Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification

TL;DR

This study develops and validates second-generation AGuIX-Bi nanoparticles that maintain MRI contrast while amplifying radiation dose, showing improved tumor control and safety in preclinical models, advancing theranostic nanomedicine for radiotherapy.

Contribution

Introduces a scalable synthesis of AGuIX-Bi nanoparticles with enhanced radiation dose amplification and confirms their safety and efficacy in preclinical cancer models.

Findings

Increased Bi content correlates with more DNA damage.

Nanoparticles show delayed tumor growth and 33% complete regression.

No observed toxicity with optimized Bi/Gd ratio.

Abstract

Background: 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$^{3+}$ cations with higher Z Bi$^{3+}$. 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. Methods: In this clinically scalable methodology, AGuIX is used as an initial chelation platform to exchange Gd$^{3+}$ for Bi$^{3+}$. AGuIX-Bi nanoparticles are synthesized with three ratios of Gd/Bi, each maintaining MR contrast while further amplifying radiation dose relative to Bi$^{3+}$. Safety, efficacy, and theranostic potential of the nanoparticles were evaluated in vitro and in vivo in a human non-small cell lung cancer model. Results: We demonstrated that increasing Bi$^{3+}$ in the nanoparticles is associated with more DNA damage and improves in vivo efficacy with a statistically significant delay in tumor growth and 33% complete regression for the largest Bi/Gd ratio tested. The addition of Bi$^{3+}$ 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. Conclusions: 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.