Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs.FAP-targeted molecular imaging agents, including FAP inhibitor (FAPI)-04 and FAPI-46, have shown promising results in tumor diagnosis. However, these molecules have relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a 68 Ga-labeled FAPI dimer (denoted as 68 Ga-DOTA-2P(FAPI)2) to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs.Methods: 68 Ga-DOTA-2P(FAPI)2 was synthesized based on the quinoline-based FAPI variants (FAPI-46), and its binding properties were assayed in CAFs.Preclinical pharmacokinetics was determined in FAP-positive patient-derived xenografts (PDXs) using small-animal PET and biodistribution experiments. The effective dosimetry of 68 Ga-DOTA-2P(FAPI)2 was evaluated in three healthy volunteers, and PET/ CT imaging of 68 Ga-FAPI-46 and 68 Ga-DOTA-2P(FAPI)2 was performed in three cancer patients. Results: 68 Ga-DOTA-2P(FAPI)2 was stable in phosphate-buffered saline and fetal bovine serum for 4 h. The FAPI dimer showed high affinity and specificity for FAP in-vitro and in-vivo. The tumor uptake of 68 Ga-DOTA-2P(FAPI)2 was approximately two-fold stronger than that of 4 68 Ga-FAPI-46 in PDXs, while the healthy organs showed low tracer uptake and fast body clearance. The effective dose of 68 Ga-DOTA-2P(FAPI)2 was 1.19E-02 mSv/MBq, calculated using OLINDA. Finally, PET/CT scans in three cancer patients revealed higher intratumoral uptake of 68 Ga-DOTA-2P(FAPI)2 than that of 68 Ga-FAPI-46 in all tumor lesions (maximum standardized uptake value: 8.1-39.0 vs. 1.7-24.0, respectively; P < 0.001). Conclusion: 68 Ga-DOTA-2P(FAPI)2 has increased tumor uptake and retention properties compared to 68 Ga-FAPI-46, and it could be a promising tracer for both diagnostic imaging and targeted therapy of malignant tumors with positive expression of FAP.
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).
Fibroblast activation protein (FAP), a fundamental component of the tumor stroma, is overexpressed in cancerassociated fibroblasts (CAFs). As a promising theranostic probe, we evaluated whether the FAP inhibitor (FAPI) dimer (DOTA-2P [FAPI] 2 ) is more effective than its monomeric analogs for FAP-targeted radionuclide therapy. [ 68 Ga]Ga/[ 177 Lu]Lu-DOTA-2P(FAPI) 2 were assayed in a stability study, small-animal positron emission tomography (PET) and single-photon emission computed tomography (SPECT), biodistribution, and radionuclide therapy to comprehensively evaluate their preclinical pharmacokinetics. The pharmacokinetics of [ 68 Ga]Ga-DOTA-2P(FAPI) 2 and [ 177 Lu]Lu-DOTA-2P(FAPI) 2 were determined in FAP-positive hepatocellular carcinoma patient-derived xenografts (PDXs) and HT-1080-FAP cell-derived xenografts (CDXs).[ 68 Ga]Ga-DOTA-2P(FAPI) 2 and [ 177 Lu]Lu-DOTA-2P(FAPI) 2 were stable in phosphate-buffered saline for 4 h. The tumor retention of [ 68 Ga]Ga-DOTA-2P(FAPI) 2 was better than that of [ 68 Ga]Ga-FAPI-46 in HT-1080-FAP CDXs, while healthy organs showed low tracer uptake and fast body clearance. In single-photon emission computed tomography, [ 177 Lu]Lu-DOTA-2P(FAPI) 2 showed a higher uptake and longer retention for tumors in both PDXs and CDXs from 1−48 h. [ 177 Lu]Lu-DOTA-2P(FAPI) 2 showed the best inhibition of tumor growth in PDXs and CDXs. DOTA-2P(FAPI) 2 has increased tumor uptake and retention properties compared to FAPI-46, which significantly improves the use of FAPI-based vectors for PET imaging and radionuclide therapy. [ 177 Lu]Lu-DOTA-2P(FAPI) 2 may be safe and effective for the treatment of FAP-positive malignant tumors.
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