Zhao_2022_Mol.Pharm_19_3640

Fibroblast activation protein (FAP), a fundamental component of the tumor stroma, is overexpressed in cancer-associated fibroblasts (CAFs). As a promising theranostic probe, we evaluated whether the FAP inhibitor (FAPI) dimer (DOTA-2P[FAPI](2)) is more effective than its monomeric analogs for FAP-targeted radionuclide therapy. [(68)Ga]Ga/[(177)Lu]Lu-DOTA-2P(FAPI)(2) were assayed in a stability study, small-animal positron emission tomography (PET) and single-photon emission computed tomography (SPECT), biodistribution, and radionuclide therapy to comprehensively evaluate their preclinical pharmacokinetics. The pharmacokinetics of [(68)Ga]Ga-DOTA-2P(FAPI)(2) and [(177)Lu]Lu-DOTA-2P(FAPI)(2) were determined in FAP-positive hepatocellular carcinoma patient-derived xenografts (PDXs) and HT-1080-FAP cell-derived xenografts (CDXs). [(68)Ga]Ga-DOTA-2P(FAPI)(2) and [(177)Lu]Lu-DOTA-2P(FAPI)(2) were stable in phosphate-buffered saline for 4 h. The tumor retention of [(68)Ga]Ga-DOTA-2P(FAPI)(2) was better than that of [(68)Ga]Ga-FAPI-46 in HT-1080-FAP CDXs, while healthy organs showed low tracer uptake and fast body clearance. In single-photon emission computed tomography, [(177)Lu]Lu-DOTA-2P(FAPI)(2) showed a higher uptake and longer retention for tumors in both PDXs and CDXs from 1-48 h. [(177)Lu]Lu-DOTA-2P(FAPI)(2) showed the best inhibition of tumor growth in PDXs and CDXs. DOTA-2P(FAPI)(2) has increased tumor uptake and retention properties compared to FAPI-46, which significantly improves the use of FAPI-based vectors for PET imaging and radionuclide therapy. [(177)Lu]Lu-DOTA-2P(FAPI)(2) may be safe and effective for the treatment of FAP-positive malignant tumors.