The development of therapeutic proteins can be hindered by poor decision-making strategies in the early stage

In this study we address two major issues related to the current development process of therapeutic proteins and their characterization. First, due to limited samples amounts, the selection of lead molecules in the early stages is often based on the results from a limited physicochemical characterization. The latter can be based on measurements of only 2-3 parameters, e.g. protein melting temperature, protein aggregation temperature, and is usually performed in only one buffer, e.g. PBS. The hypothesis we present is that such approach can lead to the rejection of lead candidates that can still be manufacturable and can move on to clinical trials. The second matter we address are the often-reported correlations between protein physicochemical parameters in the literature. We propose that such correlations can be found only in a small sample population, e.g. one protein in different solution conditions or different proteins from the same class. However, we expect that such correlations would not be valid in a large population, including various protein structures and solution conditions. In order to address the above-mentioned issues, we created the PIPPI consortium (http://www.pippi.kemi.dtu.dk) and applied systematic approach to map the physicochemical properties of a wide range of proteins and extensively study their stability as a function of the solution conditions. We show that promising therapeutic protein lead candidate can appear as non-manufacturable when only limited physicochemical characterization is performed, e.g. a few methods are used and only a few solution conditions are tested. Therefore, the rejection rate during early-stage development can be improved by more thorough physicochemical characterization. Moreover, only weak linear correlations between biophysical properties of proteins are observed in a large populations. This suggests that the often-reported correlations between parameters describing the protein stability are not representative of a global population. Understanding the connections between various physiochemical parameters would require a systematic database which is currently in development by the PIPPI consortium

Investigation of factors influencing the hydrolytic degradation of single PLGA microparticles

Abstract Poly lactide-co-glycolide (PLGA) is an important polymer matrix used to provide sustained release across a range of active pharmaceutical ingredients (APIs) and works by hydrolytic degradation within the body, thereby releasing entrapped drug. Processing and sterilisation can impact on the morphology and chemistry of PLGA therefore influencing the hydrolysis rate and in turn the release rate of any entrapped API. This paper has looked at the effect of supercritical carbon dioxide (scCO2) processing, gamma irradiation, comonomer ratio and temperature on the hydrolysis of individual PLGA microparticles, using a combination of Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) imaging, Scanning Electron Microscopy (SEM), Differential Scanning Calorimetery (DSC) and Gel Permeation chromatography (GPC) to facilitate a better understanding of the physiochemical factors affecting the hydrolysis rate. This work has shown that scCO2 processing influences hydrolysis rates by increasing the porosity of the PLGA microparticles, increasing the lactide comonomer ratio decreases hydrolysis rates by reducing the hydrophilicity of the PLGA microparticles and increasing the gamma irradiation dose systematically increases the rate of hydrolysis due to reducing the overall molecular weight of the polymer matrix via a chain scission mechanism. Moreover this work shows that ATR-FTIR imaging facilitates the determination of a range of physicochemical parameters during the hydrolysis of a single PLGA microparticle including water ingress, water/polymer interface dimensions, degradation product distribution and hydrolysis rates for both lactide and glycolide copolymer units from the same experimen

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Peptide and protein delivery / Chris van der Walle [editor].

Includes bibliographical references and index.Book fair 2013.xii, 368 p. :The growing area of peptide and protein therapeutics research is of paramount importance to medical application and advancement. A needed reference for entry level researchers and researchers working in interdisciplinary / collaborative projects, Peptide and Protein Delivery addresses the current and emerging routes for delivery of therapeutics. Covering cerebral delivery, pulmonary delivery, transdermal delivery, intestinal delivery, ocular delivery, parenteral delivery, and nasal delivery, this resource offers an overview of the main routes in therapeutics. Researchers across biochemistry, pharmaceutical, molecular biology, cell biology, immunology, chemistry and biotechnology fields will find this publication invaluable for peptide and protein laboratory research. Discusses the most recent data, ideas and concepts Presents case studies and an industrial perspective Details information from the molecular level to bioprocessing Thought provoking, for the novice to the specialist Timely, for today's biopharmaceuticals marke

Peptide and protein delivery /

The growing area of peptide and protein therapeutics research is of paramount importance to medical application and advancement. A needed reference for entry level researchers and researchers working in interdisciplinary / collaborative projects, Peptide and Protein Delivery addresses the current and emerging routes for delivery of therapeutics. Covering cerebral delivery, pulmonary delivery, transdermal delivery, intestinal delivery, ocular delivery, parenteral delivery, and nasal delivery, this resource offers an overview of the main routes in therapeutics. Researchers across biochemistry, pharmaceutical, molecular biology, cell biology, immunology, chemistry and biotechnology fields will find this publication invaluable for peptide and protein laboratory research. Covers current and emerging routes for delivery of therapeutics with a focus on end application Covers Comparative Effectiveness Research Concise, accessible information from active researchers in academia and industry.The growing area of peptide and protein therapeutics research is of paramount importance to medical application and advancement. A needed reference for entry level researchers and researchers working in interdisciplinary / collaborative projects, Peptide and Protein Delivery addresses the current and emerging routes for delivery of therapeutics. Covering cerebral delivery, pulmonary delivery, transdermal delivery, intestinal delivery, ocular delivery, parenteral delivery, and nasal delivery, this resource offers an overview of the main routes in therapeutics. Researchers across biochemistry, pharmaceutical, molecular biology, cell biology, immunology, chemistry and biotechnology fields will find this publication invaluable for peptide and protein laboratory research. Covers current and emerging routes for delivery of therapeutics with a focus on end application Covers Comparative Effectiveness Research Concise, accessible information from active researchers in academia and industry.An Overview of the Field of Peptide and Protein Delivery -- Pulmonary Delivery of Peptides and Proteins -- Nasal Delivery of Peptides and Proteins with Chitosan and Related Mucoadhesive Polymers -- Transdermal Delivery of Peptides and Proteins -- Ocular Delivery of Proteins and Peptides -- Brain Delivery of Peptides and Proteins -- Chemically Modified Polyelectrolytes for Intestinal Peptide and Protein Delivery -- Nanoparticle Mediated Oral Delivery of Peptides and Proteins: Challenges and Perspectives -- Modulation of the Intestinal Tight Junctions Using Bacterial Enterotoxins -- Peptide and Protein Delivery with Cell-penetrating Peptides -- Peptide and Protein Bioconjugation: A Useful Tool to Improve the Biological Performance of Biotech Drugs -- Peptide and Protein Application in Tissue Repair and Regeneration -- Product Quality During Manufacture and Supply -- Glossary -- Commonly encountered units and abbreviations -- Calculated properties of some clinically relevant peptides and proteins -- Index.Includes bibliographical references and index.Print version record.Elsevie

Calorimetry of hydrogen desorption from a-Si nanoparticles

The process of hydrogen desorption from amorphous silicon (a-Si) nanoparticles grown by plasma-enhanced chemical vapor deposition (PECVD) has been analyzed by differential scanning calorimetry (DSC), mass spectrometry, and infrared spectroscopy, with the aim of quantifying the energy exchanged. Two exothermic peaks centered at 330 and 410 C have been detected with energies per H atom of about 50 meV. This value has been compared with the results of theoretical calculations and is found to agree with the dissociation energy of Si-H groups of about 3.25 eV per H atom, provided that the formation energy per dangling bond in a-Si is about 1.15 eV. It is shown that this result is valid for a-Si:H films, too