An albumin-binding Gd-HPDO3A contrast agent for improved intravascular retention

Tear, Louise R.; Carrera, Carla; Dhakan, Chetan; Cavallari, Eleonora; Travagin, Fabio; Calcagno, Claudia; Aime, Silvio; Gianolio, Eliana

doi:10.1039/d1qi00128k

Cited by 5 publications

(2 citation statements)

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“…Furthermore, because both Gd chelates have the same ethoxybenzyl moiety, the higher percent HSA binding value suggests that additional electrostatic interactions were induced by partially charged protein residues and pendant arms rather than hydrophobic interactions. Several studies have found that negative Gd chelates have a similar enhanced binding effect on HSA. − In order to gain a better understanding of the HSA interaction, we measured the relaxivity change in several anionic media and HSA solutions in subsequent sections.…”

Section: Resultsmentioning

confidence: 99%

Effect of Structural Fine-Tuning on Chelate Stability and Liver Uptake of Anionic MRI Contrast Agents

Baek

Kim

et al. 2022

J. Med. Chem.

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The purpose of this study is to assess the physicochemical properties and MRI diagnostic efficacy of two newly synthesized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-type Gd chelates, Gd-SucL and Gd-GluL, with an asymmetric α-substituted pendant arm as potential hepatocyte-specific magnetic resonance imaging contrast agents (MRI CAs). Our findings show that fine conformational changes in the chelating arm affect the in vivo pharmacokinetic behavior of the MRI CA, and that a six-membered chelating substituent of Gd-SucL is more advantageous in this system to avoid unwanted interactions with endogenous species. Gd-SucL exhibited a general DOTA-like chelate stability trend, indicating that all chelating arms retain coordination bonding. Finally, the in vivo diagnostic efficacy of highly stable Gd-SucL as a potential hepatocyte-specific MRI CA was evaluated using T 1-weighted MR imaging on an orthotopic hepatocarcinoma model.

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Section: Resultsmentioning

confidence: 99%

Effect of Structural Fine-Tuning on Chelate Stability and Liver Uptake of Anionic MRI Contrast Agents

Baek

Kim

et al. 2022

J. Med. Chem.

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“…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. , …”

Section: Introductionmentioning

confidence: 99%

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

Stefania,

Palagi,

Di Gregorio

et al. 2023

J. Am. Chem. Soc.

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Gd-L1 is a macrocyclic Gd-HPDO3A derivative functionalized with a short spacer to a trisulfonated pyrene. When compared to Gd-HPDO3A, the increased relaxivity appears to be determined by both the higher molecular weight and the occurrence of an intramolecularly catalyzed prototropic exchange of the coordinated OH moiety. In water, Gd-L1 displayed a relaxivity of 7.1 mM −1 s −1 (at 298 K and 0.5 T), slightly increasing with the concentration likely due to the onset of intermolecular aggregation. A remarkably high and concentration-dependent relaxivity was measured in human serum (up to 26.5 mM −1 s −1 at the lowest tested concentration of 0.005 mM). The acquisition of 1 H-nuclear magnetic relaxation dispersion (NMRD) and 17 O-R 2 vs T profiles allowed to get an in-depth characterization of the system. In vitro experiments in the presence of human serum albumin, γ-globulins, and polylysine, as well as using media mimicking the extracellular matrix, provided strong support to the view that the trisulfonated pyrene fosters binding interactions with the exposed positive groups on the surface of proteins, responsible for a remarkable in vivo hyperintensity in T 1w MR images. The in vivo MR images of the liver, kidneys, and spleen showed a marked contrast enhancement in the first 10 min after the i.v. injection of Gd-L1, which was 2−6-fold higher than that for Gd-HPDO3A, while maintaining a very similar excretion behavior. These findings may pave the way to an improved design of MRI GBCAs, for the first time, based on the setup of weak and dynamic interactions with abundant positive groups on serum and ECM proteins.

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Feasibility of Gd-Based prostate cancer targeted magnetic resonance agents using prostate specific membrane antigen

Yang

Kim

Ahn

et al. 2022

Biochemical and Biophysical Research Communications

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An albumin-binding Gd-HPDO3A contrast agent for improved intravascular retention

Abstract: Gadolinium contrast agents that bind to human serum albumin (HSA) can achieve significantly higher relaxivity values and show improved vascular retention time. Most contrast agents of this design are linear...

Cited by 5 publications

References 50 publications

Effect of Structural Fine-Tuning on Chelate Stability and Liver Uptake of Anionic MRI Contrast Agents

Effect of Structural Fine-Tuning on Chelate Stability and Liver Uptake of Anionic MRI Contrast Agents

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

Feasibility of Gd-Based prostate cancer targeted magnetic resonance agents using prostate specific membrane antigen

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