Improving the theranostic potential of HER2 Affibody by reducing the renal radioactivity through brush border membrane enzyme-mediated degradation

Purpose: Human epidermal growth factor receptor 2 (HER2) is overexpressed in various types of tumors, & radiolabeled HER2 Affibody is believed to be an attractive tool for HER2 targeted theranostics. However, its wide application is limited by the lack of high & persistent radioactivity accumulation in kidneys. In this study, we intend to reduce the renal accumulation of radiolabeled HER2 Affibody through degradation mediated by brush border membrane enzymes. Materials and Methods: A new HER2 Affibody ligand NOTA-MVK-HER2 Affibody containing Met-Val-Lys (MVK) linker between the peptide and 1,4,7-triazacyclononane-1,4,7 -triacetic acid (NOTA) chelator was synthesized and labeled with ⁶⁸Ga. The in vitro PBS & mouse serum stability of the tracer were evaluated. The microPET images were acquired in SKOV-3 tumor model at different time points, the radioactivity uptake of ⁶⁸Ga-NOTA-MVK-HER2 Affibody in tumor & kidneys were determined & compared with the control radiotracer without MVK linker.

Results: ⁶⁸Ga-NOTA-MVK-HER2 Affibody was stable in PBS and mouse serum. MicroPET images showed that the tumor uptake of ⁶⁸Ga-NOTA-MVK-HER2 Affibody was comparable to that of the control, while the kidney uptake was significantly reduced. As a result, more favorable tumor to kidney ratios were achieved.

Conclusions: In this study, a novel HER2 Affibody analogue, NOTA-MVK-HER2 Affibody, was successfully synthesized & labeled with ⁶⁸Ga. As the high & consistent renal radioactivity accumulation could be significantly reduced, NOTA-MVK-HER2 Affibody shows great potential in the diagnosis & radiotherapy for HER2 positive tumors.

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