Antioxidant Nanomedicine Significantly Enhances the Survival Benefit of Radiation Cancer Therapy by Mitigating Oxidative Stress-Induced Side Effects.

Oxidative stress-induced off-target effects limit the therapeutic window of radiation therapy. Although many antioxidants have been evaluated as radioprotective agents, none of them are in widespread clinical use, owing to the side effects of the antioxidants themselves and the lack of apparent benefit. Aiming for a truly effective radioprotective agent in radiation cancer therapy, the performance of a self-assembling antioxidant nanoparticle (herein denoted as redox nanoparticle; RNP) is evaluated in the local irradiation of a subcutaneous tumor-bearing mouse model. Since RNP is covered with a biocompatible shell layer and possesses a core-shell type structure of several tens of nanometers in size, its lifetime in the systemic circulation is prolonged. Moreover, since 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), one of the most potent antioxidants, is covalently encapsulated in the core of RNP, it exerts intense antioxidant activity and induces fewer adverse effects by avoiding leakage of the TEMPO molecules. Preadministration of RNP to the mouse model effectively mitigates side effects in normal tissues and significantly extends the survival benefit of radiation cancer therapy. Moreover, RNP pretreatment noticeably increases the apoptosis/necrosis ratio of radiation-induced cell death, a highly desirable property to reduce the chronic side effects of ionizing irradiation.

Measurement of ambient gamma dose rate in Metro Manila, Philippines, using a portable NaI(TI) scintillation survey meter.

Radiological data such as ambient dose equivalent rate obtained from radiation monitoring in Metro Manila are useful for the detection of any anomalous increase of radiation dose rate levels due to nuclear or radiological emergencies. In this study, ambient dose equivalent rates were measured in different locations in Metro Manila using a portable NaI(Tl) scintillation survey meter to determine the background radiation levels within the capital. Ambient dose equivalent rates measured range from 32.7 ± 2.2 to 59.3 ± 8.7 nanosieverts per hour (nSv/h) with computed mean and median values of 41.7 and 39.6 nSv/h, respectively. These values were lower than the Philippines' average dose rate which is 52 nanograys per hour (nGy/h). No significant trend was also observed in the monthly variation of ambient dose equivalent rate for most locations, with the dose rates being relatively consistent throughout a year. No significant trend was further observed in the monthly variation of ambient dose equivalent rate for the whole Metro Manila. Data obtained in this study were used to develop a dose rate distribution map of Metro Manila which could be used as a baseline reference of emergency responders for environmental radioactivity monitoring during nuclear or radiological emergencies that may affect Metro Manila.

Antioxidative Nanoparticles Significantly Enhance Therapeutic Efficacy of an Antibacterial Therapy against Listeria monocytogenes Infection.

Acute inflammatory conditions such as sepsis lead to fatal conditions, including multiple organ failure. Several treatments such as steroidal anti-inflammatory drugs are currently being investigated in order to decrease the blood cytokine level, which increases remarkably. However, any of these therapeutic treatments are not always reliable and effective; none have drastically improved survival rates, and some have mostly ended with failure. Reactive oxygen species (ROS) are signaling molecules responsible for the production of cytokines and chemokines that can mediate hyperactivation of the immune response called cytokine storm. In addition to the above-mentioned agents, various antioxidants have been explored for the removal of excess ROS during inflammation. However, the development of low-molecular-weight (LMW) antioxidants as therapeutic agents has been hampered by several issues associated with toxicity, poor pharmacokinetics, low bioavailability, and rapid metabolism. In the present study, we aimed to overcome these limitations through the use of antioxidative nanoparticles possessing 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) which are covalently conjugated to polymer. Although treatment with antioxidative nanoparticles alone did not eliminate bacteria, combined treatment with an antibacterial agent was found to significantly improve survival rate of the treated mice as compared to the control group. More importantly, the antioxidative nanoparticles reduced oxidative tissue injury caused by the bacterial infection. Thus, our findings highlighted the effectiveness of combination treatment with antioxidative nanoparticles and an antibacterial agent to prevent severe inflammation caused by bacterial infection.

Development of calculation tool for iodine 131 biodistribution depending on the aerosol particle distribution.

Radiation damage to tissues depends on radiation exposure levels. Therefore, we have studied accurate estimations of radiation exposure levels so far. Recently, we developed a tool that can calculate the respiratory tract deposition of radionuclides based on polydisperse particle size distribution. As a next step, there is a need for a new calculation tool for the biodistribution of radionuclides because a fraction of the radionuclides deposited in the respiratory tract is absorbed into the body. In this study, a calculation tool for iodine 131 biodistribution depending on aerosol size distribution was developed. The developed tool in this study is used with the former tool.

Antioxidant Nanomedicine Protects against Ionizing Radiation-Induced Life-Shortening in C57BL/6J Mice.

