Reduction-responsive sulfur dioxide polymer prodrug nanoparticles loaded with irinotecan for combination osteosarcoma therapy.

Combination therapy can boost the therapeutic effectiveness of monotherapies by achieving synergy between therapeutic agents. Herein, a reduction-responsive sulfur dioxide (SO2) polymer prodrug was synthesized as a nanocarrier to load irinotecan (IRN) to be used in combination osteosarcoma therapy. The SO2 prodrug (denoted as mPEG-PLG (DNs)) was synthesized by coupling a small-molecule SO2 donor, N-(3-azidopropyl)-2,4-dinitrobenzenesulfonamide (AP-DNs), to the side chains of methoxy poly (ethylene glycol)-block-poly (γ-propargyl-L-glutamate) block copolymer. The mPEG-PLG (DNs) had the ability to self-assemble into micelles while simultaneously encapsulating IRN in aqueous media. The formed micelles led to enhanced SO2 and IRN release in reductive conditions. Using nile red as a model drug, the loaded micelles were efficiently internalized by cancer cells, demonstrated by confocal laser scanning microscopy and flow cytometry. The release of SO2 within nanoparticles (NPs) in tumor cells led to enhanced intracellular reactive oxygen species amounts together with induced oxidative destruction to cancer cells. Furthermore, the IRN-loaded SO2 polymer prodrug NPs mediated synergistic therapeutic effects against osteosarcoma cells, leading to improved biodistribution and enhanced tumor growth inhibition over control groups in a murine osteosarcoma model. Taken together, this work highlights the potential of SO2 polymer prodrugs as reduction-responsive nanocarriers to load chemotherapeutics for effective combination osteosarcoma therapy.

Hygroscopic properties of the workroom aerosol in aluminium smelter potrooms: a case for transport of HF and SO2 into the lower airways.

The hygroscopic behaviour of individual aerosol particles from workplaces in a primary aluminium smelter was investigated by environmental scanning electron microscopy. At a high relative humidity, comparable with the human respiratory tract, most particles encountered in the Søderberg and Prebake potrooms either undergo partial deliquescence (leading to a water droplet with an insoluble core) or form thin water films at the surface. As gaseous HF and SO(2) are highly soluble in water, the aerosol particles may act as carrier for these two gases into the alveolar region of the lower respiratory tract. Based on a one-dimensional mass balance model, it is estimated that under peak exposure conditions (particle surface area concentration of 10(-4) cm(2) cm(-3)) approximately 10% of the initial gaseous HF may be transferred to the particle phase. For SO(2), this fraction is much lower (approximately 1%). These results indicate that at least HF may penetrate deeper into the lung in the presence of soluble particles or particles that form surface water films compared to HF alone.

Adsorption of sulfur dioxide on hematite and goethite particle surfaces.

The adsorption of sulfur dioxide (SO(2)) on iron oxide particle surfaces at 296 K has been investigated using X-ray photoelectron spectroscopy (XPS). A custom-designed XPS ultra-high vacuum chamber was coupled to an environmental reaction chamber so that the effects of adsorbed water and molecular oxygen on the reaction of SO(2) with iron oxide surfaces could be followed at atmospherically relevant pressures. In the absence of H(2)O and O(2), exposure of hematite (alpha-Fe(2)O(3)) and goethite (alpha-FeOOH) to SO(2) resulted predominantly in the formation of adsorbed sulfite (SO(3)(2-)), although evidence for adsorbed sulfate (SO(4)(2-)) was also found. At saturation, the coverage of adsorbed sulfur species was the same on both alpha-Fe(2)O(3) and alpha-FeOOH as determined from the S2p : Fe2p ratio. Equivalent saturation coverages and product ratios of sulfite to sulfate were observed on these oxide surfaces in the presence of water vapor at pressures between 6 and 18 Torr, corresponding to 28 to 85% relative humidity (RH), suggesting that water had no effect on the adsorption of SO(2). In contrast, molecular oxygen substantially influenced the interactions of SO(2) with iron oxide surfaces, albeit to a much larger extent on alpha-Fe(2)O(3) relative to alpha-FeOOH. For alpha-Fe(2)O(3), adsorption of SO(2) in the presence of molecular oxygen resulted in the quantitative formation of SO(4)(2-) with no detectable SO(3)(2-). Furthermore, molecular oxygen significantly enhanced the extent of SO(2) uptake on alpha-Fe(2)O(3), as indicated by the greater than two-fold increase in the S2p : Fe2p ratio. Although SO(2) uptake is still enhanced on alpha-Fe(2)O(3) in the presence of molecular oxygen and water, the enhancement factor decreases with increasing RH. In the case of alpha-FeOOH, there is an increase in the amount of SO(4)(2-) in the presence of molecular oxygen, however, the predominant surface species remained SO(3)(2-) and there is no enhancement in SO(2) uptake as measured by the S2p : Fe2p ratio. A mechanism involving molecular oxygen activation on oxygen vacancy sites is proposed as a possible explanation for the non-photochemical oxidation of sulfur dioxide on iron oxide surfaces. The concentration of these sites depends on the exact environmental conditions of RH.

