Gadolinium Nanoparticles for Magnetic Resonance Guided Radiation Therapy

While more than 50% of all cancer patients receive radiation therapy during clinical care, the delivery of a curative radiation dose is often constrained by the proximity of healthy tissues. To confront this major clinical issue, MRI is increasingly used in radiation oncology for target delineation and real-time treatment guidance. The gadolinium-based nanoparticles (AGuIX) used in this study are a dual modality probe with radiosensitization properties and better MRI contrast than current FDA-approved gadolinium chelates. In advance of an approved Phase I clinical trial (to begin June 2016), we report on the efficacy and safety in a variety of animal models and clinically relevant radiation conditions. By modeling our preclinical study on current clinic workflows, we show clear compatibility with modern patient care, thus heightening the translational significance. The dual imaging and therapy functionality of AGuIX was investigated in mice with preclinical and clinical radiation beams and safety was evaluated in rats, and non-human primates. MRI was used to monitor tumor uptake and biodistribution. Due to their small size (2-3 nm), the AGuIX have good renal clearance and long blood circulation (around 20-30 min in mice). We performed in vitro cell uptake and radiosensitization studies (clonogenic assays and DNA damage quantification) of a pancreatic cancer cell line in preclinical (220 kVp) and clinical (6 MV and 6 MV FFF) beams. In vivo radiation therapy studies were performed with preclinical and clinical beams. Histology was performed to measure the increase in damage in the tumor and to evaluate the toxicity in healthy tissues. In vitro results demonstrate a significant dose enhancement and DNA damage for the combination of radiation and AGuIX (P < 0.01). Preclinical (220 kVp) irradiation and 6MV FFF irradiation demonstrated significantly higher damage relative to the standard 6 MV beam (P < 0.01). AGuIX exhibited reasonable tumor accumulation (∼3%ID) and a rapid renal clearance (12%ID) within the initial phase of in vivo administration. Targeted radiation (IR) for both preclinical and clinical beams following systemic administration of AGuIX demonstrated a significant regression in tumor burden due to radiation dose enhancement and improved animal survival by >70 days (P < 0.0001). Further histological examination of tumor specimens confirmed extensive radiation-induced DNA damage in +AGuIX/+IR cohorts compared to their non-irradiated controls. Toxicity studies in mice, rats and non-human primates (cynomolgus monkeys) demonstrated safe systemic administration and effective renal clearance. With demonstrated efficacy and negligible toxicity in mice, rats, and non-human primates, AGuIX is a biocompatible nanoplatform with strong translational potential for MR-guided radiation therapy.