This study examined a new redox nanoparticle (RNPN) for its ability to protect mice from the life-shortening effect of radiation. A single dose of RNPN was injected subcutaneously into mice 3 or 24 h before whole-body irradiation. Kaplan-Meier survival analysis showed that RNPN given 24 h before whole-body irradiation protected mice against radiation-induced mortality. Histological evaluation of the bone marrow showed that the probable cause of sporadic deaths was bone marrow aplasia. Furthermore, analysis of blood biomarkers revealed abnormalities in the irradiated control group. Such symptoms/indicators of poor health were reduced in RNPN-treated mice.

Assessment of temporal variations of natural radionuclides Beryllium-7 and Lead-212 in surface air in Tanay, Philippines.

Detection of radionuclides in surface air allows researchers to gain further insight on the behavior of radionuclides that may affect human radiation exposure especially in the event of a nuclear emergency. In this study, activity concentrations of naturally-occurring radionuclides Beryllium-7 (7Be) and Lead-212 (212Pb) in surface air and meteorological data collected in Tanay, Philippines from January 2012 to December 2017 were evaluated to determine the impact of atmospheric conditions and processes to airborne radioactivity. Surface air concentrations of 7Be and 212Pb were found to range from 0.00779 ±â€¯0.00188 to 11.2 ±â€¯0.116 mBq/m3 and from 1.371 ±â€¯0.036 to 106.6 ±â€¯1.075 mBq/m3, respectively. 7Be and 212Pb show distinct annual trends, suggesting that atmospheric conditions affect both radionuclides differently and independently. 7Be shows two peak concentrations annually, with the first peak occurring between January to April and the second lower peak occurring between October and November. 212Pb, on the other hand, shows annual peak concentrations occurring between April and June. Ambient temperature showed strong positive correlation with 212Pb concentration in surface air and a weak negative correlation with 7Be; relative humidity and precipitation showed varying degrees of negative correlation with radionuclide concentrations in surface air. Source locations for the unusually high 212Pb activity concentrations detected on 11-13 May 2013 and 19-31 May 2015 determined using WEB-GRAPE and HYSPLIT atmospheric transport models are presented as a case study. The data and findings of this study shall serve as basis for further studies on local and regional atmospheric transport and radiological impact assessment for the implementation of an effective nuclear and radiological emergency preparedness and response system in the country.

Oral nanotherapeutics: Redox nanoparticles attenuate ultraviolet B radiation-induced skin inflammatory disorders in Kud:Hr- hairless mice.

The active participation of an anti-inflammatory drug in the biological pathways of inflammation is crucial for the achievement of beneficial and therapeutic effects. This study demonstrated the development of redox nanoparticles that can circulate in the blood at significantly high levels, thus increasing their efficacy as an oral treatment against the deleterious effects of reactive oxygen species (ROS) in an in vivo inflammatory skin model. To confirm the blood bioavailability of the nanoparticles, mice were injected with the nanoparticles solution (RNPN) via oral gavage. Using electron spin resonance and radioactive labeling techniques, the blood circulation of the redox polymer that forms the nanoparticles was confirmed 24 h after oral administration. This contrasted with its low molecular weight counterpart (NH2-TEMPO), which peaked 15 min post injection and was found to be cleared rapidly within minutes after the peak. We then tested its efficacy in the inflammatory skin model. Kud:Hr-hairless mice were irradiated with UVB (302 nm) to induce skin damage and inflammation. Throughout the entire period of UVB irradiation, RNPN was administered to mice by free drinking. NH2-TEMPO was used as the control. The results showed that oral supplementation of RNPN significantly improved the therapeutic effects of the core nitroxide radical compared with its low molecular weight counterpart. Furthermore, RNPN significantly reduced UVB-induced skin aging, epidermal thickening, edema, erythema, skin lesions, and various pathological skin inflammatory disorders in vivo. From the obtained data, we concluded that the use of long-circulating redox nanoparticles (RNPN) provided an effective treatment against the damaging effects of excessive ROS in the body.

Long-term bioavailability of redox nanoparticles effectively reduces organ dysfunctions and death in whole-body irradiated mice.

Radioprotective agents have been developed to protect patients against the damaging and lethal effects of ionizing radiation. However, in addition to the intrinsic ability to target reactive oxygen species (ROS), the ability to retain a significant level of bioavailability is desirable in radioprotective agents because that would increase and prolong their radioprotective efficacy and improve its safety. Here, we report the development of a novel nanoparticle-based radioprotective agent with improved bioavailability, which suppressed the adverse effects typically associated with low-molecular-weight (LMW) antioxidants. We developed biocompatible and colloidally stable nanoparticles in which nitroxide radicals that were covalently conjugated (redox nanoparticles, RNPN) effectively scavenged radiation-induced ROS with a characteristically prolonged bioavailability and tissue-residence time compared with that of conventional LMW antioxidants. The confinement of the nitroxide radicals in the RNPN core prevented its rapid metabolism and excretion out of the body. The nano-sized formulation prevented internalization of RNPN in healthy cells, thereby preserving the normal function of the redox reactions in the cell. This improved pharmacological performance dramatically reduced the radiation-induced organ dysfunctions and increased the survival time of the lethally irradiated mice when the nanoparticles were administered 3-24 h before whole-body irradiation.

