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<p>Fibroblast activation protein (FAP), which is overexpressed in cancer-associated fibroblasts (CAFs) is an attractive stromal target for a-therapy. We previously reported moderate anti-tumor effects of <sup>211</sup>At-labeled FAP inhibitors (FAPI) in a PANC-1 xenograft mouse model, where insufficient tumor accumulation and the absence of FAP expression in tumor cells limited therapeutic efficacy. In this study, we performed in vitro mechanistic follow-up experiments using FAP-negative PANC-1 cells to clarify the radioactivity–time-dependent cytotoxicity of <sup>211</sup>At-labeled FAPI compared with free <sup>211</sup>At (non-conjugated <sup>211</sup>At). We found that, whereas free <sup>211</sup>At showed only limited cytotoxicity, <sup>211</sup>At-labeled FAPI exerted significant cytotoxic effects. Systematic variation of activity concentrations and exposure durations revealed that cytotoxicity depended primarily on sustained pericellular exposure rather than initial radioactivity levels. These findings provide mechanistic, hypothesis-generating insight into how CAF-targeted <sup>211</sup>At radiopharmaceuticals can exert effective cytotoxicity without direct tumor cell targeting and may inform future optimization of stromal-targeted a-therapy, while further in vivo and translational studies will be required.</p>

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Radioactivity- and time-dependent cellular cytotoxicity of astatine-211-labeled FAP-targeting radiopharmaceuticals

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Masayuki Takamatsu,
  • Jumpei Ueno,
  • Taketo Toda,
  • Atsushi Shimoyama,
  • Koki Mayusumi,
  • Kazuya Kabayama,
  • Yuichiro Kadonaga,
  • Yoshifumi Shirakami,
  • Tadashi Watabe,
  • Taku Yoshiya,
  • Kazuhiro Ooe,
  • Masashi Murakami,
  • Atsushi Toyoshima,
  • Hiromitsu Haba,
  • Jens Cardinale,
  • Frederik Giesel,
  • Kazuko Kaneda-Nakashima,
  • Koichi Fukase

摘要

Fibroblast activation protein (FAP), which is overexpressed in cancer-associated fibroblasts (CAFs) is an attractive stromal target for a-therapy. We previously reported moderate anti-tumor effects of 211At-labeled FAP inhibitors (FAPI) in a PANC-1 xenograft mouse model, where insufficient tumor accumulation and the absence of FAP expression in tumor cells limited therapeutic efficacy. In this study, we performed in vitro mechanistic follow-up experiments using FAP-negative PANC-1 cells to clarify the radioactivity–time-dependent cytotoxicity of 211At-labeled FAPI compared with free 211At (non-conjugated 211At). We found that, whereas free 211At showed only limited cytotoxicity, 211At-labeled FAPI exerted significant cytotoxic effects. Systematic variation of activity concentrations and exposure durations revealed that cytotoxicity depended primarily on sustained pericellular exposure rather than initial radioactivity levels. These findings provide mechanistic, hypothesis-generating insight into how CAF-targeted 211At radiopharmaceuticals can exert effective cytotoxicity without direct tumor cell targeting and may inform future optimization of stromal-targeted a-therapy, while further in vivo and translational studies will be required.