Second Generation Silica-Based Bismuth Gadolinium Nanoparticles for Tumor Dose Enhancement and Real-Time MR-Tracking
N Virani1*, P Rocchi2, 3, F Lux2, 3, T Doussineau2, 3, C Williams4, E Huynh4, E Kaza1, O Tillement2, 3, R Berbeco1, (1) Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, (2) NH Theraguix, Lyon, France, (3) Institut Lumiere Matiere, CNRS, Universite de Lyon, Villeurbanne, France, (4) Brigham and Women's Hospital, Boston, MA
Presentations
TU-D-TRACK 6-5 (Tuesday, 7/27/2021) 2:00 PM - 3:00 PM [Eastern Time (GMT-4)]
Purpose: The purpose of this study is to develop a new generation of theranostic silica-based bismuth-gadolinium nanoparticles for local tumor dose enhancement and adaptive treatment planning using a clinical Viewray MRIdian MRI-Linac System.
Methods: First generation silica-based gadolinium nanoparticles (AGuIX) were modified at different ratios to exchange gadolinium-DOTA complexes with bismuth-DOTA complexes. A new generation of AGuIX-Bi nanoparticles were developed with three ratios of Gd/Bi (70/30, 50/50, and 30/70). Nanoparticles were characterized via ICP-MS, HPLC-UV, DLS, and T1 relaxometry. In vitro toxicity analysis and clonogenic assays were conducted to confirm radiosensitization of nanoparticles in a human non-small cell lung carcinoma (NSCLC) cell line. In vivo studies in agar phantoms and NSCLC mouse models were conducted to evaluate changes in MR contrast of AGuIX-Bi nanoparticles compared to AGuIX in a clinical 3T Siemens MR scanner and a 0.35T MRIdian MRI-Linac.
Results: Each AGuIX-Bi nanoparticle formulation was characterized with final ratios of 70/30, 50/50, and 30/70 of Gd/Bi with an approximate size of 4.5-5.1 nm and 93-96% purity. As the ratio of Gd relative to Bi increased, T1 shortening was observed, confirming an enhancement of MR contrast. Even nanoparticles with the lowest ratio of Gd (30/70 Gd/Bi) showed strong T1 shortening, thus retaining improved contrast. In vitro MTT studies confirmed relatively low toxicity of all nanoparticles up to 3 g/L in a human NSCLC A549 cell line. Clonogenic assays identified a sensitizer enhancement ratio (SER = 50%) of 1.28 for 30/70 AGuIX-Bi nanoparticles compared to 1.125 for AGuIX (gadolinium only). In vivo MR imaging of subcutaneous NSCLCs further confirmed retention of strong signal enhancement of 30/70 AGuIX-Bi nanoparticles compared to AGuIX in a TrueFISP and T1-weighted MR-Linac scan and a T1-weighted 3T MR scan.
Conclusion: This study develops a new generation of theranostic nanoparticles for real-time MR-guidance and localized tumor dose amplification.
Funding Support, Disclosures, and Conflict of Interest: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA240804. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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