Release of proteins via ion exchange from albumin-heparin microspheres

Albumin-heparin and albumin microspheres were prepared as ion exchange gels for the controlled release of positively charged polypeptides and proteins. The adsorption isotherms of chicken egg and human lysozyme, as model proteins, on microspheres were obtained. An adsorption isotherm of chicken egg lysozyme on albumin-heparin microspheres was linear until saturation was abruptly reached,\ud \ud The adsorption isotherms of human lysozyme at low and high ionic strength were typical of adsorption isotherms of proteins on ion exchange gels. The adsorption of human lysozyme on albumin-heparin and albumin microspheres fit the Freundlich equation suggesting heterogeneous binding sites. This was consistent with the proposed multivalent, electrostatic interactions between human lysozyme and negatively charged microspheres. Scatchard plots of the adsorption processes of human lysozyme on albumin-heparin and albumin microspheres suggested negative cooperativity, while positive cooperativity was observed for chicken egg lysozyme adsorption on albumin-heparin microspheres.\ud \ud Human lysozyme loading of albumin-heparin microspheres was 3 times higher than with albumin microspheres, with long term release occurring via an ion exchange mechanism. Apparent diffusion coefficients of 2.1 × 10-1 and 3.9 × 10-11cm2/sec were obtained for the release of human lysozyme from albumin-heparin and albumin microspheres, respectively. The release was found to be independent of diffusion, since the rate determining step was likely an adsorption/desorption processes. An apparent diffusion coefficient of 4.1 × 10-12 cm2/sec was determined for the release of chicken egg lysozyme from albumin-heparin microspheres.\ud \ud Low release of the lysozymes from albumin-heparin microspheres was observed in deionized water, consistent with the proposed ion exchange release mechanism. Overall, albumin-heparin microspheres demonstrated enhanced ion exchange characteristics over albumin microspheres

Release of macromolecules from albumin-heparin microspheres

Hydrophilic microspheres based on albumin-heparin conjugates have been prepared as a macromolecular delivery system. The soluble albumin-heparin conjugate was synthesized and crosslinked in a water-in-oil emulsion with glutaraldehyde to form microspheres in the same manner as for albumin microsphere preparation. The microspheres were characterized in terms of their size and swelling properties. The loading of macromolecules into albumin-heparin microspheres was carried out concurrently and after microsphere preparation. FITC-dextran was applied as a model macromolecule. A higher loading content was achieved when loading was carried out concurrently with microsphere preparation than when loaded subsequently. Prolonged release of FITC-dextran from albumin-heparin microspheres was achieved and attributed to the high molecular weight of the macromolecule. The release of FITC-dextran was modulated by crosslinking density, loading content and the method of drug incorporation. Apparently, the mechanism of FITC-dextran release from albumin-heparin microspheres was dependent on the method of drug incorporation. For release of FITC-dextran from the microspheres, assuming negligible interactions, a diffusion coefficient of 1.7 × 10¿9 cm2/s was determined

Preparation and characterization of microspheres of albumin-heparin conjugates

Albumin-heparin microspheres have been prepared as a new drug carrier. A soluble albumin-heparin conjugate was synthesized by forming amide bonds between human serum albumin and heparin. After purification the albumin-heparin conjugate was crosslinked in a water-in-oil emulsion to form albumin-heparin microspheres. The composition of the conjugate was determined by amino acid analysis. The swelling properties of albumin-heparin microspheres were investigated as a function of pH and ionic strength and compared with albumin microspheres. Albumin-heparin and albumin microspheres exhibited stimuli-sensitive swelling. Both microsphere systems exhibited low swelling at low pH and high swelling at higher pH caused by ionization of amino acids of serum albumin. The swelling of albumin-heparin microspheres was more sensitive toward ionic strength than that of albumin microspheres. This was due to the greater negative charge of the albumin-heparin microspheres. Surfaces of albumin-heparin and albumin microspheres were characterized by ESCA, contact angle measurements, electrophoresis, and scanning electron microscopy. Surface analysis indicated the presence of heparin at the albumin-heparin microsphere/water interface

