ANR 2016 - CARGOLD - Superparamagnetic nanoflowers

Superparamagnetic nanoflowers: bioresorbable carriers of ultrasmall gold nanoparticles designed for early detection of atherosclerosis by integrated MRI/PET imaging

Atherosclerosis is a chronic systemic inflammatory disease affecting the large and medium-sized arteries. The development of atherosclerosis which can progress silently during decades is characterized by the thickening and loss of elasticity of the arteries owing to the formation of atherosclerotic plaques in lesion-prone areas. These plaques are built from the accumulation of fatty materials within the vessel walls and by the modification of the connective tissue of the vessel walls. As a result, the luminal narrowing (stenosis) of the modified arteries occurs and limits therefore the blood flow which can lead to tissue ischaemia. However the most severe complications arise from the rupture of the atherosclerotic plaques which accounts for 70% of heart attacks. Since atherosclerosis is involved in most cardiovascular diseases which are the leading cause of morbidity and death in the world, the identification of vulnerable plaque (i.e. rupture-prone plaques) constitute an urgent need which would result in health benefits. Among the numerous imaging modalities, the combination of magnetic resonance imaging (MRI) and positron emission tomography (PET) constitutes a promising strategy because it allies the high resolution of MRI to the exceptional sensitivity of PET imaging. Such a combination should be a significant breakthrough in the early detection of vulnerable atherosclerotic plaques. If the development of imaging device which integrates both MRI and PET is in itself a major challenge, the elaboration of nanoprobes for exploiting this promising hybrid technology for medical imaging represents a crucial step for the early detection of vulnerable atherosclerotic plaques. Facing the real and urgent need, the CARGOLD project aims at developing nanoprobes for early detection of vulnerable atherosclerotic plaques and therapy by magnetic hyperthermia from multifunctional nanostructures whose physical and chemical properties render possible the specific targeting of these plaques, their follow-up by integrated MRI/PET device and also by computed tomography (CT) after intravenous injection, a therapeutic activity and their removal by bio-degradation and renal clearance. Such attractive characteristics should be obtained by assembling in a controlled manner bio-resorbable maghemite nanoflowers and multifunctional gold nanoparticles. The gold cores which can generate the contrast enhancement of the images acquired by CT will be coated by bio-targeting groups (peptides) and by gadolinium and positron emitter chelates for a simultaneous follow-up by MRI and PET. Although these multifunctional gold nanoparticles exhibit the potential for a targeted imaging, they are handicapped by a too rapid renal clearance which should impede a sufficient accumulation in the vulnerable plaques. Their grafting onto bio-resorbable nanocarriers (iron oxide nanoflowers (~30 nm)) is expected to enhance their circulation time after intravenous injection by postponing their renal clearance which remains a pre-requisite for the in vivo application of gold nanoparticles. Besides a greater circulation time, the accumulation of these golden nanoflowers designed for multimodal imaging (MRI/PET and CT) will be ensured by the avidity of macrophages for nanoparticles which are present in a large amount in the vulnerable plaques and by the specific interaction between the peptides coated to the golden nanoflowers and cell adhesion molecules (VCAM-1). This strategy carries the promise to significantly improve the detection of vulnerable plaques and therefore to prevent from the dramatic issue of their rupture. For achieving this ambitious goal, the CARGOLD project gathers six partners (4 academic partners, 1 medical imaging platform and an industrial specialized in the production of customized particles) which are recognized for their expertise in the complementary fields explored in CARGOLD.