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

Abstract

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. 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. 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. 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.