New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumour cell survival.

© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Nuria Vilabo, Alba Bore, Francisco Martin-Saavedra, Melanie Bayford, Natalie Winfield, Stuart Firth-Clark, Stewart B. Kirton, and Richard Voellmy, 'New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumor cell survival', Nucleic Acids Research, 2017, 1, doi: 10.1093/nar/gkx194Comparative modeling of the DNA-binding domain of human HSF1 facilitated the prediction of possible binding pockets for small molecules and definition of corresponding pharmacophores. In silico screening of a large library of lead-like compounds identified a set of compounds that satisfied the pharmacophoric criteria, a selection of which compounds was purchased to populate a biased sublibrary. A discriminating cell-based screening assay identified compound 001, which was subjected to systematic analysis of structure–activity relationships, resulting in the development of compound 115 (IHSF115). IHSF115 bound to an isolated HSF1 DNAbinding domain fragment. The compound did not affect heat-induced oligomerization, nuclear localization and specific DNA binding but inhibited the transcriptional activity of human HSF1, interfering with the assembly of ATF1-containing transcription complexes. IHSF115 was employed to probe the human heat shock response at the transcriptome level. In contrast to earlier studies of differential regulation in HSF1-na¨ıve and -depleted cells, our results suggest that a large majority of heat-induced genes is positively regulated by HSF1. That IHSF115 effectively countermanded repression in a significant fraction of heat-repressed genes suggests that repression of these genes is mediated by transcriptionally active HSF1. IHSF115 is cytotoxic for a variety of human cancer cell lines, multiplemyeloma lines consistently exhibiting high sensitivity.Peer reviewedFinal Published versio

Optimising poly(lactic-co-glycolic acid) microparticle fabrication using a Taguchi orthogonal array design-of-experiment approach

© 2019 Mensah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The objective of this study was to identify, understand and generate a Taguchi orthogonal array model for the formation of 10–50 μm microparticles with applications in topical/ocular controlled drug delivery. Poly(lactic-co-glycolic acid) (PLGA) microparticles were fabricated by the single emulsion oil-in-water method and the particle size was characterized using laser diffraction and scanning electronic microscopy (SEM). Sequential Taguchi L 12 and L 18 orthogonal array (OA) designs were employed to study the influence of ten and eight parameters, respectively, on microparticle size (response). The first optimization step using the L 12 design showed that all parameters significantly influenced the particle size of the prepared PLGA microparticles with exception of the concentration of poly(vinyl alcohol) (PVA) in the hardening bath. The smallest mean particle size obtained from the L 12 design was 54.39 μm. A subsequent L 18 design showed that the molecular weight of PLGA does not significantly affect the particle size. An experimental run comprising of defined parameters including molecular weight of PLGA (89 kDa), concentration of PLGA (20% w/v), concentration of PVA in the emulsion (0.8% w/v), solvent type (ethyl acetate), organic/aqeuous phase ratio (1:1 v/v), vortexing speed (9), vortexing duration (60 seconds), concentration of PVA in hardening bath (0.8% w/v), stirring speed of hardening bath (1200 rpm) and solvent evaporation duration (24 hours) resulted in the lowest mean particle size of 23.51 μm which was predicted and confirmed by the L 18 array. A comparable size was demonstrated during the fabrication of BSA-incorporated microparticles. Taguchi OA design proved to be a valuable tool in determining the combination of process parameters that can provide the optimal condition for microparticle formulation. Taguchi OA design can be used to correctly predict the size of microparticles fabricated by the single emulsion process and can therefore, ultimately, save time and costs during the manufacturing process of drug delivery formulations by minimising experimental runs.Peer reviewedFinal Published versio

The benefits of in silico modeling to identify possible small-molecule drugs and their off-target interactions

Accepted for publication in a future issue of Future Medicinal Chemistry.The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions. Further integration of these methods into easy-to-use workflows informed by systems biology could realize the full potential of available data in the drug discovery and reduce the attrition of drug candidates.Peer reviewe

