Local delivery of low-dose docetaxel, a novel microtubule polymerizing agent, reduces neointimal hyperplasia in a balloon-injured rabbit iliac artery model.

Abstract

Docetaxel (DOC) is a novel microtubule polymerizing agent, with superior antiproliferative properties as compared to paclitaxel. DOC is therefore a potential therapeutic tool for the prevention of restenosis following angioplasty. However, DOC has systemic toxicity such as leukocytopenia, which occurs in a dose-dependent manner. To minimize such adverse effects, we carried out local delivery of low-dose DOC directly to injured vessel sites. The rabbit iliac artery was denuded, and then DOC (2 mg) or control vehicle was administered locally 20 min, via a local drug delivery catheter. The levels of DOC in the plasma were within ng/ml range, eliminating hematopoietic side effects. Seven days after the local delivery (DOC: n=4, control: n=4), DOC decreased the number of Ki-67-labeled cells in the intima (DOC: 22 +/-10 vs. control: 66 +/- 18 cells/mm(2), P<0.01), indicating a decreased proliferative activity. At 28 days (DOC: n=8, control: n=8), computer-assisted morphometric analysis demonstrated that DOC significantly reduced the intimal area (DOC: 0.15 +/- 0.13 vs. control: 0.70 +/- 0.13 mm(2), P<0.01). There was also a decrease in medial area in the DOC-treated vessels (DOC: 0.62 +/- 0.17 vs. control: 1.13 +/- 0.38 mm(2), P<0.01). Local delivery of DOC, even after a single low-dose administration, effectively inhibits neointimal hyperplasia. Such administration is associated with a minimal likelihood of systemic adverse effects (leukocytopenia), but potentially induces local toxicity (a decrease in medial wall thickness) due to extensive cytotoxic effect.