Gadolinium Dissolution from Nanocrystalline Oxides and Implications for Nanoparticle-Based T1 MRI Contrast Agents

Abstract

Magnetic Resonance Imaging (MRI) is a common, noninvasive imaging technique that requires the use of contrast agents in about a third of procedures to enhance contrast between tissues. Molecular gadolinium-based chelates are the mainstream form of T1 contrast agents used in the clinic, but their administration is associated with an increased risk of serious adverse effects for certain patient populations. Gadolinium oxide nanoparticles (GONPs) have emerged as a promising alternative to molecular-based contrast agents, with different toxicological properties that may enhance their safety compared to molecular gadolinium chelates. Recent studies have shown that GONPs can achieve larger relaxivity values, and thus better contrast, compared to molecular-based contrast agents. However, understanding the safety profile of GONPs requires quantitative characterization of free gadolinium ion (Gd3+) release across a range of physiologically relevant conditions, as free Gd3+ is the primary mediator of gadolinium-associated toxicity. This work establishes a quantitative methodology for measuring Gd3+ dissolution from GONPs in aqueous media. Gadolinium oxide nanoplates are synthesized with a diameter of 11 nm and modified using hydrophilic and amphiphilic surface coating strategies. Gadolinium dissolution is evaluated in a range of physiologically relevant media. Dissolution dependence on different GONPs surface coatings is investigated and discussed in the context of surface grafting density and charge. Among the coatings evaluated, the sulfonated amphiphilic copolymer PAMPS-LA demonstrated remarkably low dissolution. These findings provide mechanistic insight into the rational design of GONPs with low Gd3+ release, an established criterion for the safety assessment of gadolinium-based contrast agents.