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.
This article is Open Access
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