Radiotherapy-Activated Hafnium Oxide Nanoparticles Produce Abscopal Effect in a Mouse Colorectal Cancer Model.

PURPOSE: Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumor-specific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare. METHODS: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model. RESULTS: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells. CONCLUSION: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy.

Characterization of a Novel Hafnium-Based X-ray Contrast Agent.

OBJECTIVE: Characterization of BAY-576, a new x-ray contrast agent which is not based on iodine, but rather on the heavy metal hafnium. Compared with iodine, hafnium provides better x-ray absorption in the energy range of computed tomography (CT) and allows images of comparable quality to be acquired at a significantly reduced radiation dose. MATERIALS AND METHODS: A range of standard methods were used to explore the physicochemistry of BAY-576 as well as its tolerability in in vitro assays, its pharmacokinetics and toxicology in rats, and its performance in CT imaging in rabbits. RESULTS: BAY-576 is an extraordinarily stable chelate with a metal content of 42% (wt/wt) and with excellent water solubility. Formulations of 300 mg Hf/mL exhibited viscosity (3.3-3.6 mPa) and osmolality (860-985 mOsm/kg) in the range of nonionic x-ray agents. No relevant effects on erythrocytes, the coagulation, or complement system or on a panel of 87 potential biological targets were observed. The compound did not bind to plasma proteins of a number of species investigated. After intravenous injection in rats, it was excreted fast and mainly via the kidneys. Its pharmacokinetics was comparable to known extracellular contrast agents. A dose of 6000 mg Hf/kg, approximately 10 to 20 times the expected diagnostic dose, was well tolerated by rats with only moderate adverse effects. Computed tomography imaging in rabbits bearing a tumor in the liver demonstrated excellent image quality when compared with iopromide at the same contrast agent dose in angiography during the arterial phase. At 70% of the radiation dose, BAY-576 provided a contrast-to-noise ratio of the tumor, which was equivalent to iopromide at 100% radiation dose. CONCLUSIONS: The profile of BAY-576 indicates its potential as the first compound in a new class of noniodine x-ray contrast agents, which can contribute to the reduction of the radiation burden in contrast-enhanced CT imaging.

Nanoscale radiotherapy with hafnium oxide nanoparticles.

AIM: There is considerable interest in approaches that could improve the therapeutic window of radiotherapy. In this study, hafnium oxide nanoparticles were designed that concentrate in tumor cells to achieve intracellular high-energy dose deposit. MATERIALS & METHODS: Conventional methods were used, implemented in different ways, to explore interactions of these high-atomic-number nanoparticles and ionizing radiation with biological systems. RESULTS: Using the Monte Carlo simulation, these nanoparticles, when exposed to high-energy photons, were shown to demonstrate an approximately ninefold radiation dose enhancement compared with water. Importantly, the nanoparticles show satisfactory dispersion and persistence within the tumor and they form clusters in the cytoplasm of cancer cells. Marked antitumor activity is demonstrated in human cancer models. Safety is similar in treated and control animals as demonstrated by a broad program of toxicology evaluation. CONCLUSION: These findings, supported by good tolerance, provide the basis for developing this new type of nanoparticle as a promising anticancer approach in human patients.

Dose assessment for inhaling hafnium particles based on laboratory rats study.

Internal radiation from inhalation of hafnium tritide aerosols may be a significant radiation protection problem encountered by nuclear facility workers. Based on experimental results of the rat intratracheally instilled with hafnium tritide particles and on a self-absorption factor of beta particles determined by a numerical method, a biokinetic model was developed for inhaled particles of hafnium tritide. Results show that lung burdens of the tritide are well represented by a two-component exponential equation; biological half-lives derived for the retention of 3H in lung were 4.9 d and 1,257 d for the short- and long-term clearance, respectively. The tritium clearance rate via urine or feces was described by bi-phase exponential components. At the end of the experiment (180 d after instillation), only approximately 30% of the initial lung burden of 3H had been eliminated, of which approximately 98% was excreted via feces and 2% in urine, but none through exhaled air. Results also showed that a large percentage (70%) of the hafnium tritide initially present in lung still remained in the organ 6 mo after the exposure. The calculation of the radiation dose indicates that the cumulative dose to the lung directly from the tritide particles was approximately 10(6) times the lung dose from the dissolved tritium in the lung region. The committed effective dose to the lung was estimated to be 5.41 x 10(-10) Sv Bq(-1), which is over 99% of that to the whole body. The dose to the liver was 6.00 x 10(-15) Sv Bq(-1). This information will be useful in developing new guidelines for radiation protection purposes.

Dose estimate of inhaled hafnium tritide using the ICRP 66 lung model.

Metal tritide is widely used for research, purification, compression, and storage of tritium. The current understanding of metal tritide and its radiation dosimetry for internal exposure is limited, and ICRP publications do not provide the tritium dosimetry for hafnium tritide. The current radiation protection guidelines for metal tritide particles (including hafnium tritide) are based on the assumption that their biological behavior is similar to tritiated water, which is completely absorbed by the body. However, the solubility of metal tritide particles depends on the chemical form of the material. The biological half-live of hafnium tritide particles and the dosimetry of an inhalation exposure to those particles could be quite different from tritiated water. This paper describes experiments on the dissolution rate of hafnium tritide particles in a simulated lung fluid. The results showed that less than 1% of the tritium was dissolved in the simulated lung fluid for hafnium tritide particles after 215 d. The short-term and long-term dissolution half times were 46 and 4.28 x 10(5) d, respectively. This indicates that hafnium tritide is an extremely insoluble material. Self-absorption of beta rays in the hafnium tritide particles was estimated by a numerical method. The dose coefficients were calculated as a function of particle size using in vitro solubility data and a calculated self-absorption factor. The dose coefficient decreased with aerodynamic diameters in the range of 0.25 to 10 microm, mainly because the self-absorption factor decreased with increasing particle size. For a particle 1 microm in aerodynamic diameter, the dose coefficient of a hafnium tritide particle was about 10 times higher than that of tritiated water but was about 1.4 times lower than that calculated by ICRP Publication 71 for Type S tritiated particles. The ICRP estimate did not include a self-absorption factor and thus might have overestimated the dose. This finding has significant implications for current health protection guidelines.

Internal dosimetry for inhalation of hafnium tritide aerosols.

Metal tritides with low dissolution rates may have residence times in the lungs which are considerably longer than the biological half-time normally associated with tritium in body water, resulting in long-term irradiation of the lungs by low energy beta particles and bremsstrahlung X rays. Samples of hafnium tritide were placed in a lung simulant fluid to determine approximate lung dissolution rates. Hafnium hydride samples were analysed for particle size distribution with a scanning electron microscope. Lung simulant data indicated a biological dissolution half-time for hafnium tritide on the order of 10(5) d. Hafnium hydride particle sizes ranged between 2 and 10 microns, corresponding to activity median aerodynamic diameters of 5 to 25 microns. Review of in vitro dissolution data, development of a biokinetic model, and determination of secondary limits for 1 micron AMAD particles are presented and discussed.