Local delivery of imatinib mesylate (STI571)-incorporated nanoparticle ex vivo suppresses vein graft neointima formation

• Published in: Circulation (New York, N.Y.) N.Y.), 2008-09, Vol.118 (14 Suppl), p.S65-S70
• Main Authors: Kimura, Satoshi, Egashira, Kensuke, Nakano, Kaku, Iwata, Eiko, Miyagawa, Miho, Tsujimoto, Hiroyuki, Hara, Kaori, Kawashima, Yoshiaki, Tominaga, Ryuji, Sunagawa, Kenji
• Format: Article
• Language: English
• Subjects: Animals; Aorta - cytology; Aorta - metabolism; Benzamides; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Coronary Vessels - cytology; Coronary Vessels - metabolism; Drug Delivery Systems; Humans; Imatinib Mesylate; In Vitro Techniques; Intracellular Membranes - metabolism; Jugular Veins - drug effects; Jugular Veins - transplantation; Male; Muscle, Smooth, Vascular - cytology; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - physiology; Nanoparticles; Phosphorylation - drug effects; Piperazines - administration & dosage; Piperazines - pharmacokinetics; Piperazines - pharmacology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Rabbits; Rats; Receptor, Platelet-Derived Growth Factor beta - metabolism; Tissue Distribution; Tunica Intima - drug effects; Tunica Intima - pathology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.107.740613

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. 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. STI571-NP-induced suppression of vein graft neointima formation holds promise as a strategy for preventing vein graft failure.