Cavalcante Marcela Frota, Kazuma Soraya Megumi, Bender Eduardo André, Adorne Márcia Duarte, Ullian Mayara, Veras Mariana Matera, Saldiva Paulo Hilário Nascimento, Maranhão Andrea Queiroz, Guterres Silvia Stanisçuaski, Pohlmann Adriana Raffin, Abdalla Dulcineia Saes Parra
Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
Department of Organic Chemistry, Chemistry Institute, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
Eur J Pharm Biopharm. 2016 Oct;107:120-9. doi: 10.1016/j.ejpb.2016.07.002. Epub 2016 Jul 1.
Atherosclerosis is a chronic inflammatory disease responsible for the majority of cases of myocardial infarction and ischemic stroke. The electronegative low-density lipoprotein, a modified subfraction of native LDL, is pro-inflammatory and plays an important role in atherogenesis. To investigate the effects of a nanoformulation (scFv anti-LDL(-)-MCMN-Zn) containing a scFv reactive to LDL(-) on the inhibition of atherosclerosis, its toxicity was evaluated in vitro and in vivo and further it was also administered weekly to LDL receptor knockout mice. The scFv anti-LDL(-)-MCMN-Zn nanoformulation did not induce cell death in RAW 264.7 macrophages and HUVECs. The 5mg/kg dose of scFv anti-LDL(-)-MCMN-Zn did not cause any typical signs of toxicity and it was chosen for the evaluation of its atheroprotective effect in Ldlr(-/-) mice. This nanoformulation significantly decreased the atherosclerotic lesion area at the aortic sinus, compared with that in untreated mice. In addition, the Il1b mRNA expression and CD14 protein expression were downregulated in the atherosclerotic lesions at the aortic arch of Ldlr(-/-) mice treated with scFv anti-LDL(-)-MCMN-Zn. Thus, the scFv anti-LDL(-)-MCMN-Zn nanoformulation inhibited the progression of atherosclerotic lesions, indicating its potential use in a future therapeutic strategy for atherosclerosis.
动脉粥样硬化是一种慢性炎症性疾病，是大多数心肌梗死和缺血性中风病例的病因。带负电荷的低密度脂蛋白是天然低密度脂蛋白的一种修饰亚组分，具有促炎作用，在动脉粥样硬化形成中起重要作用。为了研究一种含有与低密度脂蛋白（LDL）阴性反应的单链抗体片段（scFv）的纳米制剂（scFv抗LDL（-）-MCMN-Zn）对动脉粥样硬化的抑制作用，在体外和体内对其毒性进行了评估，并进一步每周给低密度脂蛋白受体敲除小鼠给药。scFv抗LDL（-）-MCMN-Zn纳米制剂在RAW 264.7巨噬细胞和人脐静脉内皮细胞（HUVECs）中未诱导细胞死亡。5mg/kg剂量的scFv抗LDL（-）-MCMN-Zn未引起任何典型的毒性迹象，因此选择该剂量来评估其在Ldlr（-/-）小鼠中的动脉粥样硬化保护作用。与未治疗的小鼠相比，这种纳米制剂显著减小了主动脉窦处的动脉粥样硬化病变面积。此外，在用scFv抗LDL（-）-MCMN-Zn治疗的Ldlr（-/-）小鼠主动脉弓处的动脉粥样硬化病变中，Il1b mRNA表达和CD14蛋白表达下调。因此，scFv抗LDL（-）-MCMN-Zn纳米制剂抑制了动脉粥样硬化病变的进展，表明其在未来动脉粥样硬化治疗策略中的潜在应用价值。
