Large Protein Assemblies for High-Relaxivity Contrast Agents: The Case of Gadolinium-Labeled Asparaginase

Abstract

Biologics are emerging as the most important class of drugs and are used to treat a large variety of pathologies. Most of biologics are proteins administered in large amounts, either by intramuscular injection or by intravenous infusion. Asparaginase is a large tetrameric protein assembly, currently used against acute lymphoblastic leukemia. Here, a gadolinium(III)-DOTA derivative has been conjugated to asparaginase, and its relaxation properties have been investigated to assess its efficiency as a possible theranostic agent. The field-dependent 1 H longitudinal relaxation measurements of water solutions of gadolinium(III)-labeled asparaginase indicate a very large increase in the relaxivity of this paramagnetic protein complex with respect to small gadolinium chelates, opening up the possibility of its use as an MRI contrast agent.

Metal-Assembled Collagen Peptide Microflorettes as Magnetic Resonance Imaging Agents

“…A substantial decrease in rotation can be achieved by using molecules with a higher molecular weight and size. Recent studies have demonstrated that linking contrast agents to large molecules and assemblies (i.e., dextran [ 20 ], dendrimers [ 21 , 22 , 23 ], liposomes [ 24 , 25 , 26 ], nanoparticles [ 27 , 28 ], fullerenes [ 29 ], micelles [ 30 , 31 ], peptides [ 32 , 33 , 34 ] and proteins [ 35 , 36 , 37 ]) can substantially increase T1 relaxivity. In addition, the integration of Gd(III) ions within various macromolecules can lead to the formation of multiple paramagnetic centers, thereby conferring enhanced sensitivity [ 38 , 39 , 40 , 41 ].…”

Seeking for Innovation with Magnetic Resonance Imaging Paramagnetic Contrast Agents: Relaxation Enhancement via Weak and Dynamic Electrostatic Interactions with Positively Charged Groups on Endogenous Macromolecules

“…Their efficiency is first of all represented by their relaxivity (r 1 ), i.e., the relaxation enhancement brought to solvent water protons at a concentration of 1 mM. 8,9 Over the years, probe developers have paid great attention to improving the relaxivity of gadolinium-based contrast agents (GBCAs), 10,11 in particular, by optimizing their structures in terms of the number and exchange rate of the coordinated water molecules in the inner and in the second coordination sphere 12−14 and by controlling the molecular reorientational time through the introduction of substituents on the surface of the ligand capable of either increasing their molecular weight (MW) 15 or setting up suitable interactions with macromolecules. 10,16−18 Often, the target macromolecule is represented by human serum albumin (HSA) 19,20 thus endowing the GBCA with blood pool properties, with a primary aim of application in the field of the acquisition of angiographic images.…”

“…Contrast agents (CAs) play a crucial role in diagnostic magnetic resonance imaging (MRI) as they add relevant physiological information to the outstanding anatomical resolution of the images acquired with this modality. − They usually consist of paramagnetic gadolinium complexes that cause a marked reduction in the proton relaxation times in the regions where they distribute. Their efficiency is first of all represented by their relaxivity ( r 1 ), i.e., the relaxation enhancement brought to solvent water protons at a concentration of 1 mM. , Over the years, probe developers have paid great attention to improving the relaxivity of gadolinium-based contrast agents (GBCAs), , in particular, by optimizing their structures in terms of the number and exchange rate of the coordinated water molecules in the inner and in the second coordination sphere − and by controlling the molecular reorientational time through the introduction of substituents on the surface of the ligand capable of either increasing their molecular weight (MW) or setting up suitable interactions with macromolecules. ,− Often, the target macromolecule is represented by human serum albumin (HSA) , thus endowing the GBCA with blood pool properties, with a primary aim of application in the field of the acquisition of angiographic images. − In most cases, the binding to HSA has been pursued through the introduction of substituents capable of recognizinng the well-known binding sites for lipophilic drugs usually identified as the Sudlow sites. , …”