Abstract 2056: Blockade of PDGF Receptor Tyrosine Kinase by Ex Vivo Nano-DDS of Imatinib Mesylate into the Vein Suppresses Vein Graft Neointima Formation
Background: Clinical outcome of surgical revascularization using autologous vein graft is limited by vein graft failure due to neointima formation. Platelet-derived growth factor (PDGF), expressed by vascular smooth muscle cells (VSMCs), plays a central role in the pathogenesis of vein graft failure. Therefore, optimal nanotechnology-based drug delivery system (Nano-DDS) of PDGF receptor tyrosine kinase (TK) inhibitor, imatinib mesylate (STI571), can be an innovative therapeutic strategy for clinical application. We have developed such Nano-DDS using bioabsorbable PLGA nanoparticles (NP) for local ex vivo delivery.
Hypothesis: Blockade of PDGF receptor TK by Nano-DDS of imatinib suppresses vein graft neointima formation.
Methods and Results: [studies in human VSMCs in vitro] Addition of fluorescence (FITC)-encapsulated NP resulted in rapid and stable uptake by 99 % of cells. The Nano-DDS of imatinib prevented PDGF-induced phosphorylation of PDGF receptor TK, and thus normalized the PDGF-induced proliferation. [ex vivo studies] Incubation of excised rabbit jugular vein and human saphenous vein ex vivo in FITC-encapsulated NP for 30 min resulted in highly efficient intracellular delivery rate (> 90 % cells) into cells of the venous wall. [in vivo studies in rabbits] The excised jugular vein was treated ex vivo with PBS, imatinib only (100 mM), FITC NP only, or imatinib NP (100 mM) (n=5– 6, each) for 30 min, and then interposed into the carotid artery position of hypercholesterolemic rabbits. Seven and 28 days after ex vivo FITC NP treatment, FITC-positive cells were detected in many cells in the neointima and media (cellular uptake rate: 60 –70 %). Significant neointima was formed 28 days after grafting in PBS group, which was suppressed in imatinib NP group, but not in FITC NP only or imatinib only groups. Imatinib NP also inhibited the appearance of proliferating PCNA-positive cells and increased phosphorylation of PDGF receptor TK, but did not affect monocyte infiltration or endothelial regeneration process.
Conclusions: Nano-DDS of imatinib into the excised vein ex vivo was feasible and suppressed vein graft neointima formation in rabbits. Nano-DDS of imatinib may be a clinically promising therapeutic strategy for prevention of vein graft failure.