Rational Design and Pharmacomodulation of Protein-Binding Theranostic Radioligands for Targeting the Fibroblast Activation Protein

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Abstract
The fibroblast activation protein (FAP), overexpressed on cancer-associated fibroblasts (CAFs), has become a valuable target for tumor diagnosis and therapy. However, most FAP-based radioligands show insufficient tumor uptake and retention. In this study, three novel albumin-binding FAP ligands (denoted as FSDD0I, FSDD1I, and FSDD3I) were labeled with 68Ga and 177Lu to overcome these limitations. Cell-based studies and molecular docking assays were performed to identify the specificity and protein-binding properties for FAP. Positron emission tomography (PET) scans in human hepatocellular carcinoma patient-derived xenografts (HCC-PDXs) animal models revealed longer blood retention of 68Ga-FSDD0I than 68Ga-FAPI-04, 68Ga-FSDD1I, and 68Ga-FSDD3I. Remarkably, 68Ga-FSDD3I had prominent tumor-to-nontarget (T/NT) ratios. The prominent tumor retention properties of 177Lu-FSDD0I in single photon emission computed tomography (SPECT) imaging and biodistribution studies were demonstrated. In summary, this study reports a proof-of-concept study of albumin-binding radioligands for FAP-targeted imaging and targeted radionuclide therapy (TRT).
Funding Information
  • China National Nuclear Corporation (U1967222)
  • Ministry of Education of the People's Republic of China (20720210115)
  • National University of Singapore (NUHSRO/2020/133/Startup/08, NUHSRO/2021/034/TRP/09/Nanomedicine)
  • National Natural Science Foundation of China (21976150, 81901805, 91959122, U1967222)
  • XMU Training Program of Innovation and Enterpreneurship for Undergraduates (202110384044)

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