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


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.
Kimura
Satoshi
S
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Egashira
Kensuke
K
Nakano
Kaku
K
Iwata
Eiko
E
Miyagawa
Miho
M
Tsujimoto
Hiroyuki
H
Hara
Kaori
K
Kawashima
Yoshiaki
Y
Tominaga
Ryuji
R
Sunagawa
Kenji
K
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001549:Benzamides; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism; D016503:Drug Delivery Systems; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D007601:Jugular Veins / Q000187:drug effects / Q000637:transplantation*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D053758:Nanoparticles; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D014018:Tissue Distribution; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta