Relaxivity and toxicological properties of manganese oxide nanoparticles for MRI applications

Manganese oxide nanoparticles (MONs) have received growing attention as alternative T ₁ MRI contrast agents due to the association of commercial gadolinium-based contrast agents with nephrogenic systemic fibrosis. Since the seminal publication first describing the use of MONs as positive T ₁ contrast agents, there is an ongoing impetus to develop MONs of higher T ₁ signal intensity for better diagnostic efficacy. Indeed, various MON-based nanoprobe designs have been proposed, such as the employment of a mesoporous nanomaterial with MONs evenly dispersed within, or the traditional coating of a biocompatible layer onto the surface of MONs to form a core-shell configuration. Recent advances in this field also propose stimuli-responsive MONs that capitalize on an acidic dissolution or in situ reduction to release Mn²⁺ ions for a multi-fold increase in MRI contrast. However, the potential nanotoxicity of MONs remains a key obstacle to the clinical translation of MON-based T ₁ contrast agents. Due to the wide variety of functionalities and physicochemical properties of MONs, there is also a lack of consensus on the toxicological properties of MONs. In addition, the r ₁ relaxivity of MRI contrast agents typically decreases at higher field strength. Hence, it highlights the need to develop MON-based contrast agents with higher relaxivities. In this regard, this article aims to present a thorough review of MONs for MRI applications, with particular emphasis on their relaxivity and toxicological properties. In order to systematically review the current state-of-the-art for the development of MONs for MRI applications, the MON-based T ₁ contrast agents are categorized based on the structure of the nanomaterial system. Key parameters that influence the nanotoxicity of MONs are also examined while the absorption, distribution, metabolism and excretion of MON in vivo are evaluated to discern how long the nanoparticles will be present within the body, as well as to predict the organs or tissues in which they distribute.