Prostate specific membrane antigen targeted ultrasmall manganese ferrite nanoparticles for PET/MR imaging of prostate cancer

Prostate-specific membrane antigen (PSMA)-targeted molecular imaging has greatly improved the precision of prostate cancer (PCa) diagnosis; however, the integration of high-sensitivity positron emission tomography (PET) and high-resolution magnetic resonance imaging (MRI) into a single, safe nanoplatform remains a critical clinical need. Here, we report PSMA-targeted PET/MR dual-modal ultrasmall manganese ferrite nanoparticles (UMFNPs) for molecular imaging of PCa. Uniform UMFNPs were synthesized via a dynamic simultaneous thermal decomposition (DSTD) method and their surfaces were sequentially engineered with the highly specific PSMA ligand glutamic acid-urea-lysine (Glu-urea-Lys) and the chelator NOTA, followed by efficient radiolabeling with ⁶⁸Ga. The resulting ⁶⁸Ga-NOTA-UMFNPs-Glu nanoprobe exhibited a high ⁶⁸Ga radiochemical purity exceeding 97%, excellent stability, and a high longitudinal relaxivity (r₁) of 8.18 mM^-1 s^-1. In PSMA-positive LNCaP tumor-bearing mice, the probe enabled specific and clear tumor delineation by both PET and T₁-weighted MRI, with an SUVmax of approximately 0.65 and a substantial 43.5% MR signal enhancement at the tumor site at 30 minutes post-injection. This specific accumulation was significantly higher than that in PSMA-negative PC3 tumors. Pharmacokinetic and biosafety evaluations demonstrated rapid hepatic clearance and a favorable biocompatibility profile. This work demonstrates that combining the inherent MR T₁ contrast enhancement capability and favorable pharmacological properties of UMFNPs with PSMA targeting and stable ⁶⁸Ga labeling yields a highly specific, safe, and quantitative PET/MR nanoplatform, offering substantial promise as a potential clinically translatable platform for precise molecular imaging and personalized management of PCa.