• 100 years of metal coordination chemistry: from Alfred Werner to anticancer metallodrugs

      Barry, Nicolas P.E.; Sadler, P.J. (2014-12)
      Alfred Werner was awarded the Nobel Prize in Chemistry just over 100 years ago. We recall briefly the era in which he was working, his co-workers, and the equipment he used in his laboratories. His ideas were ground breaking: not only does a metal ion have a primary valency (“hauptvalenz”, now the oxidation state), but also a secondary valency, the coordination number (“nebenvalenz”). At that time some refused to accept this idea, but he realised that his new thinking would open up new areas of research. Indeed it did. We illustrate this for the emerging field of medicinal metal coordination chemistry, the design of metal-based therapeutic and diagnostic agents. The biological activity of metal complexes depends intimately not only on the metal and its oxidation state, but also on the type and number of coordinated ligands, and the coordination geometry. This provides a rich platform in pharmacological space for structural and electronic diversity. It is necessary to control both the thermodynamics (strengths of metal-ligand bonds) and kinetics of ligand substitution reactions to provide complexes with defined mechanisms of action. Outer-sphere interactions can also play a major role in target recognition. Our current interest is focussed especially on relatively inert metal complexes which were very familiar to Werner (RuII, OsII, RhIII, IrIII, PtII, PtIV).
    • (137)Cs concentrations in foliose lichens within Tsukuba-city as a reflection of radioactive fallout from the Fukushima Dai-ichi Nuclear Power Plant accident

      Ohmura, Y.; Matsukura, K.; Abe, J.P.; Hosaka, K.; Tamaoki, M.; Dohi, T.; Kakishima, M.; Seaward, Mark R.D. (2015-03)
      (137)Cs concentrations in ten species of foliose lichens collected within Tsukuba-city in August 2013 ranged from 1.7 to 35 kBq/kg. The relationships between (137)Cs in two dominant species, Dirinaria applanata and Physcia orientalis, and the air dose rate (muSv/h) at the sampling sites were investigated. (137)Cs in P. orientalis measured about 1 year after the Fukushima nuclear accident was correlated (r(2) = 0.80) more closely with the air dose rate than those measured after about 2 years (r(2) = 0.65), possibly demonstrating its continued value as a biomonitor to reflect ambient fall-out levels. In contrast, those of Dirinaria applanata were not correlated with the air dose rate in either year.
    • 1D vs. 2D shape selectivity in the crystallization-driven self-assembly of polylactide block copolymers

      Inam, M.; Cambridge, G.; Pitto-Barry, Anaïs; Laker, Z.P.L.; Wilson, N.R.; Mathers, R.T.; Dove, A.P.; O'Reilly, R.K. (2017-04-13)
      2D materials such as graphene, LAPONITE® clays or molybdenum disulfide nanosheets are of extremely high interest to the materials community as a result of their high surface area and controllable surface properties. While several methods to access 2D inorganic materials are known, the investigation of 2D organic nanomaterials is less well developed on account of the lack of ready synthetic accessibility. Crystallization-driven self-assembly (CDSA) has become a powerful method to access a wide range of complex but precisely-defined nanostructures. The preparation of 2D structures, however, particularly those aimed towards biomedical applications, is limited, with few offering biocompatible and biodegradable characteristics as well as control over self-assembly in two dimensions. Herein, in contrast to conventional self-assembly rules, we show that the solubility of polylactide (PLLA)-based amphiphiles in alcohols results in unprecedented shape selectivity based on unimer solubility. We use log Poct analysis to drive solvent selection for the formation of large uniform 2D diamond-shaped platelets, up to several microns in size, using long, soluble coronal blocks. By contrast, less soluble PLLA-containing block copolymers yield cylindrical micelles and mixed morphologies. The methods developed in this work provide a simple and consistently reproducible protocol for the preparation of well-defined 2D organic nanomaterials, whose size and morphology are expected to facilitate potential applications in drug delivery, tissue engineering and in nanocomposites.
    • 2016-2017 Chemistry Newsletter

      Swift, Thomas; Rimmer, Stephen; Martin, William (2017-01-25)
      This is the first issue of a newsletter issued by the Chemistry staff at the University of Bradford. The first issue reflects both the semester gone and the new year ahead. Edited by Dr T Swift with articles from both staff and students on the Chemistry courses. Contributions from Prof S Rimmer, Dr S Nayak, Dr W Martin, Dr S Hickey, Dr J Kendrick, Dr M Katsikogianni, E Castley, H Illing, L Lumsdale and J Mistry.
    • The 2nd MRC-DBT Workshop

