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).
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| Authors | Lingxin Meng, Jianyang Fang, Liang Zhao, Tingting Wang, Pu Yuan, Zuoquan Zhao, Rongqiang Zhuang, Qin Lin, Haojun Chen, Xiaoyuan Chen, Xianzhong Zhang, Zhide Guo |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 12 Pg. 8245-8257 (06 23 2022) ISSN: 1520-4804 [Electronic] United States |
| PMID | 35658448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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