Impact through time of different sized titanium dioxide particles on biochemical and histopathological parameters.

Due to corrosion, a titanium implant surface can be a potential source for the release of micro (MPs) and nano-sized particles (NPs) into the biological environment. This work sought to evaluate the biokinetics of different sized titanium dioxide particles (TiO2 ) and their potential to cause cell damage. Wistar rats were intraperitoneally injected with 150 nm, 10 nm, or 5nm TiO2 particles. The presence of TiO2 particles was evaluated in histologic sections of the liver, lung, and kidney and in blood cells at 3 and 12 months. Ultrastructural analysis of liver and lung tissue was performed by TEM, deposit concentration in tissues was determined spectroscopically, and oxidative metabolism was assessed by determining oxidative membrane damage, generation of superoxide anion (O2(-)), and enzymatic and non-enzymatic antioxidants. TiO2 particles were observed inside mononuclear blood cells and in organ parenchyma at 3 and 12 months. TiO2 deposits were consistently larger in liver than in lung tissue. Alveolar macrophage O2(-) generation and average particle size correlated negatively (p < 0.05). NPs were more reactive and biopersistent in lung tissue than MPs. Antioxidant activity, particularly in the case of 5 nm particles, failed to compensate for membrane damage in liver cells; the damage was consistent with histological evidence of necrosis.

Optimization of boron neutron capture therapy for the treatment of undifferentiated thyroid cancer.

PURPOSE: To analyze the possible increase in efficacy of boron neutron capture therapy (BNCT) for undifferentiated thyroid carcinoma (UTC) by using p-boronophenylalanine (BPA) plus 2,4-bis (alpha,beta-dihydroxyethyl)-deutero-porphyrin IX (BOPP) and BPA plus nicotinamide (NA) as a radiosensitizer of the BNCT reaction. METHODS AND MATERIALS: Nude mice were transplanted with a human UTC cell line (ARO), and after 15 days they were treated as follows: (1) control, (2) NCT (neutrons alone), (3) NCT plus NA (100 mg/kg body weight [bw]/day for 3 days), (4) BPA (350 mg/kg bw) + neutrons, (5) BPA + NA + neutrons, and (6) BPA + BOPP (60 mg/kg bw) + neutrons. The flux of the mixed (thermal + epithermal) neutron beam was 2.8 x 10(8) n/cm(2)/sec for 83.4 min. RESULTS: Neutrons alone or with NA caused some tumor growth delay, whereas in the BPA, BPA + NA, and BPA + BOPP groups a 100% halt of tumor growth was observed in all mice at 26 days after irradiation. When the initial tumor volume was 50 mm(3) or less, complete remission was found with BPA + NA (2 of 2 mice), BPA (1 of 4), and BPA + BOPP (7 of 7). After 90 days of complete regression, recurrence of the tumor was observed in BPA + NA (2 of 2) and BPA + BOPP (1 of 7). The determination of apoptosis in tumor samples by measurements of caspase-3 activity showed an increase in the BNCT (BPA + NA) group at 24 h (p < 0.05 vs. controls) and after the first week after irradiation in the three BNCT groups. Terminal transferase dUTP nick end labeling analysis confirmed these results. CONCLUSIONS: Although NA combined with BPA showed an increase of apoptosis at early times, only the group irradiated after the combined administration of BPA and BOPP showed a significantly improved therapeutic response.

Biodistribution of boron compounds in an animal model of human undifferentiated thyroid cancer for boron neutron capture therapy.

Undifferentiated thyroid carcinoma (UTC) is a rapidly growing, highly invasive malignant tumor that currently lacks any effective treatment. Boron neutron capture therapy (BNCT) has been investigated recently for some types of tumors including glioblastoma multiforme and malignant melanoma. In previous studies we have shown the selective uptake of p-boronophenylalanine (BPA) by undifferentiated thyroid cancer cells in vitro and in vivo, as well as the histologic cure of 50% of the nude mice transplanted with human UTC cells when treated with BPA and an appropriate neutron beam. The present studies were performed to further optimize this treatment through the investigation of a boronated porphyrin, both alone and in combination with BPA. In vitro studies with cells in culture showed that BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(alpha,beta-dihydroxyethyl)-deutero-porphyrin IX) is localized intracellularly, with a highest concentration in the 11500g (mitochondrial-enriched pellet) fraction. When BOPP was administered alone to NIH nude mice transplanted with UTC human cells, no significant tumor uptake or selectivity in our in vivo model was observed. In contrast, when BOPP was injected 5-7 days before BPA and the animals were sacrificed 60 min after administration of BPA, a significant increase in boron uptake by the tumor was found (38-45 ppm with both compounds vs 20 ppm with BPA alone). On day 5 the tissue boron selectivity ratios were tumor/blood approximately 3.8 and tumor/distal skin approximately 1.8. Other important ratios were tumor/thyroid approximately 6.6 and tumor/lung approximately 2.9. These results open the possibility of improving the efficacy of BNCT for the treatment of this so far "orphan" tumor.

