Preclinical evaluation of DOTAGA.Glu.(FAPI)<sub>2</sub> and DO3A.Glu.(FAPI)<sub>2</sub> as theranostics with human dosimetry extrapolation to lutetium-177 and terbium-161 analogs.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41105225.
- Also identified by DOI 10.1007/s00259-025-07565-9 and PMC identifier 12860872.
- Licence recorded as CC BY.
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Abstract
This study aims to assess DOTAGA.Glu.(FAPI)<sub>2</sub> and DO3A.Glu.(FAPI)<sub>2</sub>, specifically engineered as precursors for the development of theranostic FAPI-targeted radioligands. DOTAGA.Glu.(FAPI)<sub>2</sub> and DO3A.Glu.(FAPI)<sub>2</sub> were radiolabeled with gallium-68 and lutetium-177, followed by in vitro (lipophilicity, protein binding, saturation, internalization and externalization) studies on FAP<sup>+</sup> CAFs. In vivo (biodistribution, metabolic stability, blood kinetics, PET/SPECT/CT imaging) and ex vivo, (autoradiography, immunohistochemistry) conducted on PC3-mice. Murine dosimetry data were extrapolated to human estimates. All radioligands achievied > 98% radiochemical purity, demonstrating high FAP affinity (K<sub>d</sub>:0.7-0.9 nM) and rapid internalization in CAFs, with differences in lipophilicity and serum protein binding. In vivo studies, for [<sup>68</sup>Ga]Ga-DOTAGA.Glu.(FAPI)<sub>2</sub> and [<sup>68</sup>Ga]Ga-DO3A.Glu.(FAPI)<sub>2</sub> showed high and sustained tumor uptake up to 3 h p.i. (18-19%I.A./g). For [<sup>177</sup>Lu]Lu-DOTAGA.Glu.(FAPI)<sub>2</sub> and [<sup>177</sup>Lu]Lu-DO3A.Glu.(FAPI)<sub>2</sub> tumor uptake was 16.2 ± 2.5 and 15 ± 1.2% IA/g at 4 h p.i., reaching 5.1 ± 0.1 and 2.8 ± 0.4%IA/g at 48 h, respectively. All radioligands exhibited low blood retention levels. PET/SPECT/CT imaging confirmed high tumor-to-background ratios. Uptake patterns correlate well with autoradiography images of heterogeneous FAP distribution in PC3-mice, while the detection of both murine and human FAP in PC3-tumors was demonstrated through immunohistochemistry. The extrapolated human absorbed dose estimates (Gy/GBq) for [<sup>177</sup>Lu]Lu-DOTAGA.Glu.(FAPI)<sub>2</sub> were generally higher across most organs compared to [<sup>177</sup>Lu]Lu-DO3A.Glu.(FAPI)<sub>2</sub>. Human extrapolation of the <sup>161</sup>Tb-labeled radioligands delivered on average ~ 38% higher absorbed doses in tissues as compared to their <sup>177</sup>Lu-labeled counterparts. These results support the potential clinical translation of DOTAGA.Glu.(FAPI)<sub>2</sub> and DO3A.Glu.(FAPI)<sub>2</sub>, as promising candidates for precise diagnosis and treatment of FAP-expressing malignancies.
Medical subject headings
- Lutetium
- Radioisotopes
- Theranostic Nanomedicine