Second-Generation Gadolinium-Bismuth Ultrasmall Nanoparticles Amplify the Effects of Clinical Radiation Therapy and Provide Clinical Magnetic Resonance Imaging Contrast

Toby Morris; Zeinaf Muradova; Needa Brown; Léna Carmès; Romy Guthier; Meghna Iyer; Léa Seban; Arianna Liles; Stephanie Bennett; Mileni Isikawa; Michael Lavelle; Guillaume Bort; François Lux; Olivier Tillement; Sandrine Dufort; Geraldine LeDuc; Ross Berbeco

doi:10.1016/j.ijrobp.2025.04.032

Second-Generation Gadolinium-Bismuth Ultrasmall Nanoparticles Amplify the Effects of Clinical Radiation Therapy and Provide Clinical Magnetic Resonance Imaging Contrast

Int J Radiat Oncol Biol Phys. 2025 May 8:S0360-3016(25)00420-1. doi: 10.1016/j.ijrobp.2025.04.032. Online ahead of print.

Authors

Toby Morris¹, Zeinaf Muradova², Needa Brown³, Léna Carmès⁴, Romy Guthier⁵, Meghna Iyer⁶, Léa Seban⁴, Arianna Liles¹, Stephanie Bennett⁷, Mileni Isikawa⁸, Michael Lavelle¹, Guillaume Bort⁹, François Lux¹⁰, Olivier Tillement¹⁰, Sandrine Dufort¹¹, Geraldine LeDuc¹¹, Ross Berbeco¹²

Affiliations

¹ Department of Physics and Applied Physics, University of Massachusetts Lowell, Lowell, Massachusetts; Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
² Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
³ Department of Materials Science and Engineering, University of Central Florida, Orlando, Florida.
⁴ Institut Lumière-Matière, UMR, Université Lyon1-CNRS, Université de Lyon, Villeurbanne, France; NH TherAguix SA, Meylan, France.
⁵ Department of Physics and Applied Physics, University of Massachusetts Lowell, Lowell, Massachusetts.
⁶ William Beaumont School of Medicine, Oakland University, Rochester, Michigan.
⁷ Biological Sciences Division, University of Chicago, Chicago, Illinois.
⁸ Departamento de Física, FFCLRP- Universidade de São Paulo, Ribeirão Preto, Brazil.
⁹ Institut Lumière-Matière, UMR, Université Lyon1-CNRS, Université de Lyon, Villeurbanne, France; Institut Curie, PSL Research University, CNRS, UMR9187, INSERM, U1196, Chemistry and Modeling for the Biology of Cancer, Orsay, France; Université Paris-Saclay, CNRS, UMR9187, INSERM, Chemistry and Modeling for the Biology of Cancer, Orsay, France.
¹⁰ Institut Lumière-Matière, UMR, Université Lyon1-CNRS, Université de Lyon, Villeurbanne, France.
¹¹ NH TherAguix SA, Meylan, France.
¹² Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: Ross_Berbeco@dfci.harvard.edu.

PMID: 40348199
DOI: 10.1016/j.ijrobp.2025.04.032

Abstract

Purpose: AGuIX nanoparticles consisting of Gd atoms chelated to a polysiloxane matrix are under clinical evaluation as radiopharmaceuticals agents with radiation therapy (RT). A new generation, AGuIX-Bi, replaces 70% of the Gd atoms in AGuIX with Bi atoms, improving radiation dose amplification while maintaining magnetic resonance imaging (MRI) contrast. The therapeutic efficacy of AGuIX-Bi was investigated under clinical megavoltage and MRI conditions in 2 non-small cell lung cancer (NSCLC) models.

Methods and materials: Murine (LLC) and human (A549) NSCLC were studied in mice, with animals inoculated and divided into cohorts for control (saline, AGuIX, and AGuIX-Bi) and irradiation (saline + RT, AGuIX + RT, and AGuIX-Bi + RT). Nanoparticle cohorts were injected 24 hours before delivering 10 Gy of irradiation using a 6 MV flattening-filter-free beam. Tumors were measured until euthanasia was necessary, taken as time-to-tumor doubling. Additionally, AGuIX and AGuIX-Bi phantoms were constructed with T1-weighted images and maps taken using a 3T clinical MRI scanner. T1-images of A549 inoculated mice were obtained on the same scanner with injection of AGuIX or AGuIX-Bi 2- and 24 hours before imaging.

Results: No toxicity was observed because of nanoparticle injection, anesthesia, or irradiation. In both LLC and A549 models, AGuIX-Bi + RT significantly outperformed both saline + RT and AGuIX + RT in reducing tumor growth (P < .05). Median time-to-tumor doubling for AGuIX-Bi + RT compared with AGuIX + RT groups was increased by 160% for A549, and by 60% for LLC models (P < .05). Longitudinal relaxivity constants (r₁) derived from phantom T1-mapping were 6.9/mM/s for AGuIX and 8.4/mM/s for AGuIX-Bi. Additionally, T1-weighted mouse tumor imaging showed contrast-to-noise of AGuIX-Bi to be roughly half that of AGuIX.

Conclusions: AGuIX-Bi nanoparticles proved more effective than AGuIX at delaying tumor growth for both NSCLC models while maintaining sufficient MRI contrast at 3T. Replacing some Gd atoms with bismuth improves the efficacy of AGuIX nanoparticles under clinical megavoltage energies without compromising imaging.