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

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.

Chitosan Nanoparticles in Atherosclerosis—Development to Preclinical Testing

“…Most recently, a single-chain fragment variable (scFv) reactive to LDL (-) as a ligand was used to formulate surface-functionalised nanocapsules [ 87 ]. Its ability to attenuate LDL (-) uptake by primary macrophages and the progression of atherosclerotic lesions in LDLr-/-mice was studied.…”

Cholesterol of Low-Density Lipoprotein-Containing Circulating Immune Complexes Improves Prognosis of Asymptomatic Carotid Atherosclerosis

“…Ответ на этот вопрос очень важен, поскольку аутоантитела к модифицированным липопротеидам могут вырабатываться in vivo именно для быстрого удаления и элиминации атерогенных частиц. По крайней мере, использование антител к модифицированным липопротеидам в настоящее время изучается в исследованиях in vitro и in vivo как перспективный подход к разработке новых альтернативных методов профилактики и лечения атеросклероза [14,15].…”

The Oxidized Lipoproteins In Vivo: Its Diversity and Behavior in the Human Circulation

“…A new strategy to trap LDL(−) using a chitosan-based nano particle conjugated with a single-chain variable fragment of anti-LDL(−) mAb was developed. This nanoparticle was taken up by human and mouse macrophages via macro-pinocytosis, and when this nano-particle was injected intravenously into LDL receptor knockout mice the inflammatory responses in the mice and the aortic lesion size were significantly reduced [ 87 ]. Although this nano-particle has yet to be examined, this is an exciting approach to minimize the pathologic property of LDL(−).…”