Reduction of Atherosclerotic Lesions by the Chemotherapeutic Agent Carmustine Associated to Lipid Nanoparticles.

Abstract

After injection in the bloodstream, a lipid nanoparticle (LDE) resembling low-density lipoprotein (LDL) concentrates in atherosclerotic lesions of cholesterol-fed rabbits. Here, rabbits with atherosclerosis were treated with carmustine, an antiproliferative agent used in cancer chemotherapy, associated to LDE to investigate the effects on the lesions. Twenty-seven male New Zealand rabbits were fed a 1% cholesterol diet for 8weeks. After 4weeks nine animals were treated with intravenous saline solution, nine with intravenous LDE alone, and nine with intravenous LDE-carmustine (4mg/kg, weekly for 4weeks). LDE-carmustine reduced lesion size by 90% compared to the controls. LDE-carmustine reduced the presence of macrophages, vascular smooth muscle cells, and regulatory T cells in the arterial intima, as well as the presence of matrix metallopeptidase-9, interleukin-1β and TNF-α and lipoprotein receptors, namely LDL-receptor, LDL-related protein-1, scavenger receptor class B member 1. When injected alone, without association to carmustine, LDE was not different from injected saline solution. LDE-carmustine treatment resulted in marked reduction of lesion area, of the invasion of the arterial intima by macrophages and vascular smooth muscle cells and pro-inflammatory factors. Therefore, this new formulation shows great potential for therapy of atherosclerotic cardiovascular disease.