Biodegradable PLGA Based Nanoparticles for Sustained Regional Lymphatic Drug Delivery

The purpose of this work is to evaluate biodegradable drug carriers with defined size, hydrophobicity, and surface charge density for preferential lymphatic uptake and retention for sustained regional drug delivery. PLGA–PMA:PLA-PEG (PP) nanoparticles of defined size and relative hydrophobicity were prepared by nanoprecipitation method. These were compared with PS particles of similar sizes and higher hydrophobicity. PLGA–PMA:PLGA-COOH (PC) particles at 80:20, 50:50, and 20:80 ratios were prepared by nanoprecipitation for the charge study. Particle size and zeta potential were characterized by dynamic light scattering and laser doppler anemometry, respectively. Particles were administered in vivo to rats subcutaneously. Systemic and lymph node uptake was evaluated by marker recovery. Lymphatic uptake and node retention of PP nanoparticles was shown to be inversely related to size. Lymphatic uptake and node retention of PP particles, as compared to PS particles, was shown to be inversely related to hydrophobicity. Lastly, lymphatic uptake and node retention of PC nanoparticles were directly related to the anionic charge on the particles. In vivo lymphatic uptake and retention in a rat model indicates that the 50 nm PP particles are ideal for sustained regional delivery into the lymphatics for prevention/treatment of oligometastases

A Cremophor-Free Formulation for Tanespimycin (17-AAG) using PEO-b-PDLLA Micelles: Characterization and Pharmacokinetics in Rats

Tanespimycin (17-allylamino-17-demethoxygeldanamycin or 17-AAG) is a promising heat shock protein 90 inhibitor currently undergoing clinical trials for the treatment of cancer. Despite its selective mechanism of action on cancer cells, 17-AAG faces challenging issues due to its poor aqueous solubility, requiring formulation with Cremophor EL (CrEL) or ethanol (EtOH). Therefore, a CrEL-free formulation of 17-AAG was prepared using amphiphilic diblock micelles of poly(ethylene oxide)-b-poly(D,L-lactide) (PEO-b-PDLLA). Dynamic light scattering revealed PEO-b-PDLLA (12:6 kDa) micelles with average sizes of 257 nm and critical micelle concentrations of 350 nM, solubilizing up to 1.5 mg/mL of 17-AAG. The area under the curve (AUC) of PEO-b-PDLLA micelles was 1.3-fold that of the standard formulation. The renal clearance (CLrenal) increased and the hepatic clearance (CLhepatic) decreased with the micelle formulation, as compared to the standard vehicle. The micellar formulation showed a 1.3-fold increase in the half-life (t1/2) of the drug in serum and 1.2-fold increase in t1/2 of urine. As expected, because it circulated longer in the blood, we also observed a 1.7-fold increase in the volume of distribution (Vd) with this micelle formulation compared to the standard formulation. Overall, the new formulation of 17-AAG in PEO-b-PDLLA (12:6 kDa) micelles resulted in a favorable 150-fold increase in solubility over 17-AAG alone, while retaining similar properties to the standard formulation. Our data indicates that the nanocarrier system can retain the pharmacokinetic disposition of 17-AAG without the need for toxic agents such as CrEL and EtOH

