Preclinical Evaluation of 68Ga/177Lu-Labeled FAP-Targeted Peptide for Tumor Radiopharmaceutical Imaging and Therapy

Fibroblast activation protein (FAP) has been considered a promising target for tumor imaging and therapy. This study designed a novel peptide, FAP-HXN, specifically targeting FAP and exhibiting significant potential as a radionuclide-labeled theranostic agent. Preclinical studies were conducted to evaluate the potency, selectivity, and efficacy of FAP-HXN. Methods: FAP-HXN was synthesized and characterized for selectivity and specificity toward FAP. Cellular uptake of the radiolabeled FAP-HXN in human embryonic kidney (HEK)-293-FAP cells with high expressions of FAP was evaluated. The diagnostic and therapeutic potential of ⁶⁸Ga- and ¹⁷⁷Lu-labeled radioligands was evaluated in HEK-293-FAP tumor-bearing mice compared with the FAP-targeting peptide FAP-2286. Results: FAP-HXN demonstrated high binding ability to human and mouse sources of FAP. Moreover, the in vivo studies confirmed the high affinity and specificity of radiolabeled FAP-HXN. Small-animal PET imaging demonstrated that [⁶⁸Ga]Ga-FAP-HXN had continuous tumor uptake in FAP-positive tumors after administration compared with [⁶⁸Ga]Ga-FAP-2286. In the therapeutic experiments, [¹⁷⁷Lu]Lu-FAP-HXN showed significant antitumor activity in HEK-293-FAP xenografts at well-tolerated doses, which also exhibited longer tumor retention and better tumor growth inhibition compared with [¹⁷⁷Lu]Lu-FAP-2286. Conclusion: The preclinical studies revealed that radiolabeled FAP-HXN had high tumor uptake, prolonged retention, and significant anticancer efficacy in HEK-293-FAP xenografts. FAP-HXN shows promising potential as a novel theranostic radioligand for FAP-positive tumors.