      Rimmer, Stephen (2016-06-27)
      The purpose of this workshop was to promote interdisciplinary learning and collaborations between UK and India in the area of bacteria and wounds, particularly when bacteria are increasingly antibiotic resistant. To this end we invited colleagues from India with clinical experience ofmanaging bacterially infected wounds in patients, particularly when antibiotic resistant (Dr Prashant Garg) and colleagues from India with expertise in developing new drug delivery systems (Prof Nikhil Singh and Dr Vamsi Venuganti) and together with UK delegates, spanning those with international experience in investigating bacterial infections (Prof Simon Foster), investigating how biofilms communicate (Prof Paul Williams), international expertise in discovering materials for antimicrobial resistance and for instruction of macrophages (Prof Morgan Alexander), expertise in developing responsive films for detecting infection in wounds using a visible signal (Prof Toby Jenkins) and other scientists working on the axis of detecting and treating infection in wounds.
    • 3D printed drug products: Non-destructive dose verification using a rapid point-and-shoot approach

      Trenfield, S.J.; Goyanes, A.; Telford, Richard; Wilsdon, D.; Rowland, M.; Gaisford, S.; Basit, A.W. (2018-10-05)
      Three-dimensional printing (3DP) has the potential to cause a paradigm shift in the manufacture of pharmaceuticals, enabling personalised medicines to be produced on-demand. To facilitate integration into healthcare, non-destructive characterisation techniques are required to ensure final product quality. Here, the use of process analytical technologies (PAT), including near infrared spectroscopy (NIR) and Raman confocal microscopy, were evaluated on paracetamol-loaded 3D printed cylindrical tablets composed of an acrylic polymer (Eudragit L100-55). Using a portable NIR spectrometer, a calibration model was developed, which predicted successfully drug concentration across the range of 4–40% w/w. The model demonstrated excellent linearity (R2 = 0.996) and accuracy (RMSEP = 0.63%) and results were confirmed with conventional HPLC analysis. The model maintained high accuracy for tablets of a different geometry (torus shapes), a different formulation type (oral films) and when the polymer was changed from acrylic to cellulosic (hypromellose, HPMC). Raman confocal microscopy showed a homogenous drug distribution, with paracetamol predominantly present in the amorphous form as a solid dispersion. Overall, this article is the first to report the use of a rapid ‘point-and-shoot’ approach as a non-destructive quality control method, supporting the integration of 3DP for medicine production into clinical practice.
    • 3D printed oral theophylline doses with innovative 'radiator-like' design: Impact of polyethylene oxide (PEO) molecular weight

      Isreb, A.; Baj, K.; Wojsz, M.; Isreb, Mohammad; Peak, M.; Alhnan, M.A. (2019-06-10)
      Despite the abundant use of polyethylene oxides (PEOs) and their integration as an excipient in numerous pharmaceutical products, there have been no previous reports of applying this important thermoplastic polymer species alone to fused deposition modelling (FDM) 3D printing. In this work, we have investigated the manufacture of oral doses via FDM 3D printing by employing PEOs as a backbone polymer in combination with polyethylene glycol (PEG). Blends of PEO (molecular weight 100 K, 200 K, 300 K, 600 K or 900 K) with PEG 6 K (plasticiser) and a model drug (theophylline) were hot-melt extruded. The resultant filaments were used as a feed for FDM 3D printer to fabricate oral dosage forms (ODFs) with innovative designs. ODFs were designed in a radiator-like geometry with connected paralleled plates and inter-plate spacing of either 0.5, 1, 1.5 or 2 mm. X-ray diffraction patterns of the filaments revealed the presence of two distinctive peaks at 2θ = 7° and 12°, which can be correlated to the diffraction pattern of theophylline crystals. Blends of PEO and PEG yielded filaments of variable mechanically resistance (maximum load at break of 357, 608, 649, 882, 781 N for filament produced with PEO 100 K, 200 K, 300 K, 600 K or 900 K, respectively). Filaments of PEO at a molecular weight of 200–600 K were compatible with FDM 3D printing process. Further increase in PEO molecular weight resulted in elevated shear viscosity (>104 Pa.S) at the printing temperature and hindered material flow during FDM 3D printing process. A minimal spacing (1 mm) between parallel plates of the radiator-like design deemed essential to boost drug release from the structure. This is the first report of utilising this widely used biodegradable polymer species (PEOs and PEG) in FDM 3D printing.
    • 3D Printing of a Multi-Layered Polypill Containing Six Drugs Using a Novel Stereolithographic Method