Long-term SST variability on the Northwest Atlantic continental shelf and slope

Author Posting. © American Geophysical Union, 2020. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 47(1), (2020): e2019GL085455, doi:10.1029/2019GL085455.The meridional coherence, connectivity, and regional inhomogeneity in long‐term sea surface temperature (SST) variability over the Northwest Atlantic continental shelf and slope from 1982–2018 are investigated using observational data sets. A meridionally concurrent large SST warming trend is identified as the dominant signal over the length of the continental shelf and slope between Cape Hatteras in North Carolina and Cape Chidley, Newfoundland and Labrador, Canada. The linear trends are 0.37 ± 0.06 and 0.39 ± 0.06 °C/decade for the shelf and slope regions, respectively. These meridionally averaged SST time series over the shelf and slope are consistent with each other and across multiple longer observational data sets with records dating back to 1900. The coherence between the long‐term meridionally averaged time series over the shelf and slope and basin‐wide averaged SST in the North Atlantic implies approximately two thirds of the warming trend during 1982–2018 may be attributed to natural climate variability and the rest to externally forced change including anthropogenic warming.We are grateful to the Editor Dr. Kathleen Donohue and two anonymous reviewers. This work was supported by NOAA's Climate Program Office's Modeling, Analysis, Predictions, and Projections (MAPP) program (NA19OAR4320074). We acknowledge our participation in MAPP's Marine Prediction Task Force. The data of NOAA OISST used in this study are available at NOAA Earth System Research Laboratory (https://www.esrl.noaa.gov/psd/data/gridded/data.noaa.oisst.v2.highres.html). The HadISST data set is available at Met Office, Hadley Centre (https://www.metoffice.gov.uk/hadobs/hadisst/). The COBE SST and NOAA ERSST data sets are available at NOAA Earth System Research Laboratory's Physical Sciences Division (https://www.esrl.noaa.gov/psd/data/gridded/data.cobe.html; https://www.esrl.noaa.gov/psd/data/gridded/data.noaa.ersst.v5.html). The near‐surface air temperature is available at Global Historical Climatology Network‐Monthly Database (https://www.ncdc.noaa.gov/data‐access/land‐based‐station‐data/land‐based‐datasets/global‐historical‐climatology‐network‐monthly‐version‐4). The data of SSH are available at Copernicus Marine Environment Monitoring Service (http://marine.copernicus.eu/services‐portfolio/access‐to‐products/?option=com_csw&view=details&product_id=SEALEVEL_GLO_PHY_ L4_REP_OBSERVATIONS_008_047).2020-07-0

Seasonal prediction of bottom temperature on the Northeast U.S. Continental Shelf

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Chen, Z., Kwon, Y.-O., Chen, K., Fratantoni, P., Gawarkiewicz, G., Joyce, T. M., Miller, T. J., Nye, J. A., Saba, V. S., & Stock, B. C. Seasonal prediction of bottom temperature on the Northeast U.S. Continental Shelf. Journal of Geophysical Research: Oceans, 126(5), (2021): e2021JC017187, https://doi.org/10.1029/2021JC017187.The Northeast U.S. shelf (NES) is an oceanographically dynamic marine ecosystem and supports some of the most valuable demersal fisheries in the world. A reliable prediction of NES environmental variables, particularly ocean bottom temperature, could lead to a significant improvement in demersal fisheries management. However, the current generation of climate model-based seasonal-to-interannual predictions exhibits limited prediction skill in this continental shelf environment. Here, we have developed a hierarchy of statistical seasonal predictions for NES bottom temperatures using an eddy-resolving ocean reanalysis data set. A simple, damped local persistence prediction model produces significant skill for lead times up to ∼5 months in the Mid-Atlantic Bight and up to ∼10 months in the Gulf of Maine, although the prediction skill varies notably by season. Considering temperature from a nearby or upstream (i.e., more poleward) region as an additional predictor generally improves prediction skill, presumably as a result of advective processes. Large-scale atmospheric and oceanic indices, such as Gulf Stream path indices (GSIs) and the North Atlantic Oscillation Index, are also tested as predictors for NES bottom temperatures. Only the GSI constructed from temperature observed at 200 m depth significantly improves the prediction skill relative to local persistence. However, the prediction skill from this GSI is not larger than that gained using models incorporating nearby or upstream shelf/slope temperatures. Based on these results, a simplified statistical model has been developed, which can be tailored to fisheries management for the NES.This work was supported by NOAA's Climate Program Office's Modeling, Analysis, Predictions, and Projections (MAPP) Program (NA17OAR4310111, NA19OAR4320074), and Climate Program Office's Climate Variability and Predictability (CVP) Program (NA20OAR4310482). We acknowledge our participation in MAPP's Marine Prediction Task Force

