Heat Transfer Simulation of Reactor Cavity Cooling System Experimental Facility using RELAP5-3D and Generation of View Factors using MCNP

As one of the most attractive reactor types, The High Temperature Gas-cooled Reactor (HTGR) is designed to be passively safe with the incorporation of Reactor Cavity Cooling System (RCCS). In this paper, a RELAP5-3D simulation model is set up based on the 1/16 scale experimental facility established by Texas A&M University. Also, RELAP5-3D input decks are modified to replicate the experiment procedures and the experimental results are compared with the simulation results. The results show there is a perfect match between experimental and simulation results. Radiation heat transfer dominates in the heat transfer process of high temperature gas-cooled reactor due to its high operation temperature. According to experimental research done with the RCCS facility in Texas A&M University, radiation heat transfer takes up 80% of the total heat transferred to standing pipes. In radiation heat transfer, the important parameters are view factors between surfaces. However, because of the geometrical complexity in the experimental facility, it is hard to use the numerical method or analytical view factor formula to calculate view factors. In this project, MCNP based on the Monte Carlo method is used to generate view factors for RELAP5-3D input. MCNP is powerful in setting up complicated geometry, source definition and tally application. In the end, RCCS geometry is set up using MCNP and view factors are calculated

Clinical Pharmacokinetics and Pharmacocynamics of Anticancer Agents Delivered via PEGylated Liposomes

PEGylated liposome is one of the most useful nanocarriers for cancer therapy. Studies described in this dissertation provide new knowledge about (1) the nature of nonlinear PK of PEGylated liposomal anticancer agents, (2) the role of the bi-directional interaction between PEGylated liposomes and the monocytes/macrophages in the PK/PD of these agents, and (3) patient factors that significantly influence the PK/PD of PEGylated liposomal anticancer agents. The PK disposition of encapsulated CPT-11, released CPT-11, and SN-38 after IHL-305 (PEGylated liposomal CPT-11) in cancer patients was evaluated using noncompartmental, individual-based compartmental and population PK analysis. The PK of IHL-305 was characterized by a prolonged circulation time, a reduced volume of distribution and saturable clearance. The high inter-patient variability in the PK and PD of IHL-305 was associated with age, body composition, gender, and monocyte function. The PK disposition of S-CKD602 (PEGylated liposomal CKD-602) was evaluated using population PK analysis. PK of encapsulated CKD-602 was described by 1-compartment model with nonlinear clearance and PK of released CKD-602 was described by a 2-compartment model with linear clearance for all patients. The release rate of CKD-602 from S-CKD602 was influenced by age and clearance of encapsulated CKD-602 was influenced by presence of tumors in liver. A mechanism-based PK-PD model was also developed that described the relationship between PEGylated liposomal anticancer drug and monocyte in cancer patients treated with S-CKD602 and IHL-305. In this model, an irreversible uptake of liposomal drug to monocyte was used account for the bi-directional interaction between PEGylated liposomal anticancer drug and monocyte. The degradation of liposomes through routes other than uptake by monocytes was included. The estimated half-life and baseline value of monocytes were close to the published data. The mechanism-based PK-PD model was compared with a published PK-PD model used for neutropenia and leukocytopenia. Both of these two models adequately described the PK and PD of S-CKD602 and IHL-305. Overall, this work helped to explain the nonlinear PK and high interpatient variability in PK of PEGylated liposomal anticancer agents and defined the role of the bi-directional interaction between PEGylated liposomes and the monocytes in the PK/PD of these agents

Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo

Three docetaxel (DX) lipid conjugates: 2′-lauroyl-docetaxel (C12-DX), 2′-stearoyl-docetaxel (C18-DX), and 2′-behenoyl-docetaxel (C22-DX) were synthesized to enhance drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The three conjugates showed ten-fold higher solubility in the liquid oil phase Miglyol 808 than DX. To further increase the drug entrapment efficiency in NPs, orthogonal design was performed. The optimized formulation was composed of Miglyol 808, Brij 78, and Vitamin E tocopheryl polyethylene glycol succinate (TPGS). The conjugates were successfully entrapped in the reduced-surfactant NPs with entrapment efficiencies of about 50%–60% as measured by gel permeation chromatography (GPC) at a final concentration of 0.5 mg/mL. All three conjugates showed 45% initial burst release in 100% mouse plasma. Whereas C12-DX showed another 40% release over the next 8 hours, C18-DX and C22-DX in NPs showed no additional release after the initial burst of drug. All conjugates showed significantly lower cytotoxicity than DX in human DU-145 prostate cancer cells. The half maximal inhibitory concentration values (IC50) of free conjugates and conjugate NPs were comparable except for C22-DX, which was nontoxic in the tested concentration range and showed only vehicle toxicity when entrapped in NPs. In vivo, the total area under the curve (AUC0–∞) values of all DX conjugate NPs were significantly greater than that of Taxotere, demonstrating prolonged retention of drug in the blood. The AUC0–∞ value of DX in Taxotere was 8.3-fold, 358.0-fold, and 454.5-fold lower than that of NP-formulated C12-DX, C18-DX, and C22-DX, respectively. The results of these studies strongly support the idea that the physical/chemical properties of DX conjugates may be fine-tuned to influence the affinity and retention of DX in oil-filled lipid NPs, which leads to very different pharmacokinetic profiles and blood exposure of an otherwise potent chemo-therapeutic agent. These studies and methodologies may allow for improved and more potent nanoparticle-based formulations

Pharmacokinetic Comparison To Determine the Mechanisms Underlying the Differential Efficacies of Cationic Diamidines against First- and Second-Stage Human African Trypanosomiasis

This is the published version.Human African trypanosomiasis (HAT), a neglected tropical disease, is fatal without treatment. Pentamidine, a cationic diamidine, has been used to treat first-stage (hemolymphatic) HAT since the 1940s, but it is ineffective against second-stage (meningoencephalitic, or central nervous system [CNS]) infection. Novel diamidines (DB75, DB820, and DB829) have shown promising efficacy in both mouse and monkey models of first-stage HAT. However, only DB829 cured animals with second-stage infection. In this study, we aimed to determine the mechanisms underlying the differential efficacies of these diamidines against HAT by conducting a comprehensive pharmacokinetic characterization. This included the determination of metabolic stability in liver microsomes, permeability across MDCK and MDR1-MDCK cell monolayers, interaction with the efflux transporter MDR1 (P-glycoprotein 1 or P-gp), drug binding in plasma and brain, and plasma and brain concentration-time profiles after a single dose in mice. The results showed that DB829, an azadiamidine, had the highest systemic exposure and brain-to-plasma ratio, whereas pentamidine and DB75 had the lowest. None of these diamidines was a P-gp substrate, and the binding of each to plasma proteins and brain differed greatly. The brain-to-plasma ratio best predicted the relative efficacies of these diamidines in mice with second-stage infection. In conclusion, pharmacokinetics and CNS penetration influenced the in vivo efficacies of cationic diamidines against first- and second-stage HAT and should be considered when developing CNS-active antitrypanosomal diamidines

Investigation of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers for brain targeting

Background: An intimidating challenge to transporting drugs into the brain parenchyma is the presence of the blood-brain barrier (BBB). Glucose is an essential nutritional substance for brain function sustenance, which cannot be synthesized by the brain. Its transport primarily depends on the glucose transporters on the brain capillary endothelial cells. In this paper, the brain-targeted properties of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers were compared and evaluated to establish an optimized drug-delivery system. Methods: Coumarin 6-loaded liposomes (GLU200-LIP, GLU400-LIP, GLU1000-LIP, and GLU2000-LIP) composed of phospholipids and glucose-derived cholesterols were prepared by thin-film dispersion-ultrasound method. The BBB model in vitro was developed to evaluate the transendothelial ability of the different liposomes crossing the BBB. The biodistribution of liposomes in the mice brains was identified by in vivo and ex vivo nearinfrared fluorescence imaging and confocal laser scanning microscopy and further analyzed quantitatively by high-performance liquid chromatography. Results: Glucose-derived cholesterols were synthesized and identified, and coumarin 6-loaded liposomes were prepared successfully. The particle sizes of the four types of glucose-modified liposomes were around or smaller than 100 nm with a polydispersity index less than 0.300. GLU400-LIP, GLU1000-LIP, and GLU2000-LIP achieved higher cumulative cleared volumes on BBB model in vitro after 6 hours compared with GLU200-LIP (P < 0.05) and were significantly higher than that of the conventional liposome (P < 0.001). The qualitative and quantitative biodistribution results in the mice showed that the accumulation of GLU1000-LIP in the brain was the highest among all the groups (P < 0.01 versus LIP). Conclusion: The data indicated that GLU400-LIP, GLU1000-LIP, and GLU2000-LIP all possess the potential of brain targeting, among which GLU1000-LIP, as a promising drug-delivery system, exhibited the strongest brain delivery capacity.Nanoscience & NanotechnologyPharmacology & PharmacySCI(E)0ARTICLE163-175

Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach

To determine whether data obtained from the medical literature can be used to estimate the therapeutic index of 5 antiepileptic drugs (AEDs): carbamazepine, lamotrigine, phenobarbital, phenytoin, and valproate

Effects of Ultrasonic Atomization of Slightly Acidic Electrolyzed Water on the Circulation and Shelf Quality of Postharvest Baby Cabbage

To check the effect of slightly acidic electrolyzed water (SAEW) on the shelf quality of postharvest baby cabbage, the effects of ultrasonic atomization fumigation of SAEW with different concentrations (0, 50, 100 and 150 mg/L) on the postharvest preservation of baby cabbage were analyzed under low temperature circulation (4±1) ℃and shelf conditions (25±1) ℃. The results showed that, compared with the control and other concentrations of SAEW (50 and 150 mg/L), the ultrasonic atomization fumigation treatment of SAEW at 100 mg/L treatment significantly suppressed the increase in malondialdehyde content and the decrease in total glucosinolate content of baby cabbage at the 6th and 9th days of shelf life (P<0.05). Further circulation and shelf simulation results indicated that, compared with the control, the 100 mg/L SAEW ultrasonic atomization fumigation treatment reduced the total number of colonies by 17.04% and increased the total glucosinolate content by 30.11% in baby cabbage; In addition, this treatment significantly inhibited the accumulation of nitrite and malondialdehyde content (P<0.05), delayed the decline of soluble sugar, soluble protein, total phenol, ascorbic acid and isothiocyanate content, and increased the activity of myrosinase in postharvest baby cabbage. It was clear that ultrasonic atomization fumigation treatment of SAEW at 100 mg/L could not only effectively inhibit the growth of the total number of colonies in baby cabbage during circulation and shelf life, but also effectively slow down the degradation of nutritional quality in baby cabbage during this process, thus improving the preservation effect of baby cabbage

Improved electrochemical conversion of CO2 to multicarbon products by using molecular doping

The conversion of CO2 into desirable multicarbon products via the electrochemical reduction reaction holds promise to achieve a circular carbon economy. Here, we report a strategy in which we modify the surface of bimetallic silver-copper catalyst with aromatic heterocycles such as thiadiazole and triazole derivatives to increase the conversion of CO2 into hydrocarbon molecules. By combining operando Raman and X-ray absorption spectroscopy with electrocatalytic measurements and analysis of the reaction products, we identified that the electron withdrawing nature of functional groups orients the reaction pathway towards the production of C2+ species (ethanol and ethylene) and enhances the reaction rate on the surface of the catalyst by adjusting the electronic state of surface copper atoms. As a result, we achieve a high Faradaic efficiency for the C2+ formation of approximate to 80% and full-cell energy efficiency of 20.3% with a specific current density of 261.4 mA cm(-2) for C2+ products. Strategies to systematically tune CO2 electroreduction to multicarbon products are of high interests. Here the authors report electron withdrawing functional group alters the reaction pathway towards C2+ products by adjusting the oxidation state of surface copper.D.V., K.Q., and H.L.W. acknowledge funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 804320). L.L., D.V., and H.L.W acknowledge the use of TEM instrumentation provided by the Nation Facility ELECMI ICTS (`Division de Microscopia Electronica', Universidad de Cadiz, DME-UCA). L.L. acknowledges funding from the Andalusian regional government (FEDER-UCA-18-106613), the European Union's Horizon 2020 research and innovation program (grant agreement 823717-ESTEEM3), and the Spanish Ministerio de Economia y Competitividad (PID2019-107578GA-I00). K.Q. and Y.Z. acknowledge financial support from the China Postdoctoral Science Foundation (2018M633127) and the Natural Science Foundation of Guangdong Province (2018A030310602). J.L. acknowledge financial support from the National Natural Science Foundation of China (21808134). We thank Soleil Synchrotron and Andrea Zitolo for allocating beamtime at beamline Samba within the proposal 20200732