      Robles-Martinez, P.; Xu, X.; Trenfield, S.J.; Awad, A.; Goyanes, A.; Telford, Richard; Basit, A.W.; Gaisford, S. (2019-06)
      Three-dimensional printing (3DP) has demonstrated great potential for multi-material fabrication because of its capability for printing bespoke and spatially separated material conformations. Such a concept could revolutionise the pharmaceutical industry, enabling the production of personalised, multi-layered drug products on demand. Here, we developed a novel stereolithographic (SLA) 3D printing method that, for the first time, can be used to fabricate multi-layer constructs (polypills) with variable drug content and/or shape. Using this technique, six drugs, including paracetamol, cffeine, naproxen, chloramphenicol, prednisolone and aspirin, were printed with dfferent geometries and material compositions. Drug distribution was visualised using Raman microscopy, which showed that whilst separate layers were successfully printed, several of the drugs diffused across the layers depending on their amorphous or crystalline phase. The printed constructs demonstrated excellent physical properties and the different material inclusions enabled distinct drug release profiles of the six actives within dissolution tests. For the first time, this paper demonstrates the feasibility of SLA printing as an innovative platform for multi-drug therapy production, facilitating a new era of personalised polypills.
    • 3D printing of medicines: Engineering novel oral devices with unique design and drug release characteristics

      Goyanes, A.; Wang, J.; Buanz, A.B.M.; Martinez-Pacheco, R.; Telford, Richard; Gaisford, S.; Basit, A.W. (2015-10-09)
      Three dimensional printing (3DP) was used to engineer novel oral drug delivery devices, with specialised design configurations loaded with multiple actives, with applications in personalised medicine. A filament extruder was used to obtain drug-loaded - paracetamol (acetaminophen) or caffeine - filaments of polyvinyl alcohol with characteristics suitable for use in fused-deposition modelling 3D printing. A multi-nozzle 3D printer enabled fabrication of capsule-shaped solid devices, containing paracetamol and caffeine, with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different from the drug in the adjacent layers; and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least squares component matching to produce false colour representations of distribution of the drugs showed clearly the areas that contain paracetamol and caffeine, and that there is a definitive separation between the drug layers. Drug release tests in biorelevant media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both drugs was simultaneous and independent of drug solubility. With the DuoCaplet design it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device, and the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.
    • 3D structural investigation of solid dosage forms

      Yin, X.; Wu, L.; He, Y.; Guo, Z.; Ren, X.; Shao, Qun; Gu, J.; Xiao, T.; York, Peter; Zhang, J. (2015)
    • 87Sr/86Sr Isotope Composition of Bottled British Mineral Waters for Environmental and Forensic Purposes

      Montgomery, Janet; Evans, J.A.; Wildman, G. (2006)
      Mineral waters in Britain show a wide range of 87Sr/86Sr isotope compositions ranging between 87Sr/86Sr = 0.7059 from Carboniferous volcanic rock sources in Dunbartonshire, Scotland to 87Sr/86Sr = 0.7207 in the Dalradian aquifer of Aberdeenshire, Scotland. The 87Sr/86Sr composition of the waters shows a general correlation with the aquifer rocks, resulting in the waters from older rocks having a more radiogenic signature than those from younger rocks. This wide range of values means that the Sr isotope composition of mineral water has applications in a number of types of studies. In the modern commercial context, it provides a way of fingerprinting the various mineral waters and hence provides a method for recognising and reducing fraud. From an environmental perspective, it provides the first spatial distribution of bio-available 87Sr/86Sr in Britain that can be used in modern, historical and archaeological studies
    • A closer examination of childhood diet and physiology using stable isotope analysis of incremental human dentine

