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

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).