Poly(N-isopropyl acrylamide) – poly(ethylene glycol) – poly(N-isopropyl acrylamide) as a thermoreversible gelator for topical administration

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported licence: https://creativecommons.org/licenses/by-nc/3.0/.Poly(N-isopropyl acrylamide) – block– poly(ethylene glycol) – block– poly(N-isopropyl acrylamide) is known to exhibit a thermally-induced solution-to-gel transition in water, which may be exploited for biomedical applications. This “thermoreversible gelator” has great potential for application in topical drug delivery to the surfaces of the body such as the skin, eye, and vagina, but this has not yet been evaluated. This study evaluates PNIPAM98-PEG122-PNIPAM98 as a thermoreversible gelator for vaginal drug delivery, for the first time evaluating the effect of polymer concentration on gelation, studying rheological parameters relevant to topicals, measuring dissolution rates, stability and the phenomemon of mucoadhesion. Two drugs relevant to vaginal administration, progesterone and tenofovir disoproxil fumarate are investigated for use in the thermoreversible gelators, studying both hydrophobic and hydrophilic drug solubilisation and release. Throughout the study, comparison is made with poloxamer 407, the most commonly studied thermoreversible gelator. PNIPAM98-PEG122-PNIPAM98 exhibits several advantages for topical drug delivery, having low viscosity at room temperature to allow easy application, then exhibiting a gelation just below body temperature to form a viscous gel which is resistant to dissolution and relatively mucoadhesive. Drug release is highly dependent on temperature, with elevation to body temperature resulting in a dramatic retardation of progesterone release, which may be used in future medicines to provide sustained delivery of hydrophobic xenobiotics.Peer reviewedFinal Accepted Versio

Polymers exhibiting lower critical solution temperatures as a route to thermoreversible gelators for healthcare

Funding Information: M.T.C. acknowledges support from the EPSRC (EP/T00813X/1). The University of Hertfordshire are thanked for funding the research project of P.H. Publisher Copyright: © 2020 The Authors. Advanced Functional Materials published by Wiley-VCH GmbHThe ability to trigger changes to material properties with external stimuli, so-called “smart” behavior, has enabled novel technologies for a wide range of healthcare applications. Response to small changes in temperature is particularly attractive, where material transformations may be triggered by contact with the human body. Thermoreversible gelators are materials where warming triggers reversible phase change from low viscosity polymer solution to a gel state. These systems can be generated by the exploitation of macromolecules with lower critical solution temperatures included in their architectures. The resultant materials are attractive for topical and mucosal drug delivery, as well as for injectables. In addition, the materials are attractive for tissue engineering and 3D printing. The fundamental science underpinning these systems is described, along with progress in each class of material and their applications. Significant opportunities exist in the fundamental understanding of how polymer chemistry and nanoscience describe the performance of these systems and guide the rational design of novel systems. Furthermore, barriers to translating technologies must be addressed, for example, rigorous toxicological evaluation is rarely conducted. As such, applications remain tied to narrow fields, and advancements will be made where the existing knowledge in these areas may be applied to novel problems of science.Peer reviewe

Elemental fingerprinting of Hypericum perforatum (St John's Wort) herb and preparations using ICP-OES and chemometrics

