caa a22 4500 606158189 CHVBK 20210128100618.0 cr unu---uuuuu 210128e20150201xx s 000 0 eng 10.1007/s10557-014-6566-1 doi (NATIONALLICENCE)springer-10.1007/s10557-014-6566-1 Use of Combined Chemotherapy with Etoposide and Methotrexate, both Associated to Lipid Nanoemulsions for Atherosclerosis Treatment in Cholesterol-fed Rabbits [Elektronische Daten] [Antonio Leite Jr., Tatiana Solano, Elaine Tavares, Raul Maranhão] 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 2months. After the first month, the animals received 4 weekly intravenous injections of LDE-methotrexate (4mg/kg dose), LDE-etoposide (6mg/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. Springer Science+Business Media New York, 2015 Atherosclerosis treatment nationallicence Nanoparticles nationallicence Cholesterol nationallicence Methotrexate nationallicence Etoposide nationallicence Solid lipid particles nationallicence Leite Jr. Antonio Lipid Metabolism Laboratory, Heart Institute (INCOR) and the Medical School Hospital, São Paulo, Av. Dr. Eneas C. Aguiar 44, 1 subsolo, CEP 0543000, São Paulo, SP, Brazil aut Solano Tatiana Lipid Metabolism Laboratory, Heart Institute (INCOR) and the Medical School Hospital, São Paulo, Av. Dr. Eneas C. Aguiar 44, 1 subsolo, CEP 0543000, São Paulo, SP, Brazil aut Tavares Elaine Lipid Metabolism Laboratory, Heart Institute (INCOR) and the Medical School Hospital, São Paulo, Av. Dr. Eneas C. Aguiar 44, 1 subsolo, CEP 0543000, São Paulo, SP, Brazil aut Maranhão Raul Lipid Metabolism Laboratory, Heart Institute (INCOR) and the Medical School Hospital, São Paulo, Av. Dr. Eneas C. Aguiar 44, 1 subsolo, CEP 0543000, São Paulo, SP, Brazil aut Cardiovascular Drugs and Therapy Springer US; http://www.springer-ny.com 29/1(2015-02-01), 15-22 0920-3206 29:1<15 2015 29 10557 https://doi.org/10.1007/s10557-014-6566-1 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10557-014-6566-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Leite Jr Antonio Lipid Metabolism Laboratory, Heart Institute (INCOR) and the Medical School Hospital, São Paulo, Av. Dr. Eneas C. Aguiar 44, 1 subsolo, CEP 0543000, São Paulo, SP, Brazil aut NATIONALLICENCE 700 1- Solano Tatiana Lipid Metabolism Laboratory, Heart Institute (INCOR) and the Medical School Hospital, São Paulo, Av. Dr. Eneas C. Aguiar 44, 1 subsolo, CEP 0543000, São Paulo, SP, Brazil aut NATIONALLICENCE 700 1- Tavares Elaine Lipid Metabolism Laboratory, Heart Institute (INCOR) and the Medical School Hospital, São Paulo, Av. Dr. Eneas C. Aguiar 44, 1 subsolo, CEP 0543000, São Paulo, SP, Brazil aut NATIONALLICENCE 700 1- Maranhão Raul Lipid Metabolism Laboratory, Heart Institute (INCOR) and the Medical School Hospital, São Paulo, Av. Dr. Eneas C. Aguiar 44, 1 subsolo, CEP 0543000, São Paulo, SP, Brazil aut NATIONALLICENCE 773 0- Cardiovascular Drugs and Therapy Springer US; http://www.springer-ny.com 29/1(2015-02-01), 15-22 0920-3206 29:1<15 2015 29 10557