Active targeting of manganese nanoparticles for MRI contrast enhancement: prospects and challenges

The growing interest in Mn²⁺ ions for T₁-weighted contrast agents (CAs) stems from their biogenic nature, driving the development of Mn-based complexes and nanoparticles. To enhance tumor contrast and minimize side effects from retention in healthy tissues, active targeting of Mn-based CAs is crucial. Key targeting strategies for Mn²⁺-based CAs are reviewed alongside those for Gd³⁺ and iron oxide agents, as Mn²⁺ CAs were developed later. In this review, the main focus is on Mn-containing nanoparticles, since from the point of view of the contrast effect and limited delivery of Mn²⁺ ions, they are a more promising basis for CA than molecular Mn²⁺ complexes. Hydrophilic nanoplatforms such as triblock copolymer micelles, silica nanoparticles and protein nanoparticles are the focus of this review due to their widespread use in the design of CAs and their ability to be easily conjugated with functional groups required for active targeting. The literature examples show that the T₁-weighted contrast of such nanoplatforms conjugated with targeting molecules may differ from that of unconjugated ones, since the high lability of the surface exposed Mn²⁺ ions promotes their redistribution due to coordination through chelating groups on the conjugated nanoplatform. However, this aspect of the development of manganese-based nanoscale contrast agents has not been sufficiently discussed in previous reviews devoted to such nanomaterials. The bibliography includes 120 references.