      Beaumont, Julia; Montgomery, Janet (2014-06)
      Abstract: The reconstruction of the diet of past populations using the stable isotope analysis of bone collagen has become a well-established tool for examining their lifeways. For example, variations in foods ingested can demonstrate differences in the foods available to individuals of different sex, age, status and in some cases identifying migrants. However, because of the remodelling of bone throughout life, this produces average values which have been incorporated in the tissues over a period of time and gives a blurred picture of the diet. The analysis of the stable isotope ratios of carbon (δ13C) and nitrogen (δ15N) from tiny increments of dentine utilizes tissue that does not remodel and that permits comparison, at the same age, of those who survived infancy with those who did not at high temporal resolution. Here, we present a study of teeth from a Great Famine period workhouse cemetery in Kilkenny, Ireland, and a contemporary 19th-century cemetery in London, England and compare these with published data from early Neolithic individuals from Sumburgh, Shetland, Scotland. Covariation in δ13C and δ15N values suggests that even small variations have a physiological basis. We show that high-resolution intra-dentine isotope profiles can pinpoint shortduration events such as dietary change, and in the historical populations these can be related to known periods of nutritional deprivation in the juvenile years of life. We further suggest that the data from the Famine cemetery individuals suggest a physiological marker within these isotope profiles for a period of nutritional deprivation which could be utilised in other periods and geographical areas, particularly where there is a catastrophic cemetery assemblage with no known aetiology. This technique could also have applications in a forensic setting.
    • A clustering model for item selection in visual search

      McIlhagga, William H. (2013)
      In visual search experiments, the subject looks for a target item in a display containing different distractor items. The reaction time (RT) to find the target is measured as a function of the number of distractors (set size). RT is either constant, or increases linearly, with set size. Here we suggest a two-stage model for search in which items are first selected and then recognized. The selection process is modeled by (a) grouping items into a hierarchical cluster tree, in which each cluster node contains a list of all the features of items in the cluster, called the object file, and (b) recursively searching the tree by comparing target features to the cluster object file to quickly determine whether the cluster could contain the target. This model is able to account for both constant and linear RT versus set size functions. In addition, it provides a simple and accurate account of conjunction searches (e.g., looking for a red N among red Os and green Ns), in particular the variation in search rate as the distractor ratio is varied.
    • A Comparative Study on the Physicochemical Parameters and Trace Elements in Raw Milk Samples Collected from Misurata- Libya

      Elbagerma, Mohamed A.; Edwards, Howell G.M.; Alajtal, Adel I. (2014)
      This research work was carried out to compare the physicochemical parameters of milk samples from four different animal species namely cow, goat, camel and sheep. Milk samples were collected from different areas of Misurata, Libya and analyzed for the key physiochemical parameters, pH, titratable acidity, total solids, ash, fat, protein and lactose. Furthermore in this study the concentrations of Zinc (Zn), Cadmium (Cd), Chromium (Cr), Magnesium (Mg), Manganese (Mn), Potassium (K), Calcium (Ca) Copper (Cu), Iron (Fe) and Lead (Pb) in similar commercial milk specimens from the same area were determined using microwave plasma- atomic emission spectrometry In fresh cow’s milk, the mean concentrations of Pb, Cd, Cr, Cu, Fe, Zn, Mg, Mn, Ca and K were 0.13± 0.19 (mg/l), 0.004± 0.001 (mg/l), 0.04± 0.01 (mg/l), 0.17± 0.11 (mg/l), 0.72± 0.02 (mg/l), 1.98± 0.04 (mg/l), 214.00± 0.20 (mg/l), 0.080± 0.05 (mg/l), 423.0± 3.5 (mg/l) and 427.0± 2.5 (mg/l), respectively. While the mean concentration of Pb, Cd, Cr, Cu, Fe, Zn, Mg, Mn, Ca and K, in the goat’s milk were 0.761 ± 0.78 (mg/l), 0.085 ± 0.02 (mg/l), 1.253 ± 0.18 (mg/l), 0.400± 0.08 (mg/l), 1.23± 0.21 (mg/l), 3.110± 0.15 (mg/l), 140.0± 0.31 (mg/l), 0.097± 0.07 (mg/l), 473± 5.12 (mg/l) and 510± 6.05 (mg/l), respectively. The concentration of Pb, Cd, Cr, Cu, Fe, Zn, Mg, Mn, Ca and K, in the camel’s milk were 0.025 ± 0.019 (mg/l), 0.091± 0.05 (mg/l), 0.069± 0.07 (mg/l), 0.080 ± 0.05 (mg/l), 1.680 ± 0.43 (mg/l), 5.380 ± 1.17 (mg/l), 120.0 ± 0.11 (mg/l), 0.094 ± 0.04 (mg/l), 520.0 ± 0.32 (mg/l) and 571.0± 0.81 (mg/l), respectively. The concentration of Pb, Cd, Cr, Cu, Fe, Zn, Mg, Mn, Ca and K, in the sheep’s milk were 0.062± 0.03, 0.106± 0.11, 0.040± 0.01, 0.201± 0.10, 0.880± 0.31, 5.350± 0.50, 180± 1.20, 0.072± 0.01, 478± 3.10, and 593.96± 1.87, respectively.
    • A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin

      McNeilly, A.D.; Williamson, Ritchie; Balfour, D.J.; Stewart, C.A.; Sutherland, C. (2012)
      AIMS/HYPOTHESIS: We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feeding-evoked cognitive deficit by improving insulin sensitivity. METHODS: Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n = 24), standard chow (SC; n = 16), HF + metformin (144 mg/kg in diet; n = 20) or SC + metformin (144 mg/kg in diet; n = 16) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins. RESULTS: HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex. CONCLUSIONS/INTERPRETATION: Metformin prevented the metabolic but not cognitive alterations associated with HF feeding. The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet.
    • A mechanophysical phase transition provides a dramatic example of colour polymorphism: the tribochromism of a substituted tri(methylene)tetrahydrofuran-2-one

      Asiri, A.M.; Heller, H.G.; Hughes, D.S.; Hursthouse, M.B.; Kendrick, John; Leusen, Frank J.J.; Montis, R. (2014)
      Derivatives of fulgides have been shown to have interesting photochromic properties. We have synthesised a number of such derivatives and have found, in some cases, that crystals can be made to change colour on crushing, a phenomenon we have termed "tribochromism". We have studied a number of derivatives by X-ray crystallography, to see if the colour is linked to molecular structure or crystal packing, or both, and our structural results have been supported by calculation of molecular and lattice energies. A number of 5-dicyanomethylene-4-diphenylmethylene-3-disubstitutedmethylene-tetrahydrofuran-2 -one compounds have been prepared and structurally characterised. The compounds are obtained as yellow or dark red crystals, or, in one case, both. In two cases where yellow crystals were obtained, we found that crushing the crystals gave a deep red powder. Structure determinations, including those of the one compound which gave both coloured forms, depending on crystallisation conditions, showed that the yellow crystals contained molecules in which the structure comprised a folded conformation at the diphenylmethylene site, whilst the red crystals contained molecules in a twisted conformation at this site. Lattice energy and molecular conformation energies were calculated for all molecules, and showed that the conformational energy of the molecule in structure IIIa (yellow) is marginally higher, and the conformation thus less stable, than that of the molecule in structure IIIb (red). However, the van der Waals energy for crystal structure IIIa, is slightly stronger than that of structure IIIb - which may be viewed as a hint of a metastable packing preference for IIIa, overcome by the contribution of a more stabilising Coulomb energy to the overall more favourable lattice energy of structure IIIb. Our studies have shown that the crystal colour is correlated with one of two molecular conformations which are different in energy, but that the less stable conformation can be stabilised by its host crystal lattice. Graphical abstractGraphical representation of the structural and colour change in the tribochromic compound (III).
    • A neural hierarchy for illusions of time: duration adaptation precedes multisensory integration

      Heron, James; Hotchkiss, John; Aaen-Stockdale, Craig; Roach, N.W.; Whitaker, David J. (2013)
      Perceived time is inherently malleable. For example, adaptation to relatively long or short sensory events leads to a repulsive aftereffect such that subsequent events appear to be contracted or expanded (duration adaptation). Perceived visual duration can also be distorted via concurrent presentation of discrepant auditory durations (multisensory integration). The neural loci of both distortions remain unknown. In the current study we use a psychophysical approach to establish their relative positioning within the sensory processing hierarchy. We show that audiovisual integration induces marked distortions of perceived visual duration. We proceed to use these distorted durations as visual adapting stimuli yet find subsequent visual duration aftereffects to be consistent with physical rather than perceived visual duration. Conversely, the concurrent presentation of adapted auditory durations with nonadapted visual durations results in multisensory integration patterns consistent with perceived, rather than physical, auditory duration. These results demonstrate that recent sensory history modifies human duration perception prior to the combination of temporal information across sensory modalities and provides support for adaptation mechanisms mediated by duration selective neurons situated in early areas of the visual and auditory nervous system (Aubie, Sayegh, & Faure, 2012; Duysens, Schaafsma, & Orban, 1996; Leary, Edwards, & Rose, 2008).