Development of a local anesthetic lidocaine-loaded redox-active injectable gel for postoperative pain management.

Although local anesthesia is commonly applied for pain relief, there are several issues such as its short duration of action and low effectiveness at the areas of inflammation due to the acidic pH. The presence of excessive amount of reactive oxygen species (ROS) is known to induce inflammation and aggravate pain. To resolve these issues, we developed a redox-active injectable gel (RIG) with ROS-scavenging activity. RIG was prepared by mixing polyamine-b-poly(ethylene glycol)-b-polyamine with nitroxide radical moieties as side chains on the polyamine segments (PMNT-b-PEG-b-PMNT) with a polyanion, which formed a flower-type micelle via electrostatic complexation. Lidocaine could be stably incorporated in its core. When the temperature of the solution was increased to 37°C, the PIC-type flower micelle transformed to gel. The continuous release of lidocaine from the gel was observed for more than three days, without remarkable initial burst, which is probably owing to the stable entrapment of lidocaine in the PIC core of the gel. We evaluated the analgesic effect of RIG in carrageenan-induced arthritis mouse model. Results showed that lidocaine-loaded RIG has stronger and longer analgesic effect when administered in inflamed areas. In contrast, while the use of non-complexed lidocaine did not show analgesic effect one day after its administration. Note that no effect was observed when PIC-type flower micelle without ROS-scavenging ability was used. These findings suggest that local anesthetic-loaded RIG can effectively reduce the number of injection times and limit the side effects associated with the use of anti-inflammatory drugs for postoperative pain management. STATEMENT OF SIGNIFICANCE: 1. We have been working on nanomaterials, which effectively eliminate ROS, avoiding dysfunction of mitochondria in healthy cells. 2. We designed redox injectable gel using polyion complexed flower type micelle, which can eliminates ROS locally. 3. We could prepare local anesthesia-loaded redox injectable gel (lido@RIG). 4. Drug release could be extended by local administration of lido@RIG. 5. Deprotonation of lidocaine improved anesthetic effect because ROS were eliminated locally by RIG. 6. Local inflammation could be also suppressed by lido@RIG.

Data on preparation of psychrotolerant bacterium Shewanella olleyana sp. nov. cells for transmission electron microscopy.

This data article contains transmission electron microscopy (TEM) images of psychrotolerant bacterium Shewanella olleyana sp. nov. Cells of S. olleyana were grown following an optimized culture conditions in liquid medium. Procedure for the preparation of cells suitable for TEM is described in detail.

Radiation-treated ready-to-eat (RTE) chicken breast Adobo for immuno-compromised patients.

Usually in hospitals low-bacterial diets are served to immuno-compromised patients (ICPs). However, low-bacterial diets still pose a high risk of microbial infections and limit the food selection of the patients. Thus, pathogen-free dishes must be made available. This study presents the development of pathogen-free ready-to-eat (RTE) Filipino ethnic food chicken breast Adobo, sterilized by exposure to high-dose gamma rays (25 kGy) in combination with conventional treatments. Frozen vacuum-packed samples artificially inoculated with Escherichia coli, Listeria monocytogenes, Bacillus cereus, Staphylococcus aureus and Salmonella enterica subsp. enterica serovar Typhimurium, were exposed to 25 kGy gamma radiation for complete sterilization. Microbial quality and sterility of the samples were analysed following 15, 30, and 60 days of storage at -4°C. The effects of high-dose gamma irradiation on the nutritional quality and sensory characteristics of RTE chicken breast Adobo were also evaluated.

Radiation inactivation of Paenibacillus larvae and sterilization of American Foul Brood (AFB) infected hives using Co-60 gamma rays.

The effectiveness of gamma radiation in inactivating the Philippine isolate of Paenibacillus larvae was investigated. Spores of P. larvae were irradiated at incremental doses (0.1, 0.2, 0.4, 0.8 and 1.6 kGy) of gamma radiation emitted by a 6°Co source. Surviving spores were counted and used to estimate the decimal reduction (D10) value. A dose of 0.2 kGy was sufficient to inactivate 90% of the total recoverable spores from an initial count of 105- 9 × 10³ spores per glass plate. The sterilizing effect of high doses of gamma radiation on the spores of P. larvae in infected hives was determined. In this study, a minimum dose (D(min)) of 15 kGy was tested. Beehives with sub-clinical infections of AFB were irradiated and examined for sterility. All the materials were found to be free of P. larvae indicating its susceptibility to γ-rays. After irradiation, there were no visible changes in the physical appearance of the hives' body, wax and frames. Thus, a dose of 15 kGy is effective enough for sterilization of AFB-infected materials.