Author: Stephanie Bennett, Ross I. Berbeco, Guillaume Bort, Needa Brown, Lena Carmes, Sandrine Dufort, Michael John Lavelle, Geraldine Le Duc, Francois Lux, Toby Morris, Zeinaf Muradova, Andrea Protti, Olivier Tillement 👨🔬
Affiliation: University de Lyon, NH TherAGuIX, University of Massachsetts Lowell and Dana-Farber Cancer Institute Boston, Department of Radiation & Cellular Oncology, University of Chicago, University of Central Florida, Department of Radiation Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, NH TherAguix, Universite de Lyon, Brigham and Women's Hospital, Dana-Farber Cancer Institute 🌍
Purpose: AGuIX is a theranostic Gd-based nanoparticle currently under phase-2 clinical testing where patients receive 2-3 doses at 1-week intervals prior to imaging and irradiation. AGuIX-Bi is a new formulation which uses Bi to improve tumor control while maintaining MR contrast enhancement. Pre-clinical testing of AGuIX-Bi shows tumor nanoparticle retention 24-48 hours post-injection, implying multiple administrations can maintain high concentrations when combined with fractionated radiotherapy. This study used 7T MR T1-mapping in vivo to evaluate AGuIX-Bi uptake over three injections, and subsequent treatment using an SBRT-like regime.
Methods: Nude mice inoculated with A549 non-small cell lung cancer (NSCLC) were injected intravenously with AGuIX-Bi three times at 48-hour intervals. T1-weighted images and maps were acquired using RARE and RARE-VTR sequences, respectively, immediately before and 24-hours after each injection. An additional group was irradiated 24-hours after each injection following the same imaging routine. 7T T1-maps of agar AGuIX-Bi phantoms were used to determine tumor nanoparticle content. Tumors were collected post-completion and Gd/Bi content determined using ICPMS. A further long-term study investigated A549-bearing mice treated using the same injection/irradiation scheme with tumors measured every three days until sacrifice was necessary.
Results: AGuIX-Bi concentrations increased from 0.08 to 0.27 mg/mL for non-irradiated mice and 0.05 to 0.26 mg/mL for irradiated mice over three injections with a significant difference observed between groups on day 3 only. Tumor Gd and Bi content assessed via ICPMS are consistent with T1-map derived concentrations. Additionally, fractionated mice showed significant tumor volume reduction compared to saline and single injection groups, including a 57% extension in time-to-tumor doubling compared to single injection/irradiation mice.
Conclusion: AGuIX-Bi concentrations increased at the tumor site over three injections. This supports the use of AGuIX-Bi for multiple injection, multiple irradiation treatment regimes, with in vivo results showing reduced tumor volume and increased survival under fractionated treatment.