Pharmacology and Pharmaceutics

PIs: Professor Gary Hix and Dr Iain D. Nicholl

We previously generated a panel of variants of aspirin in order to identify the chemical moieties that provide toxicity against colorectal cancer cells, and identified compounds that are significantly more toxic to colorectal cancer (CRC) cells than aspirin, yet appear to retain a degree of specificity for CRC cells in vitro, and have the capacity to induce programmed cell death in cancer cells.  In addition, the compounds diaspirin and fumaryldiaspirin significantly suppressed tumour growth in vivo in the non-cachectic MAC13 mouse model of colorectal cancer with no apparent toxicity to the animal. Recently we have discovered that aspirin and aspirin analogues have the potential to synergise with platins, mainstays of chemotherapy. We wish to extend these findings and synthesise organometallic compounds based on aspirin, “diaspirins” and platinum group metals, bringing together the benefits of NSAIDs and platin-like moieties in a single drug molecule, to examine their potential as chemotherapeutic agents.  

Proposed Research 

1. Investigation into the synergistic interaction of platins with NSAIDs 
2. Development of novel metal derivatives of NSAIDS (including diaspirins)  
3. Evaluation of the stability and performance of novel compounds using cytotoxicity assays and testing lead compounds against the NCI-60 Human Tumor Cell Lines at the NIH National Cancer Institute Developmental Therapeutics programme. 

The research commenced in 2020 under the supervision of Professor Gary Hix and Dr Iain D. Nicholl at the School of Sciences with collaboration from Mr Joe Astley (Research Associate; SIRC) and colleagues from the Science Park, University of Wolverhampton. The research is funded being by ERDF via the SIRC based at the University of Wolverhampton. 

Relevant Publications 

• Claudius, A.K., Kankipati, C.S., Kilari, R.S., Hassan, S., Guest, K., Russel, S.T., Perry, C.J., Stark, L.A. and Nicholl, I.D. (2014) Identification of aspirin analogues that repress NF-kB signalling and demonstrate anti‐proliferative activity towards colorectal cancer in vitro and in vivo. Oncol Rep, 32, pp. 1670-1680. 
• Bashir, A.I.J., Kankipati, C.S., Jones, S., Newman, R.M., Safrany, S.T., Perry, C.J., and I.D. Nicholl. (2019) A novel mechanism for the anti-cancer activity of aspirin and salicylates. Int. J. Oncology 54: 1256-1270, 2019 DOI: 10.3892/ijo.2019.4701. 

PI: Dr Waseem Kaialy

Tablets are the most common pharmaceutical dosage forms due to advantageous characteristics such as ease of administration, precise dosing, and good physicochemical stability.

Direct compression is a modern, favoured method in tablet manufacturing that is continuously growing.  Fewer processing stages leads to increased productivity and cost reduction and the removal of heat and moisture effects makes it an appropriate process for hygroscopic and thermo-sensitive pharmaceuticals. Many direct compressible vehicles have been introduced with many more under development for better performance and/or lower costs. However, unfortunately, less than 20% of pharmaceutical powders can be compressed into tablets by direct compression due to their inherent poor functional properties, such as flowability, compressibility, homogeneity, lubricating properties, and disintegration.

Additionally, several potentially promising drug candidates have failed as pharmaceutical products due to their poor solubility in gastrointestinal fluid, poor dissolution in gastrointestinal tract and thus poor oral bioavailability. Many modern drugs also have poor water solubility and dissolution properties, causing several difficulties in the development of tablet dosage forms with adequate bioavailability following oral administration.

In this research, supported by the ‘Petroleum Technology Development Fund’, we are employing various particle engineering techniques to overcome the poor physicochemical, mechanical and dissolution properties of various challenging drugs.

PI: Professor John Howl

The MCRC is developing STOPSPERM bioportide technologies to inhibit sperm motility as a novel male contraceptive modality. The consortium, comprising complementary teams in the UK and Portugal, has identified several lead compounds and is now seeking to develop these towards a clinically useful formulation. Partners can become involved in the project through the routes of sponsorship, research collaboration and various partnering opportunities.

https://www.wlv.ac.uk/research/male-contractive-research-consortium-/ 

PI: Dr Bernice Wright

Our research is focussed on the discovery and bio-manufacturing of therapeutically significant cell secretome components (i.e. soluble proteins, metabolites, extracellular vesicles). Secreted proteins and exosomes are currently major developing business models for a number of biopharmaceutical companies including AstraZeneca and MedImmune (secretome therapeutics), ReNeuron (exosome therapeutics), and Codiak (exosome drug delivery vectors).  One of the key objectives of the research programme currently underway at University of Wolverhampton is to address the bottleneck for industrial processing and packaging of secretome products by devising novel bioprocessing technologies. The work programme involves construction and rapid prototyping of innovative bioreactor systems for scaled up production of soluble protein and exosome products secreted from human cells, with a focus on manufacturing skeletal myoblast secretome biologics for the treatment of arthritis

The research is supported by a multidisciplinary team of collaborators including additive layer manufacturing engineers (Dr Arun Arjunan, University of Wolverhampton); bioengineers (Professor Daniel Bracewell, Professor Gary Lye, University College London);  and biomaterials scientists (Dr Paul de Bank,  University of Bath) and  funding from the Biochemical Society Eric Reid Methodology Fund; the Dowager Countess Eleanor Peel Trust Medical Grant; and a PhD studentship funded by the European Regional Development Fund.