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Journal of Pharmaceutical and Biomedical Analysis following peer review. The version of record [Journal of Pharmaceutical and Biomedical Analysis (June 2016) Vol 125 pp 15-21, first published online March 4, 2016] is available online at doi: http://dx.doi.org/10.1016/j.jpba.2016.02.054 © 2016 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/St. John's wort (SJW) (Hypericum perforatum) is a herbal remedy commonly used to treat mild depression. The elemental profiles of 54 samples (i.e., dry herbs, tablets and capsules) were evaluated by monitoring 25 elements using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES). The major elemental constituents in the SJW samples were Ca (300-199,000 μg/g), Mg (410-3,530 μg/g), Al (4.4-900 μg/g), Fe (1.154-760 μg/g), Mn (2.4-261 μg/g), Sr (0.88-83.6 μg/g), and Zn (7-64 μg/g). For the sixteen elements that could be reliably quantified, principal component analysis (PCA) was used to investigate underlying patterns in the data. PCA models identified 7 key elements (i.e., Ba, Ca, Cd, Mg, Mo, Ni and Y), which described 85% of the variance in the dataset in the first three principal components. The PCA approach resulted in a general delineation between the three different formulations and provides a basis for monitoring product quality in this manner.Peer reviewe

Establishing the importance of oil-membrane interactions on the transmembrane diffusion of physicochemically diverse compounds

© 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This is a pre-copyedited, author produced PDF of an article accepted for publication in International Journal of Phrmaceutics following peer review. The final, definitive version of this paper Vol 56 (1-2): 429-437 , first published online March 21, 2016, is available on line at doi: 10.1016/j.ijpharm.2016.03.020The diffusion process through a non-porous barrier membrane depends on the properties of the drug, vehicle and membrane. The aim of the current study was to investigate whether a series of oily vehicles might have the potential to interact to varying degrees with synthetic membranes and to determine whether any such interaction might affect the permeation of co-formulated permeants: methylparaben (MP); butylparaben (BP) or caffeine (CF). The oils (isopropyl myristate (IPM), isohexadecane (IHD), hexadecane (HD), oleic acid (OA) and liquid paraffin (LP)) and membranes (silicone, high density polyethylene and polyurethane) employed in the study were selected such that they displayed a range of different structural, and physicochemical properties. Diffusion studies showed that many of the vehicles were not inert and did interact with the membranes resulting in a modification of the permeants’ flux when corrected for membrane thickness (e.g. normalized flux of MP increased from 1.25 ± 0.13 μg cm−1 h−1 in LP to 17.94 ± 0.25 μg cm−1 h−1in IPM). The oils were sorbed differently to membranes (range of weight gain: 2.2 ± 0.2% for polyurethane with LP to 105.6 ± 1.1% for silicone with IHD). Membrane interaction was apparently dependent upon the physicochemical properties including; size, shape, flexibility and the Hansen solubility parameter values of both the membranes and oils. Sorbed oils resulted in modified permeant diffusion through the membranes. No simple correlation was found to exist between the Hansen solubility parameters of the oils or swelling of the membrane and the normalized fluxes of the three compounds investigated. More sophisticated modelling would appear to be required to delineate and quantify the key molecular parameters of membrane, permeant and vehicle compatibility and their interactions of relevance to membrane permeation.Peer reviewe

A Design-of-Experiments Approach to Developing Thermoresponsive Gelators From Complex Polymer Mixtures

© 2020 Royal Society of Chemistry. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1039/D0ME00093K.This study investigated the effects of additives on the properties of poloxamer (P) 407 thermogels, employing a design-of-experiments (DoE) approach. P407 is a thermoresponsive triblock copolymer that exhibits a solution to gel transition at a critical temperature, typically between 15-25 °C, dependant on polymer concentration. This thermoresponsive gelation has made P407 attractive for many applications including drug delivery, cell culture and tissue engineering. However, the gels formed do not have sufficient strength for some applications where the materials will be exposed to shear, such as topical drug delivery. There have been attempts to improve P407 thermogel properties by the addition of other hydrophilic polymers. However, these studies were limited to a small number of polymers, typically in binary mixtures, exploring one variable at a time. In this study, a DoE approach was carried out using a two-level model exploring P407, P188, poly(vinyl alcohol), poly(ethylene glycol), and poly(acrylic acid) as variables, including an exploration of molecular weight of the latter three additives. The variables were given two different levels (concentrations) to generate a total of 16 training formulations. The thermoresponsive gelation of these 16 formulations was studied by rheometry and predictive models built for gel strength (G’) and gelation temperature (Tgel) responses. The model was able to predict the thermoresponsive gelation of complex octonary test blends, significantly streamlining formulation development processes relative to current methods. The model was then able to identify novel thermoresponsive gel formulations with 20 % improved gel strength compared to a standard 20 % P407 solution, which may be used as temperature-responsive materials for advanced healthcare applications.Peer reviewe

