Use of Combined Chemotherapy with Etoposide and Methotrexate, both Associated to Lipid Nanoemulsions for Atherosclerosis Treatment in Cholesterol-fed Rabbits

• Published in: Cardiovascular drugs and therapy Vol. 29; no. 1; pp. 15 - 22
• Main Authors: Leite, Antonio C. A., Solano, Tatiana V., Tavares, Elaine R., Maranhão, Raul C.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.02.2015; Springer Nature B.V
• Subjects: Animals; Aorta - drug effects; Aorta - pathology; Atherosclerosis - drug therapy; Atherosclerosis - pathology; Cardiology; Drug Therapy, Combination; Emulsions; Etoposide - administration & dosage; Etoposide - therapeutic use; Lipids - administration & dosage; Lipids - chemistry; Male; Medicine; Medicine & Public Health; Methotrexate - administration & dosage; Methotrexate - therapeutic use; Nanostructures - administration & dosage; Nanostructures - chemistry; Original Article; Rabbits; Nanoparticles; Etoposide; Solid lipid particles; Atherosclerosis treatment; Methotrexate; Cholesterol
• ISSN: 0920-3206; 1573-7241
• DOI: 10.1007/s10557-014-6566-1

Purpose Treatment of atherosclerotic rabbits with intravenous methotrexate or etoposide carried in lipid nanoemulsions (LDE) markedly reduced the lesions in the aorta. Here, the combined treatment with LDE-methotrexate and LDE-etoposide was investigated aiming to increase the anti-atherosclerosis effect. Methods Thirty-six male rabbits received a diet with 1 % cholesterol for 2 months. After the first month, the animals received 4 weekly intravenous injections of LDE-methotrexate (4 mg/kg dose), LDE-etoposide (6 mg/kg), or a combination of those two drugs, while the control animals were injected with LDE ( n  = 9 for each group). Results LDE-methotrexate+LDE-etoposide reduced aortic lesion areas by 95 % compared with controls and the intima-media ratio was reduced five-fold, whereas LDE-methotrexate reduced the lesions by 81 % and LDE-etoposide by 83 %. Compared to controls, the positive area of macrophages and MMP-9 in the arterial intima was significantly reduced in all treated groups ( p  < 0.001), but the MMP9 reduction was greater with the combined chemotherapy than the reduction achieved by the isolated treatments. Presence of CD3 positive cells was equal in controls and LDE-methotrexate+LDE-etoposide treated animals. However, FOXP3 positive T lymphocytes in the intima were increased in the LDE-methotrexate+LDE-etoposide rabbits. Weight, food intake evolution and the hematologic parameters suggested that the treatment had very low toxicity. Conclusions Compared to the single treatments with LDE-methotrexate and LDE-etoposide, the combined treatment was more effective in reducing the atherosclerotic lesions. Because the toxicity of the novel drug-target combined scheme was low, those results favor the possibility of future clinical studies in patients with cardiovascular disease.