Two Novel PET Radiopharmaceuticals for Endothelial Vascular Cell Adhesion Molecule-1 (VCAM-1) Targeting.

Vanessa Cossu,Guendalina Zuccari,Silvana Alfei,Cecilia Marini,Tullio Florio,Andrea Petretto,Sara Baldassari,Gabriele Caviglioli,Giorgia Ailuno,Sara Pastorino,Giuliana Drava,Gianmario Sambuceti

doi:10.3390/pharmaceutics13071025

Abstract

Atherosclerosis is a chronic progressive disease involving inflammatory events, such as the overexpression of adhesion molecules including the endothelial Vascular Cell Adhesion Molecule-1 (VCAM-1). VCAM-1 is rapidly overexpressed in the first stages of atherosclerosis, thus representing a promising target for early atheroma detection. Two novel Positron Emission Tomography (PET) radiopharmaceuticals (MacroP and NAMP), based on the VCAM-1-binding peptide having sequence VHPKQHRGGSKGC, were synthesized and characterized. MacroP is derived from the direct conjugation of a DOTA derivative with the peptide, while NAMP is a biotin derivative conceived to be employed in a three-step pretargeting system, involving the use of a double-chelating derivative of DOTA. The identity of the newly synthesized radiopharmaceuticals was confirmed by mass spectrometry and, after radiolabeling with 68Ga, both showed high radiochemical purity; in vitro tests on human umbilical vein endothelial cells evidenced their VCAM-1 binding ability, with higher radioactive uptake in the case of NAMP. Moreover, NAMP might also be employed in a theranostic approach in association with functionalized biotinylated nanoparticles.

Highlights

Atherosclerosis is the most diffused cardiovascular disease in developed countries [1].It is a chronic progressive disease characterized by the subendothelial accumulation of lipids, immune cells, foam cells, fibrous elements, platelets and extracellular matrix, forming the atherosclerotic plaque [2,3]
The relevance of the overexpression of endothelial adhesion proteins in the early stages of atherosclerosis development was firstly demonstrated by the observation that cholesterol accumulation in the vasal intima induced the increased expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) on endotheliocyte membranes [6]
Vascular Cell Adhesion Molecule-1 plays a crucial role in atherosclerotic plaque

Summary

Introduction

Atherosclerosis is the most diffused cardiovascular disease in developed countries [1]. It is a chronic progressive disease characterized by the subendothelial accumulation of lipids, immune cells, foam cells (i.e., cholesterol-engorged macrophages), fibrous elements, platelets and extracellular matrix, forming the atherosclerotic plaque [2,3]. A prominent role in atherosclerosis and its complications is attributed to inflammation [4,5]. The relevance of the overexpression of endothelial adhesion proteins in the early stages of atherosclerosis development was firstly demonstrated by the observation that cholesterol accumulation in the vasal intima induced the increased expression of VCAM-1 on endotheliocyte membranes [6]. The relevance of the overexpression of endothelial adhesion proteins in the early stages of atherosclerosis development was firstly demonstrated by the observation that cholesterol accumulation in the vasal intima induced the increased expression of VCAM-1 on endotheliocyte membranes [6]. 4.0/).

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