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Theranostics 2023; 13(14):4711-4729. doi:10.7150/thno.85663 This issue Cite

Research Paper

Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification

Needa Brown^1,2#✉, Paul Rocchi^3,4#, Léna Carmès^3,4, Romy Guthier^2,5, Meghna Iyer^1,2, Léa Seban², Toby Morris^2,5, Stephanie Bennett², Michael Lavelle^2,5, Johany Penailillo⁶, Ruben Carrasco⁶, Chris Williams², Elizabeth Huynh², Zhaohui Han², Evangelia Kaza², Tristan Doussineau³, Sneh M. Toprani⁷, Xingping Qin^7,8,9,10, Zachary D. Nagel⁷, Kristopher A. Sarosiek^7,8,9,10, Agnès Hagège¹¹, Sandrine Dufort³, Guillaume Bort⁴, François Lux^4,12, Olivier Tillement⁴, Ross Berbeco^2✉

1. Department of Physics, Northeastern University, Boston 02115, USA.
2. Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, Boston 02115, USA.
3. NH TherAguix, Meylan 38240, France.
4. Institut Lumière-Matière, UMR 5306, Université Lyon1-CNRS, Université de Lyon, Villeurbanne Cedex 69100, France.
5. Department of Physics and Applied Physics, University of Massachusetts Lowell, Lowell 01854, USA.
6. Department of Pathology, Harvard Medical School and Dana-Farber Cancer Institute, Boston 02115, USA.
7. John B. Little Center for Radiation Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
8. Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA.
9. Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
10. Department of Medical Oncology, Dana-Farber Cancer Institute/ Harvard Cancer Center, Boston, MA, 02115, USA.
11. Institut des Sciences Analytiques, Université de Lyon, CNRS, Université Claude Bernard Lyon 1, UMR 5280, 69100, Villeurbanne, France.
12. Institut Universitaire de France (IUF), Paris 75005, France.
^#These authors contributed equally to this work.

✉ Corresponding authors: Ross Berbeco, Ph.D. Email: ross_berbecoharvard.edu; Needa Brown, Ph.D. Email: ne.brownedu.

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 Gd³⁺ cations with higher Z Bi³⁺. 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 Gd³⁺ for Bi³⁺. AGuIX-Bi nanoparticles are synthesized with three ratios of Gd/Bi, each maintaining MR contrast while further amplifying radiation dose relative to Bi³⁺. 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 Bi³⁺ 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 Bi³⁺ 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.

Keywords: nanoparticle, bismuth, theranostics, magnetic resonance, radiation therapy

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