Conclusion
Two albumin binder-conjugated FAPI radiopharmaceuticals have been developed and evaluated in vitro and in vivo. Significantly improved tumor uptake and retention were observed, compared with the original FAPI tracer. Both 177Lu-TEFAPI-06 and 177Lu-TEFAPI-07 showed remarkable growth inhibition of PDX tumors, whereas the side effects were almost negligible, demonstrating that these radiopharmaceuticals are promising for further clinical translational studies.
Methods
TEFAPI-06 and TEFAPI-07 were synthesized and labeled with 68Ga, 86Y, and 177Lu successfully. A series of cell assays was performed to identify the binding affinity and FAP specificity in vitro. PET imaging, SPECT imaging, and biodistribution studies were performed to evaluate the pharmacokinetics in pancreatic cancer patient-derived xenograft (PDX) animal models. The cancer treatment efficacy of 177Lu-TEFAPI-06 and 177Lu-TEFAPI-07 were evaluated in pancreatic cancer PDX-bearing mice.
Results
The binding affinities (dissociation constants) to FAP of 68Ga-TEFAPI-06 and 68Ga-TEFAPI-07 were 10.16 ± 2.56 nM and 7.81 ± 2.28 nM, respectively, which were comparable with that of 68Ga-FAPI-04. Comparative PET imaging of HT-1080-FAP and HT-1080 tumor-bearing mice and a blocking study showed the FAP-targeting ability in vivo of these 2 tracers. Compared with 177Lu-FAPI-04, PET imaging, SPECT imaging, and biodistribution studies of TEFAPI-06 and TEFAPI-07 demonstrated their remarkably enhanced tumor accumulation and retention, respectively. Notable tumor growth inhibition by 177Lu-TEFAPI-06 and 177Lu-TEFAPI-07 were observed, whereas the control group and the group treated by 177Lu-FAPI-04 showed a slight therapeutic effect.