A drug-incorporated-microparticle-eggshell-membrane-scaffold (DIMES) dressing: a novel biomaterial for localised wound regeneration

Chronic wounds affect millions of people annually and have emotional and financial Implications in addition to health issues. The current treatment for chronic wounds involves the repeated use of bandages and drugs such as antibiotics over an extended period. A cost-effective and convenient solution for wound healing is the development of drug-incorporated bandages. This study aimed to develop a biocompatible bandage made of drug-incorporated poly (lactic-co-glycolic acid) (PLGA) microparticles (MPs) and eggshell membrane (ESM) for cornea wound healing. ESM has desirable properties for wound healing and can be isolated from eggshells using acetic acid or ethylenediaminetetraacetic acid (EDTA) protocols. Fluorescein isothiocyanate-labelled Bovine Serum Albumin (FITC-BSA) was used as a model drug, and the PLGA MPs were fabricated using a solvent extraction method. The MPs were successfully attached to the fibrous layer of the ESM using NaOH. The surface features of the ESM samples containing MPs were studied using a field emission scanning electron microscope (FESEM) and compared with blank ESM images. The findings indicated that the MPs were attached to the ESM fibres and had similar shapes and sizes as the control MPs. The fibre diameters of the MPs samples were assessed using Fiji-ImageJ software, and no significant changes were observed compared to the blank ESM. The surface roughness, Ra values, of the MPs incorporated ESM samples were evaluated and compared to the blank ESM, and no significant changes were found. Fourier transform infrared (FTIR) spectroscopy was used to analyse the chemical Composition of the bandage, and the spectra showed that the FBM were effectively incorporated into the ESM. The FTIR spectra identified the major peaks of the natural ESM and the PLGA polymer in the bandage. The bandage was transparent but had a reduced visibility in the waterproof test card method. The bandage achieved sustained drug release up to 10 days and was found to be biocompatible and non-toxic in a chorioallantoic membrane (CAM) assay. Overall, the drug-incorporated PLGA MPs-ESM bandage has great potential for treating chronic wounds

Survey of knowledge of legal highs (novel psychoactive substances) amongst London pharmacists

Purpose – The purpose of this paper is to determine pharmacists’ knowledge of legal highs (novel psychoactive substances (NPS)). Design/methodology/approach – A questionnaire was handed out at two London pharmacist continuing education events in mid-2014. These events update pharmacists about developments of interest/relevance to the profession and to improve their practice. A total of 54 forms were returned; a response rate of 26 percent. Findings – Most pharmacists had poor knowledge of NPS and many considered that NPS were not important to their work, with few having had to advise customers in this area. Despite this, the majority thought that they had insufficient information about NPS. There was a negative correlation between the age of the pharmacist and knowledge of NPS. Research limitations/implications – The sample is a self-selected one drawn from registered pharmacists working in community pharmacies in northwest London, and thus does not include hospital pharmacies. Self-selection means that respondents may only reflect those who are interested in the NPS phenomenon and not the wider pharmacy community. The geographical area covered may not be representative of London as a whole, or indeed other parts of the UK or other EU countries. Practical implications – It is clear that pharmacists do not know much about NPS but would like to know more. This information might improve their practice. Social implications – Pharmacists, easier to see than general practitioners, could be a useful source of information for NPS misusers. Originality/value – There have been no previous attempts to gauge the level of knowledge by pharmacists of legal highs/NPS in the UK or elsewhere to our knowledge