PIs: Professor John Howl and Dr Sarah Jones

One or more cationic helices are often located at the sites of protein-protein interactions (PPIs). Similar sequences (~ 10-18 AA) are also excellent cell penetrating peptides (CPPs). Hence, proteomimetic CPPs, derived from PPIs, may act by a dominant-negative mechanism to interfere with critical cell signalling events. We have introduced the term bioportide to describe this novel genre of bioactive CPP.

One validated target for bioportide technologies is the planarian neoblast. These totipotent stem cells control the remarkable regenerative capacity of our model organism Schmidtea meditteranea.  When exogenously applied to decapitated specimens of S. meditteranea, bioportides mimicking key proteins involved in this unique process, inhibit the usual rapid regeneration of head and eyes. We will expand these studies to include other stem cell systems in which it is prudent to manipulate stem cell function in development and oncology.

Recent Publications: 

• Jones, S., Osman, S. & Howl, J. (2019) The planarian Schmidtea mediterranea as a model system for the discovery and characterization of cell penetrating peptides and bioportides. Chem. Biol. Drug Des. 93, 1036-1049.

PI: Dr Opelou Ojo

The link between the pathogenesis of Parkinson’s disease (PD) and mechanisms underlying insulin resistance has been reported. Over the past few years, studies indicate that elevated glucose concentrations can damage blood vessel in the brain and significantly increase the risk of stroke and other neurodegenerative diseases. It has been further indicated that elevated blood glucose levels and reduced insulin sensitivity can significantly contribute to inflammation in the brain and impaired neuronal processes. Unfortunately, available PD pharmacotherapies lack the capacity to prevent neurodegenerative processes and have undesirable side effects.  Our efforts are currently dedicated to the characterization of the beneficial effects of several agents used in the treatment of type 2 diabetes in cellular and animal models of PD.

Ongoing studies in our laboratory focus on the investigation of anti-oxidative, anti-inflammatory and neuroprotective effects of a selection of native and structurally modified amphibian skin peptides with incretin-like actions. These studies particularly aim at investigating how these agents could prevent diabetes-related oxidative stress and vascular damage leading to the development of PD as well as their effects on the defective expression of key biomarkers of PD (such as alpha synuclein). These studies are also taking the advantage of the versatility, affordability and genetic toolkit offered by Drosophila melanogaster to study beneficial effects and mechanisms underlying actions of selected native and structurally modified peptides in PD.

These studies are conducted in collaboration with Professor Ilar Davies, University of Oxford and Dr Amos Abolaji, University of Ibadan, Nigeria.

PI: Dr Opelou Ojo

Despite improvements in type 2 diabetes (T2D) therapy, substantial mortality (even in optimally treated patients) still exits. The need for novel/more effective therapeutic strategies to combat the disease is therefore clear. Our approach aims at the isolation and characterization of novel antidiabetic agents from natural sources, design of hybrid peptides and novel analogues of endogenous and exogenous peptides with the ability to stimulate insulin secretion; enhance insulin sensitivity and/or facilitate improved glucose uptake. The focus of this research is on the elucidation of the sites and mode of actions of these novel antidiabetic agents, as well as their potential therapeutic roles in correcting metabolic problems characterising type 2 diabetes.

Ongoing studies under this theme include:

1. Investigations of targets and mechanisms of action of novel amphibian skin peptides with insulin-releasing or glucose-lowering properties
2. Structural modification of endogenous and exogenous peptides, and characterization of their antidiabetic effects
3. Investigation of insulin-releasing and glucose-lowering effects of extracts of edible plants

These studies are conducted in collaboration with Dr Simon Dunmore, University of Wolverhampton; Professor Peter Flatt, University of Ulster; and the Bioscience Research Education and Advisory Centre, Nigeria.

Recent Publications:

• Anyanwu, G.O., Iqbal, J., Khan, S.U., Zaib, S., Rauf, K., Onyeneke, C.E. and Ojo, O.O., 2019. Antidiabetic activities of chloroform fraction of Anthocleista vogelii Planch root bark in rats with diet-and alloxan-induced obesity-diabetes. Journal of ethnopharmacology, 229, pp.293-302.
• Ojo, O.O., Srinivasan, D.K., Owolabi, B.O., McGahon, M.K., Moffett, R.C., Curtis, T.M., Conlon, J.M., Flatt, P.R. and Abdel-Wahab, Y.H., 2016. Molecular mechanisms mediating the beneficial metabolic effects of [Arg4] tigerinin-1R in mice with diet-induced obesity and insulin resistance. Biological chemistry, 397(8), pp.753-764.