A study of uniformity of elements deposition on glass fiber filters after collection of airborne particulate matter (PM-10), using a high-volume sampler.

A study was conducted to evaluate the homogeneity of the distribution of metals and metalloids deposited on glass fiber filters collected using a high-volume sampler equipped with a PM-10 sampling head. The airborne particulate matter (APM)-loaded glass fiber filters (with an active surface of about 500cm(2)) were weighed and then each filter was cut in five small discs of 6.5cm of diameter. Each disk was mineralized by acid-assisted microwave (MW) digestion using a mixture of nitric, perchloric and hydrofluoric acids. Analysis was performed by axial view inductively coupled plasma optical emission spectrometry (ICP OES) and the elements considered were: Al, As, Cd, Cr, Cu, Fe, Mn, Ni, Pb, Sb, Ti and V. The validation of the procedure was performed by the analysis of the standard reference material NIST 1648, urban particulate matter. As a way of comparing the possible variability in trace elements distribution in a particular filter, the mean concentration for each element over the five positions (discs) was calculated and each element concentration was normalized to this mean value. Scatter plots of the normalized concentrations were examined for all elements and all sub-samples. We considered that an element was homogeneously distributed if its normalized concentrations in the 45 sub-samples were within +/-15% of the mean value ranging between 0.85 and 1.15. The study demonstrated that the 12 elements tested showed different distribution pattern. Aluminium, Cu and V showed the most homogeneous pattern while Cd and Ni exhibited the largest departures from the mean value in 13 out of the 45 discs analyzed. No preferential deposition was noticed in any sub-sample.

BNCT of 3 cases of spontaneous head and neck cancer in feline patients.

Having demonstrated BPA-BNCT induced control of experimental squamous cell carcinomas (SCC) of the hamster cheek pouch mucosa with no damage to normal tissue we explored the feasibility and safety of treating spontaneous head and neck tumors, with particular focus on SCC, of terminal feline patients with low dose BPA-BNCT employing the thermal beam of the RA-1 Reactor within a preclinical context. The biodistribution studies showed that, in all three cases evaluated, BPA delivered absolute boron values to tumor in the range that proved therapeutically useful in the experimental model of SCC. BPA-BNCT studies showed no radiotoxic effects, partial tumor control in terms of impaired growth and partial necrosis, an improvement in clinical condition and prolonged survival beyond the terminal condition of the feline patients at the time of recruitment.

Biodistribution of a carborane-containing porphyrin as a targeting agent for Boron Neutron Capture Therapy of oral cancer in the hamster cheek pouch.

Boron Neutron Capture Therapy (BNCT) is a bimodal cancer treatment based on the selective accumulation of 10B in tumors and concurrent irradiation with thermalized neutrons. The short-range, high-LET radiation produced by the capture of neutrons by 10B could potentially control tumor while sparing normal tissue if the boron compound targets tumor selectively within the treatment volume. In previous studies, we proposed and validated the hamster cheek pouch model of oral cancer for BNCT studies, proved that absolute and relative uptake of the clinically employed boron compound boronophenylalanine (BPA) would be potentially therapeutic in this model and provided evidence of the efficacy of in vivo BPA-mediated BNCT to control hamster oral mucosa tumors with virtually no damage to normal tissue. We herein present the biodistribution and pharmacokinetics of a lipophilic, carborane-containing tetraphenylporphyrin (CuTCPH) in the hamster oral cancer model. CuTCPH is a novel, non-toxic compound that may be advantageous in terms of selective and absolute delivery of boron to tumor tissues. For potentially effective BNCT, tumor boron concentrations from a new agent should be greater than 30 ppm and tumor/blood and tumor/normal tissue boron concentration ratios should be greater than 5/1 without causing significant toxicity. We administered CuTCPH intraperitoneally (i.p.) as a single dose of 32 microg/g body weight (b.w.) (10 microg B/g b.w.) or as four doses of 32 microg/g b.w. over 2 days. Blood (Bl) and tissues were sampled at 3, 6, 12, 24, 48, and 72 h in the single-dose protocol and at 1-4 days after the last injection in the multidose protocol. The tissues sampled were tumor (T), precancerous tissue surrounding tumor, normal pouch (N), skin, tongue, cheek and palate mucosa, liver, spleen, parotid gland and brain. The maximum mean B ratios for the single-dose protocol were T/N: 9.2/1 (12h) and T/Bl: 18.1/1 (72 h). The B value peaked to 20.7+/-18.5 ppm in tumor at 24h. The multidose protocol maximum mean ratios were T/N: 11.9/1 (3 days) and T/Bl: 235/1 (4 days). Absolute boron concentration in tumor reached a maximum value of 116 ppm and a mean value of 71.5+/-48.3 ppm at 3 days. The fact that absolute and relative B values markedly exceeded the BNCT therapeutic threshold with no apparent toxicity may confer on this compound a therapeutic advantage. CuTCPH-mediated BNCT would be potentially useful for the treatment of oral cancer in an experimental model.