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

Marcela Frota Cavalcante; Márcia Duarte Adorne; Walter Miguel Turato; Marina Kemmerer; Mayara Klimuk Uchiyama; Ana Carolina Cavazzin Asbahr; Aline de Cristo Soares Alves; Sandra Helena Poliselli Farsky; Carine Drewes; Marina Cecília Spatti; Soraya Megumi Kazuma; Marcel Boss; Silvia Stanisçuaski Guterres; Koiti Araki; Bernhard Brüne; Dmitry Namgaladze; Adriana Raffin Pohlmann; Dulcineia Saes Parra Abdalla

doi:10.3389/fmed.2021.652137

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

Front Med (Lausanne). 2021 Apr 20:8:652137. doi: 10.3389/fmed.2021.652137. eCollection 2021.

Authors

Marcela Frota Cavalcante¹, Márcia Duarte Adorne², Walter Miguel Turato¹, Marina Kemmerer³, Mayara Klimuk Uchiyama⁴, Ana Carolina Cavazzin Asbahr², Aline de Cristo Soares Alves⁵, Sandra Helena Poliselli Farsky¹, Carine Drewes¹, Marina Cecília Spatti¹, Soraya Megumi Kazuma¹, Marcel Boss³, Silvia Stanisçuaski Guterres⁵, Koiti Araki⁴, Bernhard Brüne³, Dmitry Namgaladze³, Adriana Raffin Pohlmann², Dulcineia Saes Parra Abdalla¹

Affiliations

¹ Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
² Department of Organic Chemistry, Chemistry Institute, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
³ Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany.
⁴ Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
⁵ Department of Production and Control of Medicines, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

Abstract

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.

Keywords: atherosclerosis; electronegative LDL; macrophage; nanocapsules; nanoformulation; single chain fragment variable.