Polyethyleneimine-Coated Manganese Oxide Nanoparticles for Targeted Tumor PET/MR Imaging

A Mn₃O₄ nanoparticle (NP)-based dual-modality probe has been developed for tumor positron emission tomography (PET)/magnetic resonance (MR) imaging. The dual-modality imaging probe was constructed by modifying multifunctional polyethyleneimine (PEI)-coated Mn₃O₄ NPs with folic acid (FA), followed with the radiolabeling with ⁶⁴Cu. The formed imaging probe was utilized for PET/MR imaging of human cervical cancer mouse xenografts, which overexpress folate receptor (FR). The PEI-coated Mn₃O₄ NPs were synthesized using a solvothermal approach via decomposition of acetylacetone manganese. Multifunctional groups, including fluorescein isothiocyanate (FI), PEGylated FA, and NOTA chelator, were then sequentially loaded onto the surface of the amine groups of the Mn₃O₄ NPs. The remaining PEI amines were neutralized by the acetylation reaction. The resulting NOTA-FA-FI-PEG-PEI-Ac-Mn₃O₄ NPs were fully characterized and evaluated in vitro and successfully radiolabeled with ⁶⁴Cu for tumor PET/MR imaging in small animals. In vivo blocking experiments were performed to determine the FR binding specificity of NPs. PET imaging results demonstrated that ⁶⁴Cu-labeled Mn₃O₄ NPs display good tracer uptake in the FR-expressing HeLa tumors (tumor-to-muscle (T/M) ratio: 5.35 ± 0.31 at 18 h postinjection (pi)) and substantially reduced tracer uptake in the FR-blocked HeLa tumors (T/M ratio: 2.78 ± 0.68 at 18 h pi). The ex vivo data, including PET imaging and biodistribution, further confirmed the tumor binding specificity of the ⁶⁴Cu-labeled Mn₃O₄ NPs. Moreover, the FR-targeted Mn₃O₄ NPs exhibited efficient T₁-weighted MR imaging (MRI), leading to the precise tumor MRI at 18 h pi. PET/MR imaging with the ⁶⁴Cu-NOTA-FA-FI-PEG-PEI-Ac-Mn₃O₄ NPs may offer a new quantitative approach to precisely measure the FR in tumors. The strategy of incorporating PEI nanotechnology into the construction of new biomaterials may be applied for the construction of novel nanoplatforms for cancer diagnosis and therapy.