FAPI-functionalised melanin nanoparticles for PET/MRI/PA imaging of glioma

Introduction: Fibroblasts activated protein (FAP), a membrane-bound enzyme, is up-regulated in tumor-associated fibroblasts in more than 90% of epithelial tumor and low or . In this study, the novel multifunctional organic melanin nanoparticles (MNPs) loaded with small molecule FAP inhibitor (FAPI) for photoacoustic imaging (PAI), magnetic resonance imaging (MRI), and positron emission tomography (PET) imaging of glioma in U87 MG xenograft mice.

Methods: The ultrasmall MNPs were prepared by ultrasonic fragmentation, and modified with polyethylene glycol (PEG) and small molecule FAP inhibitor to synthesis nanoprobe FAPI-PEG-MNPs. FAPI-PEG-MNPs were fully characterized for morphology, imaging properties and toxicity in vivo and in vitro. FAP expression levels were determined in human glioma U87MG and human lung adenocarcinoma A549 cancer cells via western blot. MNPs have an excellent PAI function and can be chelated with the magnetic resonance contrast agent Mn²⁺, and labeled the long half-life radionuclide ⁶⁴Cu without the chelator. In vitro cell uptake was completed with the U87MG and A549 cell lines to evaluate the specificity of . The pharmacokinetics, and multimodal imaging ability of the nanoprobe were researched in healthy Kunming (KM) and U87MG tumor-bearing mice.

Results: The more regular morphology of FAPI-PEG-MNPs were confirmed under transmission electron microscopy, the hydrodynamic diameters of FAPI-PEG-MNPs were 10.47 ± 1.44 nm as measured by dynamic light scattering, and exhibited excellent biocompatibility and biodegradability. The U87MG cells expressed high levels of FAP, while A549 cells expressed low levels of FAP. Additionally, the (⁶⁴Cu, Mn)-FAPI-PEG-MNPs exhibited excellent high specificity and stability. In U87MG tumor-bearing mice, the PA signal and T₁-weighted signal gradually increased with time, and peaked at 24 h after nanoprobe injection. Micro-PET/CT imaging and semi-quantitative analysis showed that nanoprobe accumulated in the U87MG tumors, which was significantly higher than that of A549 tumors.

Conclusions: The (⁶⁴Cu, Mn)-FAPI-PEG-MNPs successfully realizes multimodal imaging of U87MG tumor-bearing mice with high FAP expression. This nanoprobe may be have great potential as a PET/MR/ PA multimodal imaging candidate agent for clinical application.

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