Organotrifluoroborate enhances tumor targeting of fibroblast activation protein inhibitors for targeted radionuclide therapy

Purpose: Fibroblast activation protein (FAP) is a pan-cancer target and now the state-of-the-art to develop radiopharmaceuticals. FAP inhibitors have been of great success in developing imaging tracers. Yet, the overly rapid clearance cannot match with the long half-lives of regular therapeutic radionuclides. Though strategies that aim to elongate the circulation of FAPIs are being developed, here we describe an innovation that uses α-emitters of short half-lives (e.g., ²¹³Bi) to pair the rapid pharmacokinetics of FAPIs.

Methods: An organotrifluoroborate linker is engineered to FAPIs to give two advantages: (1) selectively increases tumor uptake and retention; (2) facile ¹⁸F-radiolabeling for positron emission tomography to guide radiotherapy with α-emitters, which can hardly be traced in general.

Results: The organotrifluoroborate linker helps to improve the internalization in cancer cells, resulting in notably higher tumor uptake while the background is clean. In FAP-expressed tumor-bearing mice, this FAPI labeled with ²¹³Bi, a short half-life α-emitter, exhibits almost complete suppression to tumor growth while the side effect is negligible. Additional data shows that this strategy is generally applicable to guide other α-emitters, such as ²¹²Bi, ²¹²Pb, and ¹⁴⁹Tb.

Conclusion: The organotrifluoroborate linker may be of importance to optimize FAP-targeted radiopharmaceuticals, and the short half-lived α-emitters may be of choice for the rapid-cleared small molecule-based radiopharmaceuticals.