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. 2024 Jun;630(8015):206-213.
doi: 10.1038/s41586-024-07461-6. Epub 2024 May 22.

Covalent targeted radioligands potentiate radionuclide therapy

Xi-Yang Cui #  1   2 , Zhu Li #  3 , Ziren Kong #  4 , Yu Liu  1 , Hao Meng  2 , Zihao Wen  1 , Changlun Wang  1 , Junyi Chen  1 , Mengxin Xu  1   2 , Yiyan Li  1 , Jingyue Gao  1 , Wenjia Zhu  5 , Zhixin Hao  5 , Li Huo  5 , Shaoyan Liu  4 , Zhi Yang  3 , Zhibo Liu  6   7   8   9
Affiliations

Covalent targeted radioligands potentiate radionuclide therapy

Xi-Yang Cui et al. Nature. 2024 Jun.

Abstract

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted β- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

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