Abstract
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 the FAP inhibitors (FAPIs) 04 and 46, have shown promising results in tumor diagnosis. However, these molecules have a relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a 68Ga-labeled FAPI dimer, 68Ga-DOTA-2P(FAPI)2, to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs. Methods:68Ga-DOTA-2P(FAPI)2 was synthesized on the basis of the quinoline-based FAPI variant (FAPI-46), and its binding properties were assayed in CAFs. Preclinical pharmacokinetics were determined in FAP-positive patient-derived xenografts using small-animal PET and biodistribution experiments. The effective dosimetry of 68Ga-DOTA-2P(FAPI)2 was evaluated in 3 healthy volunteers, and PET/CT imaging of 68Ga-FAPI-46 and 68Ga-DOTA-2P(FAPI)2 was performed on 3 cancer patients. Results:68Ga-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 invitro and invivo. The tumor uptake of 68Ga-DOTA-2P(FAPI)2 was approximately 2-fold stronger than that of 68Ga-FAPI-46 in patient-derived xenografts, whereas healthy organs showed low tracer uptake and fast body clearance. The effective dose of 68Ga-DOTA-2P(FAPI)2 was 1.19E-02 mSv/MBq, calculated using OLINDA. Finally, the PET/CT scans of the 3 cancer patients revealed higher intratumoral uptake of 68Ga-DOTA-2P(FAPI)2 than of 68Ga-FAPI-46 in all tumor lesions (SUVmax, 8.1-39.0 vs. 1.7-24.0, respectively; P < 0.001). Conclusion:68Ga-DOTA-2P(FAPI)2 has increased tumor uptake and retention properties compared with 68Ga-FAPI-46, and it could be a promising tracer for both diagnostic imaging and targeted therapy of malignant tumors with positive expression of FAP.
Highlights
Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment and can constitute over half of the mass in various tumors
We present the results of 68Ga-DOTA-2P(FAPI)2 testing in patient-derived xenografts (PDXs) models, healthy volunteers, and cancer patients
Two radioligands were prepared as controls and tests: 68Ga-FAPI-46, first reported by Loktev A et al [3], and 68Ga-DOTA-2P(FAPI)2, the dimer of FAPI-46. 68Ga-DOTA-2P(FAPI)2 and 68Ga-FAPI-46 were radiolabeled at an average specific activity of 37 and 16.5 GBq/μmol, respectively, with > 95% radiochemical purity after purification (Supplemental Fig. 2A-B)
Summary
Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment and can constitute over half of the mass in various tumors. The reports on PTRT are mainly based on the FAP-inhibitor (FAPI)-04 and FAPI-46 peptides, which showed a relatively short tumor-retention time in preclinical models and human subjects [10,11,12]. Another FAPI variant, FAP-2286, has been studied in PTRT to improve tumor-retention time [13]. Mouse models used to evaluate the pharmacokinetics of FAPI variants were cancer cell-derived xenografts (CDXs) in previous research [7,10,11]. The potential of PDXs for PET imaging of CAFs has been rarely investigated
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