiology
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Nanoparticles*
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Phosphorylation / drug effects
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Piperazines / administration & dosage*
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Protein Kinase Inhibitors / administration & dosage*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Pyrimidines / administration & dosage*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rabbits
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Rats
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Tissue Distribution
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Tunica Intima / drug effects*
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Tunica Intima / pathology
Substances
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Benzamides
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Imatinib Mesylate
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Receptor, Platelet-Derived Growth Factor beta