A Nano-Emulsion Platform Functionalized with a Fully Human scFv-Fc Antibody for Atheroma Targeting: Towards a Theranostic Approach to Atherosclerosis.

Samuel Bonnet,Geoffrey Prévot,Martine Duonor-Cérutti,Stéphane Sanchez,Stéphane Mornet,Yannick Mousli,Gisèle Clofent-Sanchez,Mathieu Duttine,Audrey Hemadou,Aurélien Trotier,Sylvie Crauste-Manciet,Marie-Josée Jacobin-Valat

doi:10.3390/ijms22105188

Abstract

Atherosclerosis is at the onset of the cardiovascular diseases that are among the leading causes of death worldwide. Currently, high-risk plaques, also called vulnerable atheromatous plaques, remain often undiagnosed until the occurrence of severe complications, such as stroke or myocardial infarction. Molecular imaging agents that target high-risk atheromatous lesions could greatly improve the diagnosis of atherosclerosis by identifying sites of high disease activity. Moreover, a “theranostic approach” that combines molecular imaging agents (for diagnosis) and therapeutic molecules would be of great value for the local management of atheromatous plaques. The aim of this study was to develop and characterize an innovative theranostic tool for atherosclerosis. We engineered oil-in-water nano-emulsions (NEs) loaded with superparamagnetic iron oxide (SPIO) nanoparticles for magnetic resonance imaging (MRI) purposes. Dynamic MRI showed that NE-SPIO nanoparticles decorated with a polyethylene glycol (PEG) layer reduced their liver uptake and extended their half-life. Next, the NE-SPIO-PEG formulation was functionalized with a fully human scFv-Fc antibody (P3) recognizing galectin 3, an atherosclerosis biomarker. The P3-functionalized formulation targeted atheromatous plaques, as demonstrated in an immunohistochemistry analyses of mouse aorta and human artery sections and in an Apoe−/− mouse model of atherosclerosis. Moreover, the formulation was loaded with SPIO nanoparticles and/or alpha-tocopherol to be used as a theranostic tool for atherosclerosis imaging (SPIO) and for delivery of drugs that reduce oxidation (here, alpha-tocopherol) in atheromatous plaques. This study paves the way to non-invasive targeted imaging of atherosclerosis and synergistic therapeutic applications.

Highlights

Atherosclerosis is characterized by the development of lipid-rich plaques, called atheromatous plaques, in the artery wall [1]
As cardiovascular complications caused by atherosclerosis are the leading cause of As cardiovascular complications caused by atherosclerosis are the leading cause of death in Western countries, it is crucial to develop tools for the early detection of vulnerable death in Western countries, it is crucial to develop tools for the early detection of vulneratheromatous plaques
human antibody (HuAb) represent a class of ligands that are theoretically safer for clinical translation

Summary

Introduction

Atherosclerosis is characterized by the development of lipid-rich plaques, called atheromatous plaques, in the artery wall [1]. Atheromatous plaques can be classified into two types: stable plaques and vulnerable plaques [2]. Stable plaques are usually rich in extracellular matrix and smooth muscle cells that maintain the integrity of these fibrous 4.0/). Vulnerable plaques are rich in macrophages and inflammatory cells that make them prone to rupture, leading to cardiovascular complications [3,4,5]. Angiography is normally used for imaging peripheral arterial disease [6]. It gives information only on vessel lumen reduction (stenosis) but not on the plaque morphology and risk of rupture [7]. Intravascular ultrasound and optical coherence tomography [10,11,12,13]

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