Tumor visualization based on nuclear medicine molecular imaging techniques offer a robust approach for early malignancy detection, staging, and prognosis assessment. Screening pathological targets is fundamental to advance the development of targeted radiopharmaceuticals. Recently, radiolabeled inhibitors targeting fibroblast activation protein (FAP) in the tumor microenvironment have shown considerable promise for tumor radiotheranostics. However, their clinical efficacy is hindered by rapid systemic clearance, insufficient tumor uptake, and poor retention, resulting in limited imaging contrast and therapeutic outcomes. Herein, we constructed a novel FAP inhibitor (FAPI)-derived radiotracer ([68Ga]Ga-TRAP-(FAPI)3) via a TRAP-centered polyvalency engineering strategy for positron emission tomography (PET) imaging of FAP-positive malignancies. Compared to the monomeric [68Ga]Ga-FAPI-04, [68Ga]Ga-TRAP-(FAPI)₃ with excellent stability demonstrated a 33-fold enhancement in cellular uptake, and a 7.39-fold higher tumor accumulation at late time points in U87MG xenograft models. The effective dose of [68Ga]Ga-TRAP-(FAPI)3 was 2.15E-02 ± 3.13E-03 mSv/MBq, and the clinical PET/CT scans in a primary liver cancer patient demonstrated that [68Ga]Ga-TRAP-(FAPI)3 achieves higher intratumoral radioactivity accumulation (SUVmax: 10.54) than 2-[18F]FDG (SUVmax: 3.52) and [68Ga]Ga-FAPI-04 (SUVmax: 8.77). Collectively, [68Ga]Ga-TRAP-(FAPI)3 establish a robust platform for cancer PET imaging, demonstrating tremendous potential for clinical translation and paving the way for a shift from standalone diagnosis toward integrated theranostic applications.
Keywords: FAP trimer; Fibroblast activation protein; PET imaging; TRAP chelator; cancer-associated fibroblasts.
Copyright © 2024. Published by Elsevier B.V.