The molar dose of FAPI administered impacts on the FAP-targeted PET imaging and therapy in mouse syngeneic tumor models

Since fibroblast activation protein (FAP), one predominant biomarker of cancer associated fibroblasts (CAFs), is highly expressed in the tumor stroma of various epidermal-derived cancers, targeting FAP for tumor diagnosis and treatment has shown substantial potentials in both preclinical and clinical studies. However, in preclinical settings, tumor-bearing mice exhibit relatively low absolute FAP expression levels, leading to challenges in acquiring high-quality PET images using radiolabeled FAP ligands (FAPIs) with low molar activity, because of which a saturation effect in imaging is prone to happen. Moreover, how exactly the molar dose of FAPI administered to a mouse influences the targeted PET imaging and radiotherapy remains unclear now. Therefore, this study aims to investigate the impacts of the molar dose of the administered FAPI on FAP-targeted PET imaging and radiotherapy in mouse syngeneic tumor models. [68Ga]Ga-FAPI-04 with various molar doses of FAPI-04 was administered to wild-type 4T1 tumor-bearing mice, followed by static PET imaging. Sigmoidal curves were generated to analyze the correlation between the standard uptake value (SUV) and the administered molar doses of FAPI-04. Similarly, [177Lu]Lu-DOTAGA.(SA.FAPi)2 with a consistent dose of radioactivity but containing different moles of DOTAGA.(SA.FAPi)2 were injected into 4T1 tumor-bearing mice to assess the therapeutic effect. [68Ga]Ga-FAPI-04 was also applied to different tumor models for PET/CT imaging. A gradient blocking effect was observed with increasing FAPI molar dose in [68Ga]Ga-FAPI-04 PET imaging and [177Lu]Lu-DOTAGA.(SA.FAPi)2 treatment, with various imaging and therapeutic outcomes. [68Ga]Ga-FAPI-04 PET exhibit potentials to characterize murine derived FAP expression with low molar dose of administered FAPI-04 using various tumor models. The molar dose of FAPI in [68Ga]Ga/[177Lu]Lu-FAPI had a substantial impact on FAP-targeted imaging and therapy in mouse syngeneic tumor models. To acquire enhanced reliability and reproducibility in preclinical situation, it is critical to carefully consider the molar dose of the radiotracer when applying radiolabeled FAP ligands to FAP-targeted imaging and radiotherapy.