Abstract
A one-pot three-component double-click process for preparing tumor-targeting agents for cancer radiotherapy is described here. By utilizing DOTA (or NOTA) containing tetrazines and the TCO-substituted aldehyde, the two click reactions, the tetrazine ligation (an inverse electron-demand Diels-Alder cycloaddition) and the RIKEN click (a rapid 6π-azaelectrocyclization), could simultaneously proceed under mild conditions to afford covalent attachment of the metal chelator DOTA or NOTA to biomolecules such as to albumin and anti-IGSF4 antibody without altering their activities. Subsequently, radiolabeling of DOTA- or NOTA-attached albumin and anti-IGSF4 antibody (an anti-tumor-targeting antibody) with [67Cu], a β−-emitting radionuclide, could be achieved in a highly efficient manner via a simple chelation with DOTA proving to be a more superior chelator than NOTA. Our work provides a new and operationally simple method for introducing the [67Cu] isotope even in large quantities to biomolecules, thereby representing an important process for preparations of clinically relevant tumor-targeting agents for radiotherapy.
Highlights
Recent efforts have been devoted to development of radiolabeled tumor-targeting biomolecules, and in evolving new and efficient synthetic methods for incorporating radionuclides into biomolecules
As examples of RIKEN click reaction applied to biomolecule labeling, we succeeded in preparing the [68Ga]-labeled somatostatin and N-glycoconjugates via introduction of a DOTA chelating motif
To identify a more reactive “click” reaction that can be employed in conjunction with our RIKEN click reaction, we were inspired by the tetrazine ligation, which is an inverse electro-demand Diels-Alder reaction that was developed by Fox[36]
Summary
Recent efforts have been devoted to development of radiolabeled tumor-targeting biomolecules, and in evolving new and efficient synthetic methods for incorporating radionuclides into biomolecules. As examples of RIKEN click reaction applied to biomolecule labeling, we succeeded in preparing the [68Ga]-labeled somatostatin and N-glycoconjugates via introduction of a DOTA chelating motif (DOTA: 1,4,7,10-tetraazadodecane-1,4,7,10-tetraacetic acid) using the RIKEN click process with DOTA containing aldehyde 1, followed by chelation with the [68Ga] metal radioisotope (Fig. 1a)[17,18,19]. This radiolabeling enabled in vivo visualization of their kinetics for the first time. We wish to report a new and practical method for introducing radiolabels to proteins and antibodies that could serve as tumor-targeting radio-therapeutics
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