Development of ⁶⁸Ga-NOTA-cRGD Probe Mediated by Sulfenic Acid for Prolonging Tumor Imaging

High reactive oxygen species (ROS) serve as important signaling molecules in the tumor microenvironment, and their excessive generation is closely associated with tumor growth, drug resistance, and metastasis of tumors. Rrecently, probes based on 1,3-cyclohexanedione have been proposed, enabling real-time monitoring of ROS levels in the tumor microenvironment. Herein, as a proof of concept, we aimed at synthesizing a novel tumor diagnostic probe, ⁶⁸Ga-NOTA-cRGD, by connecting NOTA and the tumor-targeting peptide cRGD with a 1,3-cyclohexanedione group that specifically undergoes cross-linking with sulfenic acid, to enhance the targeting and prolong the imaging time of the probe in tumors. Moreover, the study also evaluated the capability of the synthesized probe in both in vitro and in vivo experiments. The results indicated that the radiolabeling process was efficient and stable, and the stability of the probe under physiological conditions was also outstanding. Compared to the control probe ⁶⁸Ga-NOTA-cRGD-1 lacking 1,3-cyclohexanedione, the experimental probe ⁶⁸Ga-NOTA-cRGD-2 not only exhibited significant improvements in cell uptake efficiency, tumor imaging contrast, and biodistribution characteristics but also demonstrated enhanced cell affinity and a prolonged in vivo biological half-life. The addition of 1,3-cyclohexanedione enhanced the probe's tumor-targeting capability, resulting in higher uptake in A549 tumor cells. In conclusion, this study confirmed the crucial role of 1,3-cyclohexanedione in prolonging tumor targeting. It is anticipated to provide a theoretical foundation and experimental support for the development of more efficient probes in the future.