Reduction of atherosclerotic lesions in rabbits treated with etoposide associated with cholesterol-rich nanoemulsions

Abstract

Objectives Cholesterol-rich nanoemulsions (LDE) bind to low-density lipoprotein (LDL) receptors and after injection into the bloodstream concentrate in aortas of atherosclerotic rabbits. Association of paclitaxel with LDE markedly reduces the lesions. In previous studies, treatment of refractory cancer patients with etoposide associated with LDE had been shown devoid of toxicity. In this study, the ability of etoposide to reduce lesions and inflammatory factors in atherosclerotic rabbits was investigated. Methods Eighteen New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30, nine animals were treated with four weekly intravenous injections of etoposide oleate (6 mg/kg) associated with LDE, and nine control animals were treated with saline solution injections. Results LDE-etoposide reduced the lesion areas of cholesterol-fed animals by 85% and intima width by 50% and impaired macrophage and smooth muscle cell invasion of the intima. Treatment also markedly reduced the protein expression of lipoprotein receptors (LDL receptor, LDL-related protein-1, cluster of differentiation 36, and scavenger receptor class B member 1), inflammatory cytokines (interleukin-1β and tumor necrosis factor-α), matrix metallopeptidase-9, and cell proliferation markers (topoisomerase IIα and tubulin). Conclusion The ability of LDE-etoposide to strongly reduce the lesion area and the inflammatory process warrants the great therapeutic potential of this novel preparation to target the inflammatory-proliferative basic mechanisms of the disease.

Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles

“…Treatment with LDE-paclitaxel resulted in a several fold reduction of the gene expression of both pro- and anti-inflammatory factors in the grafted hearts 20 . It is worthwhile to note that similar results were achieved following the treatment of cholesterol-fed rabbits with other preparations of chemotherapeutic agents associated with LDE, such as LDE-etoposide 21 and LDE-methotrexate 22 . Thus, it can be assumed that lesion size reduction, as was observed in patients 1, 4, 5 and 7 in the current study, is a consequence not only of the anti-proliferative actions of the drug but also of the reduction of inflammation in the lesion area.…”

Evaluation of atherosclerotic lesions in cholesterol-fed mice during treatment with paclitaxel in lipid nanoparticles: a magnetic resonance imaging study

“…The body weight in all groups was unchanged, which supports lack of important toxicity in the LDE-paclitaxel group. The results are similar to our previous studies, demonstrating further indication that the LDE-paclitaxel treatment has the ability to reduce the toxicity of chemotherapeutics [ 6 , 14 , 23 ] .…”

“…Paclitaxel has been used in most vascular fields, and several trials using paclitaxel coated stents for local delivery of the drug for the treatment of lower-extremity peripheral arterial disease have been reported [ 20 ­ 22 ] . In our previous studies, rabbits with atherosclerosis induced by cholesterol feeding, treatment of paclitaxel, etoposide or methotrexate associated to lipid nanoparticles resulted in reduction of the lesion extension in the range of 60-85% [ 6 , 14 , 23 ] . The results of the present study are consistent with previous findings: LDE-paclitaxel decreased wall area and percentage of stenosis as observed by MRI, and reduced lesioned area by macroscopic morphometry.…”

Combating atherosclerosis with targeted nanomedicines: recent advances and future prospective

“…Tavares et al evaluated the ability of cholesterol-rich LNE associated etoposide on the reduction of lesions and inflammatory processes in atherosclerotic rabbits. 64 Based on their findings, the lesion areas of cholesterol-fed animals reduced by 85% and the intima width reduced by 50% upon treatment with LNE associated etoposide. Furthermore, this therapeutic modality decreased lipoprotein receptors, pro-inflammatory factors, and proliferation markers.…”