Issue 30, 2024

A first-in-class dual-chelator theranostic agent designed for use with imaging-therapy radiometal pairs of different elements

Abstract

A covalent adduct of DFOB and DOTA separated by a L-lysine residue (DFOB-L-Lys-N6-DOTA) exhibited remarkable regioselective metal binding, with {1H}-13C NMR spectral shifts supporting Zr(IV) coordinating to the DFOB unit, and Lu(III) coordinating to the DOTA unit. This first-in-class, dual-chelator theranostic design could enable the use of imaging-therapy radiometal pairs of different elements, such as 89Zr for positron emission tomography (PET) imaging and 177Lu for low-energy β-particle radiation therapy. DFOB-L-Lys-N6-DOTA was elaborated with an amine-terminated polyethylene glycol extender unit (PEG4) to give DFOB-N2-(PEG4)-L-Lys-N6-DOTA (compound D2) to enable installation of a phenyl-isothiocyanate group (Ph-NCS) for subsequent monoclonal antibody (mAb) conjugation (mAb = HuJ591). D2-mAb was radiolabeled with 89Zr or 177Lu to produce [89Zr]Zr-D2-mAb or [177Lu]Lu-D2-mAb, respectively, and in vivo PET/CT imaging and in vivo/ex vivo biodistribution properties measured with the matched controls [89Zr]Zr-DFOB-mAb or [177Lu]Lu-DOTA-mAb in a murine LNCaP prostate tumour xenograft model. The 89Zr-immuno-PET imaging function of [89Zr]Zr-D2-mAb and [89Zr]Zr-DFOB-mAb showed no significant difference in tumour accumulation at 48 or 120 h post injection. [89Zr]Zr-D2-mAb and [177Lu]Lu-D2-mAb showed similar ex vivo biodistribution properties at 120 h post-injection. Tumour uptake of [177Lu]Lu-D2-mAb shown by SPECT/CT imaging at 48 h and 120 h post-injection supported the therapeutic function of D2, which was corroborated by similar therapeutic efficacy between [177Lu]Lu-D2-mAb and [177Lu]Lu-DOTA-mAb, both showing a sustained reduction in tumour volume (>80% over 65 d) compared to vehicle. The work identifies D2 as a trifunctional chelator that could expand capabilities in mixed-element radiometal theranostics to improve dosimetry and the clinical outcomes of molecularly targeted radiation.

Graphical abstract: A first-in-class dual-chelator theranostic agent designed for use with imaging-therapy radiometal pairs of different elements

Supplementary files

Article information

Article type
Edge Article
Submitted
30 apr 2024
Accepted
21 may 2024
First published
03 iyn 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2024,15, 11748-11760

A first-in-class dual-chelator theranostic agent designed for use with imaging-therapy radiometal pairs of different elements

J. L. Wood, S. Ghosh, Z. H. Houston, N. L. Fletcher, J. Humphries, K. Mardon, D. T. Akhter, W. Tieu, A. Ivashkevich, M. P. Wheatcroft, K. J. Thurecht and R. Codd, Chem. Sci., 2024, 15, 11748 DOI: 10.1039/D4SC02851A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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