Biological applications of nanoparticles are rapidly increasing, which introduces new possibilities to improve the efficacy of radiotherapy. Here, we synthesized titanium peroxide nanoparticles (TiOxNPs) and investigated their efficacy as novel agents that can potently enhance the effects of radiation in the treatment of pancreatic cancer. TiOxNPs and polyacrylic acid-modified TiOxNPs (PAA-TiOxNPs) were synthesized from anatase-type titanium dioxide nanoparticles (TiO2NPs). The size and morphology of the PAA-TiOxNPs was evaluated using transmission electron microscopy and dynamic light scattering. The crystalline structures of the TiO2NPs and PAA-TiOxNPs with and without X-ray irradiation were analyzed using X-ray absorption. The ability of TiOxNPs and PAA-TiOxNPs to produce reactive oxygen species in response to X-ray irradiation was evaluated in a cell-free system and confirmed by flow cytometric analysis in vitro. DNA damage after X-ray exposure with or without PAA-TiOxNPs was assessed by immunohistochemical analysis of γ-H2AX foci formation in vitro and in vivo. Cytotoxicity was evaluated by a colony forming assay in vitro. Xenografts were prepared using human pancreatic cancer MIAPaCa-2 cells and used to evaluate the inhibition of tumor growth caused by X-ray exposure, PAA-TiOxNPs, and the combination of the two. The core structures of the PAA-TiOxNPs were found to be of the anatase type. The TiOxNPs and PAA-TiOxNPs showed a distinct ability to produce hydroxyl radicals in response to X-ray irradiation in a dose- and concentration-dependent manner, whereas the TiO2NPs did not. At the highest concentration of TiOxNPs, the amount of hydroxyl radicals increased by >8.5-fold following treatment with 30 Gy of radiation. The absorption of PAA-TiOxNPs enhanced DNA damage and resulted in higher cytotoxicity in response to X-ray irradiation in vitro. The combination of the PAA-TiOxNPs and X-ray irradiation induced significantly stronger tumor growth inhibition compared to treatment with either PAA-TiOxNPs or X-ray alone (p < 0.05). No apparent toxicity or weight loss was observed for 43 days after irradiation. TiOxNPs are potential agents for enhancing the effects of radiation on pancreatic cancer and act via hydroxyl radical production; owing to this ability, they can be used for pancreatic cancer therapy in the future.

The kidney is the critical target of uranium exposure because uranium accumulates in the proximal tubules and causes tubular damage, but the chemical nature of uranium in kidney, such as its chemical status in the toxic target site, is poorly understood. Micro-X-ray absorption fine-structure (µXAFS) analysis was used to examine renal thin sections of rats exposed to uranyl acetate. The UL_III-edge X-ray absorption near-edge structure spectra of bulk renal specimens obtained at various toxicological phases were similar to that of uranyl acetate: their edge position did not shift compared with that of uranyl acetate (17.175 keV) although the peak widths for some kidney specimens were slightly narrowed. µXAFS measurements of spots of concentrated uranium in the micro-regions of the proximal tubules showed that the edge jump slightly shifted to lower energy. The results suggest that most uranium accumulated in kidney was uranium (VI) but a portion might have been biotransformed in rats exposed to uranyl acetate.

Although the kidneys comprise a critical target of uranium exposure, the dynamics of renal uranium distribution have remained obscure. Uranium is considered to function physiologically in the form of uranyl ions that have high affinity for phosphate groups. The present study applied microbeam-based elemental analysis to precisely determine the distribution of phosphorus and uranium in the kidneys of male Wistar rats exposed to uranium. One day after a single subcutaneous injection of uranyl acetate (2 mg/kg), areas of concentrated phosphorus were scattered in the S3 segments of the proximal tubule of the kidneys, whereas the S3 segments in control rats and in rats given a lower dose of uranium (0.5 mg/kg) contained phosphorus without concentrated phosphorus. Areas with concentrated phosphorus contained uranium 4- to 14-fold more than the mean uranium concentration (126–472 vs. 33.1 ± 4.6 μg/g). The chemical form of uranium in the concentrated phosphorus examined by XAFS was uranium (VI), suggesting that the interaction of uranyl ions with the phosphate groups of biomolecules could be involved in the formation of uranium concentration in the proximal tubules of kidneys in rats exposed to uranium.

Extraction of Pb(II) with picrate ion [Pic⁻] and 0, 0.58, 15, 48, or 97 mmol·dm⁻³ Cd(NO₃)₂ by benzo-18-crown-6 ether (B18C6; L as its symbol) into benzene (Bz) was studied. Three kinds of extraction constants, K_ex, K_ex±, and K_Pb/PbL (or K_ex2±), were determined at 298 K: these constants were defined as [PbLPic₂]_Bz/P, [PbLPic⁺]_Bz[Pic⁻]_Bz/P, and [PbL²⁺]_Bz/[Pb²⁺][L]_Bz (or [PbL²⁺]_Bz([Pic⁻]_Bz)²/P), respectively. The symbol P shows [Pb²⁺][L]_Bz[Pic⁻]² and the subscript “Bz” denotes the Bz phase, Bz saturated with water. Simultaneously, conditional distribution constants, K_D,Pic (=[Pic⁻]_Bz/[Pic⁻]), of Pic⁻ with distribution equilibrium-potential differences (dep) were determined. Then, based on the above four constants and others, the component equilibrium constants of K_1,Bz (=[PbLPic⁺]_Bz/[PbL²⁺]_Bz[Pic⁻]_Bz), K_2,Bz (=[PbLPic₂]_Bz/[PbLPic⁺]_Bz[Pic⁻]_Bz), and K_D,PbL (=[PbL²⁺]_Bz/[PbL²⁺]) were obtained. Using these constants, the Pb(II) extraction with B18C6 under the co-presence of Cd(II) in the water phase was characterized. In such a characterization, I and I_Bz dependences on the constants were mainly discussed, where their symbols denote the ionic strength of the water phase and that of the Bz one, respectively.