Novel therapy for gastric cancer peritoneal dissemination using genetically modified dental pulp cells and astatine-211

Kuge, K.; Du, W.-Y.; Masuda, H.; Yasuda, T.; Tatsumi, T.; Yin, X.; Yoshino, M.; Sugiyama, A.; Numata, R.; Yokoyama, W.; Shibahara, H.; Tanaka, T.; Kobayashi, M.; Taguchi, A.; Kohro, T.; Takubo, N.; Nakamura, M.; Jang, J.; Kumakura, Y.; Yoshida, H.; Yoshikawa, A.; Haba, H.; Wada, Y.; Imagawa, K.; Nomura, S.

doi:10.1101/2025.10.15.682497

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bioRxiv · 10.1101/2025.10.15.682497

Novel therapy for gastric cancer peritoneal dissemination using genetically modified dental pulp cells and astatine-211

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Abstract

Peritoneal dissemination of gastric cancer is a terminal stage with limited treatment options and a five-year survival rate below 10%. To develop a more effective treatment, we created a new approach that uses genetically engineered human dental pulp cells (DPCs) that express the sodium/iodide symporter (NIS). These cells (NIS-DPCs) deliver astatine-211 (At-211) directly to tumor sites. When injected intraperitoneally into a mouse model of gastric cancer dissemination, DPCs, which were isolated and expanded, showed strong tumor-homing ability. Chemotaxis mediated by the CXCR4/SDF-1 axis has been reported to play a role in this accumulation. In addition to histological analysis, fluorescent imaging confirmed the selective accumulation of NIS-DPCs within tumor lesions. Introducing the NIS gene markedly increased SLC5A5 expression, enabling efficient At-211 uptake. To avoid nonspecific binding, sodium At-211 was utilized. High-resolution alpha-particle imaging visualized alpha-ray emission specifically from NIS-DPCs, confirming the radionuclides intracellular retention. In vivo, the sequential administration of NIS-DPCs, followed by Na[At-211], resulted in the pronounced regression of peritoneal tumors and a significant extension of survival compared to controls. The therapeutic mechanism involves three coordinated steps: tumor-directed migration of NIS-DPCs, At-211 uptake via NIS transporters, and localized alpha-particle-mediated cytotoxicity. This study introduces the novel concept of cell-based alpha-radiotherapy, which integrates regenerative and nuclear medicine. Due to the well-documented safety profile of DPCs in human clinical trials (J-REPAIR, jRCT1080224505), the NIS-DPC platform emerges as a promising approach for the precise, localized irradiation of disseminated gastric cancer and other challenging malignancies.

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Kuge, K., Du, W.-Y., Masuda, H., Yasuda, T., Tatsumi, T., Yin, X., Yoshino, M., Sugiyama, A., Numata, R., Yokoyama, W., Shibahara, H., Tanaka, T., Kobayashi, M., Taguchi, A., Kohro, T., Takubo, N., Nakamura, M., Jang, J., Kumakura, Y., Yoshida, H., Yoshikawa, A., Haba, H., Wada, Y., Imagawa, K., Nomura, S.. 2025-10-15. Novel therapy for gastric cancer peritoneal dissemination using genetically modified dental pulp cells and astatine-211. https://doi.org/10.1101/2025.10.15.682497

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