Construction and application of prostate cancer-targeted PET/MRI contrast agent

Although molecular imaging in nuclear medicine has made remarkable progress, the development of tumor-targeted magnetic resonance imaging (MRI) contrast agents based on tumor-cell–specific targets remains a major challenge. Conventional non-targeted gadolinium chelates such as Gd-DTPA are widely used in clinical MRI but often require high doses to achieve diagnostically meaningful enhancement, and their performance is constrained by modest relaxivity and the lack of tumor-targeting capability. Attempts to introduce targeting ligands onto small-molecule gadolinium complexes may increase molecular complexity, alter pharmacokinetics, and raise biosafety concerns. Meanwhile, superparamagnetic iron oxide nanoparticles have been explored as alternative MRI agents due to their high magnetic sensitivity, yet metal deposition, biodegradation, and long-term retention toxicity continue to hinder clinical translation. Current prostate-specific membrane antigen (PSMA)-targeted PET tracers enable highly sensitive lesion detection, yet a corresponding PSMA-targeted MRI agent capable of providing high-resolution anatomical and functional information is still lacking. Therefore, constructing a true PET–MRI dual-modality nanoplatform is expected to overcome the spatial-resolution limitations of PET alone while compensating for the insufficient molecular specificity of conventional MRI contrast agents. In this study, we developed a novel multifunctional organic nanoplatform based on natural melanin nanoparticles (MNPs). By simply integrating nanocarriers, imaging moiety and targeting ligands within one system, a PSMA-targeted MRI contrast agent was obtained. The PSMA ligand was covalently conjugated onto the surface of PEG-modified MNPs, while large numbers of paramagnetic Gd 3+ ions were chelated/adsorbed onto the melanin scaffold, yielding prostate-cancer-targeted PSMA-GMNs. The hydrodynamic diameters of MNPs and PSMA-GMNs were 3.56 ± 2.09 nm and 15.74 ± 1.63 nm, respectively. PSMA-GMNs exhibited a T 1 -enhancing effect more than five-fold stronger than that of Gd-DTPA in vitro . In vivo MRI demonstrated a high T 1 -weighted signal within LNCaP tumors at 4 h and 24 h post-intravenous administration. Furthermore, 64 Cu-labeled PSMA-GMNs achieved peak tumor uptake at 16 h (SUVmax = 4.24 ± 0.50), indicating sustained PSMA-mediated internalization and prolonged tumor retention. The successfully constructed 64 Cu-PSMA-GMN s achieve functional complementarity between the high-sensitivity molecular detection of PET and the high-resolution anatomical visualization of MRI within a single nano-platform. This work addresses the current lack of prostate-cancer-specific MRI contrast agents and the separation of PET and MRI molecular information in clinical practice.