Manganese Oxide Nanoparticles for MRI-Based Multimodal Imaging and Theranostics

Abstract

Manganese-based MRI contrast agents have recently attracted much attention as an alternative to Gd-based compounds. Various nanostructures have been proposed for potential applications in in vivo diagnostics and theranostics. This review is focused on the discussion of different types of Mn oxide-based nanoparticles (Mn_xO_y NPs) obtained at the +2, +3 and +4 oxidation states for MRI, multimodal imaging or theranostic applications. These NPs show favorable magnetic properties, good biocompatibility, and an improved toxicity profile relative to Gd(III)-based nanosystems, showing that the Mn paramagnetic ions offer advantages for the next generation of nanoscale MRI and theranostic contrast agents. Their potential for enhancing relaxivity and MRI contrast effects is illustrated through discussion of selected examples published in the past decade.

Keywords: contrast agents; functionalized nanoparticles; magnetic resonance imaging; manganese oxides; multimodal imaging; theranostics.

Figure 1

Center: structure of the MnO@Fe₃O₄-OH-PEG-PH NPs; Simultaneous in vivo T_1w MR image (left), and in vivo T_2w MR image (right) of a BALB/c mouse 1 h after injection in the tail vein of MnO@Fe₃O₄-OH-PEG-PH NPs (1.5 mg [Fe] kg⁻¹). Reproduced with permission from Ref. [68]. Copyright (2019) by the American Chemical Society.

Figure 2

Structure of the Mn₃O₄-PEI-Ac-FI-mPEG-(PEG-FA) NPs. Adapted from Ref. [96].

Figure 3

Left: In vivo T_1w MR images (a) and signal intensity (b) of HeLa tumors post i.v. administration of the NOTA−FA−FI−PEG−PEI−Ac−Mn₃O₄ NPs or the NOTA−FI−PEG−PEI−Ac−Mn₃O₄ NPs (500 mg Mn, in 0.2 mL saline) at different times. Tumors are indicated by white arrows. Mean values were compared via one-way analysis of variance and Student’s t-test and data were marked with (**) for p < 0.01, and (***) for p < 0.001, respectively.; right: micro-PET images of nude mice bearing HeLa xenografted tumors at different times post i.v. injection of the ⁶⁴Cu−NOTA−FA−FI−PEG−PEI−Ac−Mn₃O₄ NPs (targeted NPs), the ⁶⁴Cu−NOTA−FA−FI−PEG−PEI−Ac−Mn₃O₄ NPs with FA blocking, and the ⁶⁴Cu−NOTA−FI−PEG−PEI−Ac−Mn₃O₄ NPs (non-targeted NPs). The whole-body coronal (top) and transverse (bottom) micro-PET images of nude mice bearing HeLa xenografted tumors are presented. Tumors are indicated by arrows. Reproduced with permission from Ref. [101], Copyright (2018) by the American Chemical Society.

Figure 4

Scheme illustrating the core/shell nanotheranostic Mn₃O₄@PDA NP design and synthesis for MRI guided synergetic chemo-/photothermal therapy. Reproduced from Ref. [108].

Figure 5

Schematic illustration of nanosheets and their biofunctions. (A) Preparation of MnO₂/HA/CDDP nanosheets; (B) the drug release in response to the pH decrease and the GSH increase in the tumor microenvironment; (C) the biofunctions of MnO₂/HA/CDDP nanosheets. Reproduced from Ref. [133].

Figure 6

(A) Schematic illustration of the hybrid polymeric system consisting of Ce6, DOX, and MnO₂ co-loaded NPs (CDM NPs) prepared by a double emulsion solvent evaporation method. (B) Schematic illustration of tumor-targeting CDM NPs for combined O₂-generating chemo-photodynamic cancer therapy and trimodal fluorescence (FL), photoacoustic (PA) and magnetic resonance (MRI) imaging. Reproduced from Ref [138].