Investigation of zirconium interactions with a DOTA based theranostic hybrid nanoparticle using X-ray absorption spectroscopy

Abstract

Chelator-based nanoparticles have gained significant attention for theranostic applications due to their tunable properties and biocompatibility. Among them, AGuIX nanoparticles (NPs) are promising ultrasmall nanoparticles composed of a polysiloxane core surrounded by DOTAGA chelates, derivatives of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), enabling both radiosensitization and medical imaging. ⁸⁹Zr is a particularly promising radioisotope and its radiolabeling on the AGuIX nanoparticles is highly efficient, whereas Zr–DOTA-complex formation requires heating. Understanding the interaction between radionuclides and nanoparticles is crucial to achieve successful radiolabeling strategies. In this regard, X-ray absorption spectroscopy (XAS) is one of the few experimental techniques capable of providing structural information for such nanoparticles in solution. By combining EXAFS, XANES and theoretical calculations, the coordination chemistry of zirconium in Zr–AGuIX nanoparticles is compared to Zr–DOTA, explaining the high ⁸⁹Zr labeling yield of AGuIX. In the Zr–DOTA complex, Zr adopts an eight-coordinated structure and is inserted into the DOTA cage. In contrast, in Zr–AGuIX, zirconium is not bound within the DOTAGA cage but instead coordinates with six oxygen atoms at shorter distances from deprotonated silanols groups and carboxylate groups from DOTAGA, increasing its stability. These findings indicate that flexible carboxylate groups could effectively enhance the zirconium radiolabeling efficiency of such silica-based nanoparticles.