Evaluating the potential of chelation therapy to prevent and treat gadolinium deposition from MRI contrast agents (Mar 2018).

Article link: https://www.nature.com/articles/s41598-018-22511-6

Journal: Scientific Reports

Authors of the article: Julian Rees, Gauthier J.-P. Deblonde, Dahlia D. An, Camille Ansloborlo, Stacey S. Gauny & Rebecca J. Abergel

“In one study, the linear contrast agent Gadodiamide (Omniscan), a derivative of the diethylenetriaminepentaacetic acid (DTPA) chelator currently in use as a metal decorporation agent5, was found to release 24% of its Gd3+ payload after only a single day in human serum; a number that increases to 64% in the presence of elevated phosphate levels.”

“Gd recovered from the excreta of all study groups, as well as the relative amounts found in the urine and feces. The excreta of the control group contained 34.4% RD on day 1, with a roughly 95% urine and 5% feces ratio. On all subsequent days an additional ≈3% was found in the total excreta. Interestingly, while on day 2 an equal amount of 153Gd was found in the urine and feces, on days 3 and 4 the ratio of excreted Gd shifted towards increased concentration in the feces, indicating that while the urinary metabolism is responsible for the initial clearance of Gd, over time the remaining metal is cleared through solid waste. For the treatment groups, the cumulative total excreta on day 4 are, as expected, the inverse of the total bodily accumulations (Figure S1). The most dramatic difference between treatment groups is that upon treatment with HOPO, a substantial increase in fecal clearance is observed, whereas DTPA promotes clearance through the urinary pathway only. This is most clearly observed in the groups receiving HOPO 24 and 48 h post-contamination; those treatment groups are statistically identical to the control until treatment, whereupon a significant increase in fecal excretion is found. It is noted that this is consistent with the observed capacity of HOPO to reduce liver concentrations of 153Gd when administered 48 h post-contamination. In contrast, DTPA is cleared via the renal pathway, and even a 1 h post-contamination administration leaves substantial Gd accumulation in the liver tissue.”

“Additionally, efforts to characterize the speciation of Gd in both brain and other tissues have identified insoluble Gd-containing deposits high in phosphate and calcium, strongly suggesting that Gd is no longer associated with the intended chelating agent.”

“We have therefore performed speciation simulations for the most common Gd3+-MRI chelator systems, utilizing published thermodynamic parameters and accounting for the presence of the most abundant and relevant natural chelators: phosphates, carbonates, hydroxides, oxalates, lactates, and citrates, as well as the synthetic chelators themselves”

Speciation studies included utilizing the Hyperquad Simulation and Speciation software (HySS).

“HySS software was implemented with the published stability constants for the soluble species of Gd3+, Zn2+, and Ca2+ with the synthetic chelators of interest (DOTA, DTPA, DTPA-BMA, EDTA, and HOPO) and the endogenous chelators (hydroxides, phosphates, carbonates, citrates, lactates, and oxalates). The protonation constants of the chelators were also implemented in HySS software. Each speciation simulation contained between 40 and 74 equilibria.”

“From the perspective of coordination chemistry, the design of a successful agent for contrast MRI is somewhat paradoxical. The ligand must have sufficient affinity and selectivity for Gd so as to be stable in vivo, either from competition for Gd by endogenous ligands or transmetallation of the chelator by bioavailable metals; however, without at least one open coordination site for water to bind, t1 relaxation enhancement is quenched and the complex ceases to perform as a contrast agent. Thus, many of the best ligands for chelating Gd, including HOPO, may be unsuitable as contrast agents because the chelator occupies all available coordination sites. Recognizing the value of the clinical data afforded by contrast-enhanced MRI, such insight inspires a critical evaluation of the current strategies employed for GBCAs, and in particular raises the question of whether a single-chelator approach is in fact the safest and most effective means to provide MRI contrast. We eagerly anticipate the creative consideration of the points raised herein, as well as the properties of f-block-specific chelators such as HOPO, in the rapidly-expanding body of literature in this field.

Commentary: Still hopeful for HOPO… Chelators: Identifying a need for patients that retain gad and are symptomatic: HOPO (2018)