PI: Dr Ayman Antoun Reyad

In this research, we aim to evaluate the efficacy and safety of new atypical antipsychotic medications such as cariprazine and brexpiprazole in the management of schizophrenia and bipolar disorders. Through collaboration with Dr R Mishriky,  Consultant Psychiatrist, Birmingham and Solihull Mental Health Trust and Prof G. Tadros, Consultant Psychiatrist, ACPN, we are evaluating the evidence regarding these new medications for their efficacy and tolerability using psychiatric scales such as Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity of Illness Score (CGI-S), Young Mania Rating Scale (YMRS), Montgomery Asberg depression rating scale (MADRS) and Hamilton rating scale for depression (HAM-D), while highlighting the side effects associated with their use in the management of psychiatric conditions.

Recent Publications:

• Antoun Reyad A, Girgis E, Mishriky R (2020) Efficacy and safety of brexpiprazole in acute management of psychiatric disorders: a meta-analysis of randomized controlled trials. International Clinical Psychopharmacology, 35(3):119-128
• Cooper H, Mishriky R and Antoun Reyad A (2020) Efficacy and safety of cariprazine in acute management of psychiatric disorders: a meta-analysis of randomized controlled trials. Psychiatria Danubina, 2020, 32(1):36-45.

PI: Professor Weiguang Wang

The clinical need for anticancer drugs is urgent but their development is a time (15 years) and cash ($1.5 billon) consuming procedure. Drug repositioning is an effective strategy for drug development. 

Disulfiram is an anti-alcoholism drug used clinically for over 6 decades. The Experimental Cancer Therapeutic Group (ECTG) demonstrated that Disulfiram has very strong anticancer activity in the laboratory. However, the very short half-life of Disulfiram in the blood stream is the bottleneck for translation into cancer treatment, leading to the failure of many clinical trials. We have successfully used nanotechnology (liposome and PLGA) to protect Disulfiram in the blood stream and deliver it to cancer tissues. The new formulations of Disulfiram demonstrated very strong anticancer activity in animal cancer models. This project has led to filing patents (EP2648709B1, US10695299) and based on these IPRs, the University of Wolverhampton set up a spin-out company, Disulfican Ltd.

The ECTG has an extensive collaborative network in the UK, USA, EU and China, including

Dr Angel Armesilla; Professor Patrick Ball; Professor Supratik Basu; Dr Daniel Keddie; Dr Mark Morris; Dr Hana Morrissey; and Professor Tracy Warr at University of Wolverhampton

Dr James Brown (Aston University); Professor Bin He (Sichuan University); Professor Christopher Heeschen (Jiaotong University); Professor Jean-Philippe Hugnot (Montpellier University);  Professor Juan Irache (University of Navarra);Professor Wenguo Jiang (Cardiff University); Dr Chris MacConville (University of Birmingham); Dr Mohammad Najlah (Anglia Ruskin University); Professor Yaohe Wang (Queen Mary University of London); Professor Bing Xu (Xiamen University).

The research is supported by a Innovate UK and Jiangsu Science and Technology Department grant “Formulation and testing of PLGA-DS as an anti-cancer therapy for FDA and EMA new drug application.” 2018 – 2020 (98996-572202); Professor Weiguang Wang, Prof Andrew Pollard, Prof Bin He; £645,000

Recent Publications:

• AS Suliman, M Khoder, I Tolaymat, M Webster, RG Alany, W Wang, A Elhissi and M Najlah. Cyclodextrin Diethyldithiocarbamate Copper II Inclusion Complexes: A Promising Chemotherapeutic Delivery System against Chemoresistant Triple Negative Breast Cancer Cell Lines. Pharmaceutics 2021; 13:84
• M Najlah, AS Suliman, I Tolaymat, S Kurusamy, V Kannappan, AMA Elhissi and W Wang. Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment. Pharmaceutics 2019; 11:610
• Najlah M, Ahmed Z, Iqbal M, Wang Z, Tawari P, Wang W, McConville. Development and characterisation of disulfiram-loaded PLGA nanoparticles for the treatment of non-small cell lung cancer. Eur J Pharm Biopharm. 2016; 112:224-33
• Wang Z,Tan J, McConville C, Kannappan V, Tawari PE, Brown J, Ding J, Armesilla AL, Irache JM, Mei QB, Tan Y, Liu Y, Jiang W, Bian X, Wang W. Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells. Nanomedicine 2017; 13:641-57