scFv-Anti-LDL(-)-Metal-Complex Multi-Wall Functionalized-Nanocapsules as a Promising Tool for the Prevention of Atherosclerosis Progression

Frontiers in Medicine

Marcela Frota Cavalcante¹  Dulcineia Saes Parra Abdalla¹  Walter Miguel Turato¹  Sandra Helena Poliselli Farsky¹  Marina Cecília Spatti¹  Soraya Megumi Kazuma¹  Carine Drewes¹  Koiti Araki²  Mayara Klimuk Uchiyama²  Adriana Raffin Pohlmann³  Ana Carolina Cavazzin Asbahr³  Márcia Duarte Adorne³  Aline de Cristo Soares Alves⁴  Silvia Stanisçuaski Guterres⁴  Bernhard Brüne⁵  Marcel Boss⁵  Dmitry Namgaladze⁵  Marina Kemmerer⁵ 

[1] Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil;Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil;Department of Organic Chemistry, Chemistry Institute, Federal University of Rio Grande do Sul, Porto Alegre, Brazil;Department of Production and Control of Medicines, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil;Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany;

关键词: atherosclerosis;    nanocapsules;    electronegative LDL;    macrophage;    single chain fragment variable;    nanoformulation;   

DOI  :  10.3389/fmed.2021.652137

来源: Frontiers

【 摘 要 】

Atherosclerosis can be originated from the accumulation of modified cholesterol-rich lipoproteins in the arterial wall. The electronegative LDL, LDL(-), plays an important role in the pathogenesis of atherosclerosis once this cholesterol-rich lipoprotein can be internalized by macrophages, contributing to the formation of foam cells, and provoking an immune-inflammatory response. Herein, we engineered a nanoformulation containing highly pure surface-functionalized nanocapsules using a single-chain fragment variable (scFv) reactive to LDL(-) as a ligand and assessed whether it can affect the LDL(-) uptake by primary macrophages and the progression of atherosclerotic lesions in Ldlr−/− mice. The engineered and optimized scFv-anti-LDL(-)-MCMN-Zn nanoformulation is internalized by human and murine macrophages in vitro by different endocytosis mechanisms. Moreover, macrophages exhibited lower LDL(-) uptake and reduced mRNA and protein levels of IL1B and MCP1 induced by LDL(-) when treated with this new nanoformulation. In a mouse model of atherosclerosis employing Ldlr−/− mice, intravenous administration of scFv-anti-LDL(-)-MCMN-Zn nanoformulation inhibited atherosclerosis progression without affecting vascular permeability or inducing leukocytes-endothelium interactions. Together, these findings suggest that a scFv-anti-LDL(-)-MCMN-Zn nanoformulation holds promise to be used in future preventive and therapeutic strategies for atherosclerosis.

【 授权许可】

CC BY