Rectal Indomethacin Dose Escalation (RIDE) for Prevention of Post-ERCP Pancreatitis in High-Risk Patients: a Randomized Trial

Background Although rectal indometacin 100 mg is effective in reducing the frequency and severity of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients, the optimal dose is unknown, and pancreatitis incidence remains high. The aim of this study was to compare the efficacy of two dose regimens of rectal indometacin on the frequency and severity of pancreatitis after ERCP in high-risk patients. Methods In this randomised, double-blind, comparative effectiveness trial, we enrolled patients from six tertiary medical centres in the USA. Eligible patients were those at high risk for the development of pancreatitis after ERCP. We randomly assigned eligible patients (1:1) immediately after ERCP to receive either two 50 mg indometacin suppositories and a placebo suppository (standard-dose group) or three 50 mg indometacin suppositories (high-dose group). 4 h after the procedure, patients assigned to the high-dose group received an additional 50 mg indometacin suppository, whereas patients in the standard-dose group received an additional placebo suppository. The randomisation schedule, stratified according to study centre and with no other restrictions, was computer generated by an investigator who was uninvolved in the clinical care of any participants, distributed to the sites, and kept by personnel not directly involved with the study. These same personnel were responsible for packaging the drug and placebo in opaque envelopes. Patients, study personnel, and treating physicians were masked to study group assignment. The primary outcome of the study was the development of pancreatitis after ERCP. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01912716, and enrolment is complete. Findings Between July 9, 2013, and March 22, 2018, 1037 eligible patients were enrolled and randomly assigned to receive either standard-dose (n=515) or high-dose indometacin (n=522). Pancreatitis after ERCP occurred in 141 (14%) of 1037 patients—76 (15%) of 515 patients in the standard-dose indometacin group and 65 (12%) of 522 patients in the high-dose indometacin group (risk ratio [RR] 1·19, 95% CI 0·87–1·61; p=0·32). We observed 19 adverse events that were potentially attributable to study drug. Clinically significant bleeding occurred in 14 (1%) of 1037 patients—six (1%) of 515 patients in the standard-dose indometacin group and eight (2%) of 522 patients in the high-dose indometacin group (p=0·79). Three (1%) of 522 patients in the high-dose indometacin group developed acute kidney injury versus none in the standard-dose group (p=0·25). A non-ST elevation myocardial infarction occurred in the standard-dose indometacin group 2 days after ERCP. A transient ischaemic attack occurred in the high-dose indometacin group 5 days after ERCP. All 19 adverse events, in addition to the 141 patients who developed pancreatitis after ERCP, were considered serious as all required admission to hospital. We observed no allergic reactions or deaths at 30 day follow-up. Interpretation Dose escalation to rectal indometacin 200 mg did not confer any advantage compared with the standard 100 mg regimen, with pancreatitis incidence remaining high in high-risk patients. Current practice should continue unchanged. Further research should consider the pharmacokinetics of non-steroidal anti-inflammatory drugs to determine the optimal timing of their administration to prevent pancreatitis after ERCP

Shattered pellet injection experiments at JET in support of the ITER disruption mitigation system design

A series of experiments have been executed at JET to assess the efficacy of the newly installed shattered pellet injection (SPI) system in mitigating the effects of disruptions. Issues, important for the ITER disruption mitigation system, such as thermal load mitigation, avoidance of runaway electron (RE) formation, radiation asymmetries during thermal quench mitigation, electromagnetic load control and RE energy dissipation have been addressed over a large parameter range. The efficiency of the mitigation has been examined for the various SPI injection strategies. The paper summarises the results from these JET SPI experiments and discusses their implications for the ITER disruption mitigation scheme