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Updated: Sep 21, 2025
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Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment
Published on: April 25, 2025
Rational Design and Pharmacomodulation of Protein-Binding Theranostic Radioligands for Targeting the Fibroblast
Lingxin Meng1, Jianyang Fang1, Liang Zhao2,3
1State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China.
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).
Insights
Novel albumin-binding ligands targeting fibroblast activation protein (FAP) show improved tumor uptake and retention for cancer diagnosis and therapy. These radioligands offer potential for enhanced FAP-targeted imaging and radionuclide therapy.
Area of Science:
- Nuclear Medicine
- Oncology
- Radiopharmaceutical Chemistry
Background:
- Fibroblast activation protein (FAP) is overexpressed on cancer-associated fibroblasts (CAFs), making it a crucial target for cancer diagnosis and therapy.
- Existing FAP-targeting radioligands often exhibit inadequate tumor uptake and retention, limiting their clinical utility.
- Development of novel radioligands with enhanced pharmacokinetic properties is essential for effective FAP-targeted applications.
Purpose of the Study:
- To develop and evaluate novel albumin-binding fibroblast activation protein (FAP) ligands for improved tumor targeting.
- To assess the potential of these novel ligands for both diagnostic imaging and targeted radionuclide therapy (TRT).
- To overcome the limitations of insufficient tumor uptake and retention seen with current FAP-based radioligands.
Main Methods:
- Three novel albumin-binding FAP ligands (FSDD0I, FSDD1I, FSDD3I) were synthesized and radiolabeled with Gallium-68 (68Ga) and Lutetium-177 (177Lu).
- Cell-based assays and molecular docking were employed to confirm FAP specificity and protein-binding characteristics.
- In vivo evaluation involved positron emission tomography (PET) scans in human hepatocellular carcinoma patient-derived xenografts (HCC-PDXs) and single photon emission computed tomography (SPECT) imaging.
Main Results:
- 68Ga-labeled FSDD0I demonstrated longer blood retention compared to 68Ga-FAPI-04, 68Ga-FSDD1I, and 68Ga-FSDD3I in HCC-PDX models.
- 68Ga-FSDD3I exhibited superior tumor-to-nontarget (T/NT) ratios, indicating enhanced tumor visualization.
- 177Lu-FSDD0I showed significant tumor retention in SPECT imaging and biodistribution studies, highlighting its therapeutic potential.
Conclusions:
- This study presents a proof-of-concept for albumin-binding radioligands as a strategy to enhance FAP-targeted imaging and therapy.
- The novel FSDD ligands demonstrate promising characteristics for improved tumor uptake and retention.
- These findings support the further development of these albumin-binding radioligands for clinical applications in FAP-positive cancers.
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