Abstract
Restenosis after coronary intervention still remains a serious problem in clinical cardiology. Recent advances in nanotechnology have enabled us to selectively deliver an antiproliferative drug to the balloon-injured artery. Here we report our results with NK911 that is a doxorubicin containing nanocapsule and is characterized to selectively accumulate in vascular lesions with increased permeability. We first confirmed by Evans-blue staining that in the rat carotid artery, vascular permeability was markedly increased at least for one week after balloon injury. We then examined the inhibitory effect of NK911 on the restenotic changes 4 weeks after the injury either in the normal artery (single injury protocol) and in the arteriosclerotic artery that had been induced by a previous balloon injury (double injury protocol). NK911 was intravenously administered only three times (immediately after, and 3 and 6 days after the injury) at three different doses (0.1, 1.0 and 10 mg/kg). Corresponding doses of doxooruhicin alone (0.016, 0.16, 1.6 mg/kg) were also administered in the same manner. In both protocols. NK911 dose-dependently suppressed neointimal formation (P<0.001, n=6 each). Immunohistochemical examination demonstrated that the inhibitory effect of NK911 was mainly due to suppression of vascular smooth muscle proliferation. Measurement of vascular concentrations of doxorubicin demonstrated that NK911 effectively delivered the drug to the balloon-injured carotid arteries. Finally, NK911 was well tolerated without any systemic adverse effects. Thus, the treatment with nanocapsules containing antiproliferative agents may be a novel and promising strategy for the prevention of restenosis after balloon angioplasty.
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