Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification

The introduction of magnetic resonance (MR)-guided radiation treatment planning has opened a new space for theranostic nanoparticles to reduce acute toxicity while improving local control. In this work, second-generation AGuIX nanoparticles (AGuIX-Bi) are synthesized and validated. AGuIX-Bi are shown to maintain MR positive contrast while further amplifying the radiation dose by the replacement of some Gd cations with higher Z Bi . These next-generation nanoparticles are based on the AGuIX platform, which is currently being evaluated in multiple Phase II clinical trials in combination with radiotherapy. In this clinically scalable methodology, AGuIX is used as an initial chelation platform to exchange Gd for Bi . AGuIX-Bi nanoparticles are synthesized with three ratios of Gd/Bi, each maintaining MR contrast while further amplifying radiation dose relative to Bi . Safety, efficacy, and theranostic potential of the nanoparticles were evaluated and in a human non-small cell lung cancer model. We demonstrated that increasing Bi in the nanoparticles is associated with more DNA damage and improves efficacy with a statistically significant delay in tumor growth and 33% complete regression for the largest Bi/Gd ratio tested. The addition of Bi by our synthetic method leads to nanoparticles that present slightly altered pharmacokinetics and lengthening of the period of high tumor accumulation with no observed evidence of toxicity. We confirmed the safety and enhanced efficacy of AGuIX-Bi with radiation therapy at the selected ratio of 30Gd/70Bi. These results provide crucial evidence towards patient translation.