Immuno-PET Imaging of Tumor Mesothelin Expression with a Gallium-68 Radiolabeled Nanobody

Mesothelin (MSLN) is overexpressed in various solid tumors but limited in normal tissues, making it a promising candidate for molecular imaging and targeted therapy. Nanobodies, the smallest antibody derived fragments, are facile to modify for functional agent conjugation. With radionuclides, nanobody-based immunopositron emission tomography (immuno-PET) will provide valuable whole-body information for analysis of related target properties. The objective of this work was to evaluate the in vivo distribution peculiarity of 68Ga-NOTA-MS3 as an MSLN-overexpressing tumor-directing probe. After rigorous quality control, xenograft models exhibiting differential MSLN expression were constructed for in vivo behavior evaluation of 68Ga-NOTA-MS3. In addition, to improve the visualization of intra-abdominal tumors and mitigate potential radiation-related nephrotoxicity, a strategy involving preadministration of sodium maleate was employed to reduce the renal uptake of 68Ga-NOTA-MS3. The nondecay corrected radiolabeling yield of 68Ga-NOTA-MS3 was approximately 47%, and the radiochemical purity was >98%. Both immuno-PET imaging and biodistribution studies revealed that the uptake of 68Ga-NOTA-MS3 was high in BxPC-3 and OVCAR-3 tumors, while HuH-7 tumors showed low uptake. These results aligned with the MSLN expression assessment. Moreover, 2 h postinjection of the imaging agent was identified as the optimal timing for immuno-PET. Furthermore, the preadministration of sodium maleate significantly reduced the renal accumulation of 68Ga-NOTA-MS3 (from 61.14 ± 7.57%ID/g to 4.31 ± 1.31%ID/g), hence ameliorating the delineation of orthotopic pancreatic tumors. The study validates 68Ga-NOTA-MS3 as an effective probe for the precise, noninvasive imaging of MSLN, which, in turn, allows for the accurate diagnosis of MSLN-expressing lesions.

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