Protective effects of seabuckthorn seed oil on mouse injury induced by sulfur dioxide inhalation.

Sulfur dioxide (SO2) is a common but important air pollutant. Micronuclei (MN) in the polychromatic erythrocytes (PCE) of mouse bone marrow and the ratio between organ and body weight of treatment mouse were determined and analyzed in vivo in order to study injury of sulfur dioxide inhalation on organs and germ plasm of mouse as well as protective effect of seabuckthorn seed oil against this injury. It was showed that SO2 inhalation induced the change of the ratio between organ and body of mouse organs, such as liver, lung, kidney, and spleen, and a significant increase of number of MNPCE, while seabuckthorn seed oil offered a protection against such injury.

Spatio-temporal variations of sulphur dioxide patterns with wind conditions in central Taiwan.

Sulphur dioxide (SO2) is one of the main atmospheric pollutants in central Taiwan. This article analyses the SO2 concentration seasonal variations and spatial distribution using data obtained from ten air quality monitoring stations and the Taiwan Weather Bureau. It reveals that SO2 concentration is high in winter and low in summer and that high concentration centers are located south of the Taichung coal-fired power plant, the main source of SO2 emissions in the region. The location of high concentration centers changes with different prevailing winds. SO2 variations due to wind direction are not unique. During short periods, when meteorological conditions are constant, variation in the pollution sources cause variations in the spatial distribution. This has been deduced by appreciation of 'Intervention analysis' to time series of hourly data.

Comparison of sulphur dioxide and metabisulphite airway reactivity in subjects with asthma.

BACKGROUND: In asthmatic subjects bronchoconstriction is induced by inhalation of the common food preservatives sulphur dioxide (SO2) and metabisulphite (MBS). SO2 and MBS challenges share many similarities, but it is not known whether they are equivalent. In this study of subjects with mild clinical asthma equivalence was assessed by comparing SO2 and MBS reactivity by estimating the total dose of SO2 inhaled during SO2 and MBS challenges, and by calculating SO2 uptake during both challenges. In addition, as the MBS solutions inhaled were acidic and hyperosmolar, the effect of these factors on MBS responsiveness was investigated. METHODS: Fifteen subjects were challenged on separate days with doubling (0.5 to 8.0 ppm) concentrations of SO2 gas inhaled during three minute periods of isocapnic hyperventilation and MBS administered in doses ranging from 0.1 to 12.8 mumol using the Wright protocol. On two other days SO2 and MBS challenges were preceded by a challenge with phosphate buffered saline (PBS) solutions of pH and osmolarity similar to MBS solutions. Response was measured as the dose or concentration causing a 20% fall in FEV1 (PD20 or PC20). RESULTS: All subjects reacted to MBS and 14 responded to SO2. Geometric mean histamine PD20 was 1.61 mumol (95% confidence interval 0.72 to 3.60). MBS and SO2 airway responsiveness were not significantly related. Estimates of the mean concentration of SO2 inhaled during SO2 and MBS challenges differed, as did estimates of the mean SO2 uptake during both challenges. MBS and SO2 reactivity were not affected by prior challenge with PBS solutions. CONCLUSIONS: SO2 and MBS challenges are not comparable. MBS reactivity was not affected by the hyperosmolar, acidic nature of its solutions.

Biological markers of exposure to SO2: S-sulfonates in nasal lavage.

