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Objectives: The unique properties of Mn3O4 nanoparticles(NPs)provide a great opportunity for developing PET/MR imaging probes.In this study,we developed multifunctional polyethyleneimine(PEI)-coated Mn3O4 NPs and radiolabel the NPs with 64Cu for folate receptor(FR)-targeted dual-mode PET/MR imaging in mice bearing human cervical cancer xenografts.Methods: A solvothermal route was used to create PEI-coated Mn3O4 NPs by decomposition of acetylacetone manganese in the presence of PEI.Fluorescein isothiocyanate(FI),PEGylated folic acid(FA),and NOTA chelator were conjugated on the surface of PEI,and followed by acetylation of the remaining amines.The resulting NOTA-Mn3O4-PEI-Ac-FI-(PEG-FA)NPs were characterized,and the cytotoxicity of NPs was evaluated by MTT cell viability assay.The specific binding of NPs with HeLa cells overexpressing FR was confirmed by flow cytometry and confocal microscopy.The NOTA-Mn3O4-PEI-Ac-FI-(PEG-FA)NPs were then radiolabeled with 64Cu and subjected to small animal PET/MR imaging,and biodistribution studies.The FR binding specificity of NPs was further evaluated by in vivo blocking studies.Results: Multifunctional FR-targeted Mn3O4 NPs were successfully synthesized,and radiolabeled with 64Cu in >85%decay-corrected yield with radiochemical purity of >99%.The MTT assay showed that NOTA-Mn3O4-PEI-Ac-FI-(PEG-FA)NPs are non-cytotoxic at the concentration up to 100 μg/mL.The FA modification renders the NPs with targeting specificity to cancer cells overexpressing FR,which is confirmed by flow cytometry and confocal microscopy studies.MicroPET imaging results showed that 64Cu-labeled Mn3O4 NPs exhibit excellent tumor uptake in FR-positive HeLa tumor xenografts(T/M ratio: 6.03 ± 2.35 at 18 h pi)via FR-mediated active targeting pathway,and significantly lower tumor uptake in the FR-blocking group(T/M ratio: 2.78 ± 0.68 at 18 h pi).Tumor binding specificity was also confirmed by ex vivo PET imaging and biodistribution studies.In addition,FR-targeted Mn3O4 NPs enabled efficient T1-weighted MR imaging,and the excellent tumor MR imaging was achieved at 18 h pi.Conclusions: The 64Cu-labeled multifunctional Mn3O4 NPs have been successfully developed for PET/MR imaging of FR overexpression.PET/MRI with 64Cu-NOTA-Mn3O4-PEI-Ac-FI-(PEG-FA)NPs may provide a unique approach to quantitatively localize and characterize FR-expressing tumors.