Dissolution of metal-based nanomaterials (MNMs) leads to the release of metal ion species; this phenomenon is a major concern affecting the widespread application of MNMs because it can affect their subsequent biodistribution patterns and toxic responses toward living biological systems. It is crucial that we thoroughly understand the dissolution behavior and chemical fate-and associated health effects-of MNMs when assessing their safety considerations. To date, however, quantitative characterization of the transformations of MNMs within living animal bodies has remained a methodological challenge. In this Review, we address the technical issues, the state of the art, and the limitations of currently available sample preparation procedures, as well as the various differentiation schemes coupled with inductively coupled plasma mass spectrometry (ICP-MS) techniques for analysis, that have been employed to reveal MNM dissolution in complicated biological tissue samples. In addition, we highlight the importance of developing new analytical strategies for ICP-MS to facilitate unbiased investigations into the dissolution behavior of MNMs with respect to their long-term biological effects and nanotoxicological properties.
4MNMs through recapitulation of known toxic mechanisms at cellular levels. 17 The transformations and fates of MNMs are very complex, but can be classified broadly into two states: residual nanostructures and released metal ion species. 19,20 When they remain in the form of intact nanoparticulate matter, MNMs in biological systems can adhere to organ cells to influence membrane properties or penetrate into intracellular space to interrupt normal cell functions; alternatively, after they have dissolved, their ionic species can inactivate or compromise the functionality of vital enzymes. 15 Therefore, if exposed MNMs persist or do not meet the criteria for being excreted via renal and hepatic clearance, 21-23 it is believed that the physiological responses to MNMs finally should be similar to the species associated to their chemical compositions. 24 For QDs, for example, concerns about their toxicity are attributed mainly to their degradation and release of notorious heavy metals (e.g., Cd ions), despite several QD toxicity studies having demonstrated minimized adverse effects in living rats and primates. 25-27 Accordingly, the dissolution of MNMs is dependent on the metal ions' solubility and association with available ligands in a given aqueous medium (possessing various ionic strengths, pH, and existing biological molecules), the concentration gradient between the particle's surfaces and the phase of the bulk solution, and the aggregation states of the MNMs. MNMs of smaller sizes and higher surface-to-volume ratios can also display peculiar physicochemical properties that are responsible for their reactivity, dissolution, and interactions with biological components. 24,28 In addition, reactive oxygen species generated during their metabolic processes can also accelerate the dissolution effects of MNMs...