2. Academic Validation
  3. Preparation and Characterization of an Engineered FGF1 Conjugated to 161Tb for Targeting of FGFRs

Preparation and Characterization of an Engineered FGF1 Conjugated to 161Tb for Targeting of FGFRs

  • ACS Omega. 2025 Feb 6;10(6):5730-5743. doi: 10.1021/acsomega.4c09179.
Linlin Song 1 2,  Michal Kostas 1 2,  Jon K Laerdahl 3 4,  Marie Skálová 5,  Tereza Janská 5,  Asta Juzeniene 6,  Svein Ræstad 7,  Alexander Krivokapic 7,  Georgios N Kalantzopoulos 7,  Jaroslav Soltes 8,  Martin Vlk 5,  Jan Kozempel 5,  Sindre Hassfjell 9,  Jørgen Wesche 1 2 10
Affiliations

Affiliations

  • 1 Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo 0379, Norway.
  • 2 Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, Oslo 0379, Norway.
  • 3 Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo 0424, Norway.
  • 4 ELIXIR Norway, Department of Informatics, University of Oslo, Oslo 0316, Norway.
  • 5 Faculty of Nuclear Sciences and Physical Engineering, Czech Technical University in Prague, Břehová 7, Prague 1 110 00, Czech Republic.
  • 6 Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, 0379 Norway.
  • 7 Department of Tracer Technology, Institute of Energy Technology, Instituttveien 18, Kjeller 2007, Norway.
  • 8 Centrum výzkumu Řež s.r.o., Hlavní 130, Řež, Husinec 250 68, Czech Republic.
  • 9 Thor Medical, Karenslyst allé 9C, Oslo 0278, Norway.
  • 10 Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo 0372, Norway.
PMID: 39989790 DOI: 10.1021/acsomega.4c09179
Abstract

The Fibroblast Growth Factor receptor family members, FGFR1-4, are frequently overexpressed in various solid tumors, including breast Cancer and sarcomas. This overexpression highlights the potential of the family of FGFRs as promising targets for Cancer therapy. However, conventional FGFR kinase inhibitors often encounter challenges such as limited efficacy or drug resistance. In this study, we pursue an alternative strategy by designing a conjugate of the FGFR ligand FGF1 with the radioisotope 161Tb, for targeted therapy in FGFR-overexpressing Cancer cells. FGF1 was engineered (eFGF1) to incorporate a single cysteine at the C terminus for site-specific labeling with a DOTA chelator. eFGF1-DOTA was mixed with the radioisotope 161Tb under mild conditions, resulting in a labeling efficiency above 90%. The nonradioactive ligands were characterized by mass spectrometry, while radioligands were characterized by thin-layer chromatography. The targeting function of the radioligands was assessed through confocal microscopy, flow cytometry, and Western blot analysis, focusing on binding to Cancer cells and the activation of downstream signaling pathways related to FGFR. When compared to MCF-7 and RD cell lines with low FGFR expression, eFGF1-DOTA-Tb[161Tb] radioligands demonstrated significantly higher accumulation in FGFR-overexpressing cell lines (MCF-7 FGFR1 and RMS559), leading to enhanced cytotoxicity. Besides radionuclides, eFGF1 can also deliver doxorubicin (DOX) into Cancer cells. Considering these characteristics, eFGF1-DOTA-Tb[161Tb] and eFGF1-DOX emerge as promising candidates for FGFR-targeted Cancer therapy, and further evaluation in vivo is warranted.

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