S-sulfonate levels were measured in the nasal lavage (NAL) fluid of humans exposed to sulfur dioxide as a potential biological marker of exposure. These levels were determined by treating NAL fluid protein with cyanide to cleave the S-S linkage and release the sulfite. The cyanolytically released sulfite was measured by ion chromatography. In two experiments, humans were exposed to air or 1 ppm SO2 for 10 minute, and to air or 7 ppm SO2 for 20 minutes and lavaged immediately after exposure. Releasable sulfite levels in NAL fluid were 1.06 +/- 0.24 and 2.61 +/- 0.55 micrograms SO=3/mg protein, respectively (mean +/- SE, n = 5), for the first experiment, and 1.16 +/- 0.37 and 4.91 +/- 0.76 micrograms SO=3/mg protein, respectively (mean +/- SE, n = 8), for the second. The subjects in the former study were persons with asthma. In both experiments, S-sulfonate levels were statistically elevated in the exposed group compared with the control groups (p < 0.05, paired t-test). The same individuals in the second experiment received five additional 20-minute exposures to 7 ppm SO2 every other day, for a total of six exposures. NAL fluid taken at the conclusion of the final exposure had releasable sulfite levels of 4.99 +/- 1.36 micrograms SO=3/mg protein; these levels were statistically elevated relative to controls but were not elevated relative to the 1-day exposure (mean +/- SE, n = 8). The lack of accumulation of S-sulfonates after 6 days of short-term exposure suggests clearance of these compounds from the nasal passages within 24 hours. The levels of S-sulfonates observed in NAL fluid in this study are almost three orders of magnitude higher than those measured in plasma following similar SO2 exposures. Measurement of S-sulfonates in the nasal passage may be an effective short-term biomarker of exposure to SO2.

Dynamics of sulfur dioxide absorption in excised porcine tracheae.

The absorption of sulfur dioxide (SO2) into excised porcine tracheae was characterized by a step-response experiment in which SO2 outlet concentration was monitored during the 30-min interval following introduction of inlet concentrations of 0.1-0.6 ppm at steady air flows of 2.7-11.0 liter/min. These data were analyzed with a diffusion-reaction theory incorporating three independent parameters--a gas phase mass transfer coefficient, kg, a tissue phase diffusivity x solubility product, D(alpha RT)2, and a tissue phase reaction constant, kr. While single values of 17 sec-1 for kr and 0.28 m2/sec for D(alpha RT)2 were sufficient to simulate all the data, it was necessary to vary kg from a 0.032 to 0.121 m/sec in direct proportion to the gas flow. Based on these parameter values, gas phase resistance accounts for about one-fourth of the total resistance to absorption in gas and tissue phases combined. All three parameters were independent of inlet concentration, implying that diffusion, solubility, and irreversible reaction of SO2 in tissue are all linear processes.

Effects of repeated inhalation exposures to 1-nitropyrene, benzo[a]pyrene, Ga2O3 particles, and SO2 alone and in combinations on particle clearance, bronchoalveolar lavage fluid composition, and histopathology.

The toxicities of 1-nitropyrene (NP) and benzo[a]pyrene (BaP), inhaled alone and in combination with particles and an irritant gas, were examined to evaluate synergisms among the organic compounds, particles, and gas. Groups of F344 rats were exposed 2 h/d, 5 d/wk for 4 wk to atmospheres of pure NP aerosol (7.5 mg/m3), and to these same compounds adsorbed to Ga2O3 particles (27 mg/m3) both with and without coexposure to 5 ppm SO2. Rats were also exposed to Ga2O3 and SO2 alone. Measurements were made of lung burdens of Ga2O3 particles and retention of radiolabeled tracer particles after the cessation of exposure to evaluate effects on particle clearance. Bronchoalveolar lavage fluid was analyzed to assess inflammation and cytotoxicity. Histopathology was examined to assess the nature and extent of lung injury. Particle clearance was significantly impaired (p less than .05) in all groups whose exposure atmosphere included Ga2O3, but was not significantly changed in the other exposure groups.

Changes in specific airway conductance in healthy volunteers following nasal and oral inhalation of SO2

Specific airway conductance (sGaw) was measured using a body plethysmograph in 49 healthy volunteers exposed by nose and mouth to sulphur dioxide (SO2) below and above the maximum allowable daily concentration of 5 p.p.m., for periods of up to 1 hour. SO2 caused a decrease in sGaw with both nose and mouth breathing at low concentrations. The decrease in sGaw was greater with mouth breathing. At high concentrations (above 5 p.p.m.) however, there was no significant difference between nose and mouth breathing. In subjects exposed to 5 p.p.m. SO2 for up to 1 hour, there was no further significant decrease in sGaw after 5 minutes. These results suggest that changes in sGaw following SO2 inhalation are related to stimulation of tracheobronchial receptors and that after a period acclimatization occurs (AU)