Angew Chem Int Ed Engl. 2026 May 7:e1429706. doi: 10.1002/anie.1429706. Online ahead of print.

ABSTRACT

We report the first enzymatic synthesis of precisely defined metal-oligonucleotide conjugates through template-directed polymerase-mediated primer extension with two different (radio)metal-chelator-modified deoxyribonucleoside triphosphates. We successfully incorporated five different metals (Ga, In, Tb, Lu, and Y) along designed oligonucleotide templates, including the simultaneous incorporation of two different metal chelates within a given strand. To provide bio-orthogonality, this approach exploits the well-known enzymatic fidelity of DNA polymerase to generate uniformly metal-loaded DNA constructs with well-defined and programmable compositions. The platform is validated using chelators DOTA and DTPA and confirmed by both inductively coupled plasma mass spectrometry (ICP-MS) quantification and autoradiographic analysis following gel electrophoresis to demonstrate radioisotope incorporation with clinically relevant metals (⁶⁸Ga for PET, ¹¹¹In for SPECT, ¹⁶¹Tb and ¹⁷⁷Lu for β^– therapy), establishing the potential for using the information content of DNA to create multi-metalated radiopharmaceuticals. This programmable platform establishes a new paradigm for metalated molecular probe development with versatility for potential therapeutic, theranostic, and mass spectrometry-based applications, and potentially generalizable to other metal isotopes based on diagnostic or therapeutic requirements.

PMID:42095405 | DOI:10.1002/anie.1429706