Perivascular Delivery of Paclitaxel with F-127 Pluronic Gel Inhibits Neointimal Hyperplasia in a Rat Carotid Artery Injury Model

ABSTRACT

BACKGROUND AND OBJECTIVES: The local delivery of drugs to the arterial wall represents a strategy for the treatment of fibroproliferative vascular disease. Paclitaxel has been shown to inhibit vascular smooth muscle cell proliferation and migration, which contribute to neointimal formation. This study tested whether the perivascular delivery of paclitaxel can prevent neointimal formation in a rat carotid artery injury model. MATERIALS AND METHODS: The ability of locally-administered paclitaxel to prevent the neointimal hyperplastic response was tested by incorporating 10 microgram paclitaxel into 40% F-127 pluronic gel, which was then applied to the adventitial surface of the rat carotid artery immediately following balloon injury. Fourteen days after angioplasty, the neointimal growth was compared between paclitaxel- (n=12) and pluronic gel only treated (control group, n=11) rats. RESULTS: The paclitaxel-treated group showed significant neointimal formation reductions compared to the control group (0.10+/-0.05 versus 0.21+/-0.05 mm2, p<0.05). The perivascular application of paclitaxel produced a highly localized pattern of neointimal growth inhibition in the arterial cross-section. Although 10 microgram paclitaxel showed no significant cytotoxicity, 20 microgram paclitaxel (n=3) demonstrated cytotoxicity, with medial cell drop out in the region of application. CONCLUSION: We have demonstrated that the local extravascular application of 40% F-127 pluronic gel containing paclitaxel provides an effective mechanism for inhibiting the proliferative response to vascular injury in the rat. The cellular response to paclitaxel is highly focal. Locally sustained delivery of paclitaxel, as little as 10 microgram, was effective in preventing neointimal growth, without destroying medial wall smooth muscle cells.