Publications by authors named "Valerie A Ferro"

68 Publications

Functionalisation of Inorganic Material Surfaces with Staphylococcus Protein A: A Molecular Dynamics Study.

Int J Mol Sci 2022 Apr 27;23(9). Epub 2022 Apr 27.

Department of Chemical and Process Engineering, University of Strathclyde, 75 Montrose Street, Glasgow G1 1XJ, UK.

Staphylococcus protein A (SpA) is found in the cell wall of bacteria. Its ability to bind to the constant Fc regions of antibodies means it is useful for antibody extraction, and further integration with inorganic materials can lead to the development of diagnostics and therapeutics. We have investigated the adsorption of SpA on inorganic surface models such as experimentally relevant negatively charged silica, as well as positively charged and neutral surfaces, by use of fully atomistic molecular dynamics simulations. We have found that SpA, which is itself negatively charged at pH7, is able to adsorb on all our surface models. However, adsorption on charged surfaces is more specific in terms of protein orientation compared to a neutral Au (111) surface, while the protein structure is generally well maintained in all cases. The results indicate that SpA adsorption is optimal on the siloxide-rich silica surface, which is negative at pH7 since this keeps the Fc binding regions free to interact with other species in solution. Due to the dominant role of electrostatics, the results are transferable to other inorganic materials and pave the way for new diagnostic and therapeutic designs where SpA might be used to conjugate antibodies to nanoparticles.
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http://dx.doi.org/10.3390/ijms23094832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103475PMC
April 2022

Editorial: Ethnopharmacological Strategies for Drug Discovery Against African Neglected Diseases.

Front Pharmacol 2022 21;13:851064. Epub 2022 Apr 21.

Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, United Kingdom.

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http://dx.doi.org/10.3389/fphar.2022.851064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9068890PMC
April 2022

The Antiprotozoal Activity of Papua New Guinea Propolis and Its Triterpenes.

Molecules 2022 Mar 1;27(5). Epub 2022 Mar 1.

Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.

Profiling a propolis sample from Papua New Guinea (PNG) using high-resolution mass spectrometry indicated that it contained several triterpenoids. Further fractionation by column chromatography and medium-pressure liquid chromatography (MPLC) followed by nuclear magnetic resonance spectroscopy (NMR) identified 12 triterpenoids. Five of these were obtained pure and the others as mixtures of two or three compounds. The compounds identified were: mangiferonic acid, ambonic acid, isomangiferolic acid, ambolic acid, 27-hydroxyisomangiferolic acid, cycloartenol, cycloeucalenol, 24-methylenecycloartenol, 20-hydroxybetulin, betulin, betulinic acid and madecassic acid. The fractions from the propolis and the purified compounds were tested in vitro against , , drug-resistant and multidrug-resistant (B48). They were also assayed for their toxicity against U947 cells. The compounds and fractions displayed moderate to high activity against parasitic protozoa but only low cytotoxicity against the mammalian cells. The most active isolated compound, 20-hydroxybetulin, was found to be trypanostatic when different concentrations were tested against growth.
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http://dx.doi.org/10.3390/molecules27051622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911803PMC
March 2022

Limited Impact of the Protein Corona on the Cellular Uptake of PEGylated Zein Micelles by Melanoma Cancer Cells.

Pharmaceutics 2022 Feb 18;14(2). Epub 2022 Feb 18.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.

The formation of a protein layer "corona" on the nanoparticle surface upon entry into a biological environment was shown to strongly influence the interactions with cells, especially affecting the uptake of nanomedicines. In this work, we present the impact of the protein corona on the uptake of PEGylated zein micelles by cancer cells, macrophages, and dendritic cells. Zein was successfully conjugated with poly(ethylene glycol) (PEG) of varying chain lengths (5K and 10K) and assembled into micelles. Our results demonstrate that PEGylation conferred stealth effects to the zein micelles. The presence of human plasma did not impact the uptake levels of the micelles by melanoma cancer cells, regardless of the PEG chain length used. In contrast, it decreased the uptake by macrophages and dendritic cells. These results therefore make PEGylated zein micelles promising as potential drug delivery systems for cancer therapy.
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http://dx.doi.org/10.3390/pharmaceutics14020439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877401PMC
February 2022

Mucosal and systemic immune responses following mucosal immunisation of tetanus toxoid entrapped in lipid nanoparticles prepared by microwave reactor.

Eur J Pharm Biopharm 2022 Feb 4;171:11-18. Epub 2022 Jan 4.

University of Strathclyde, Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, Glasgow G4 0NR, United Kingdom.

In this study, the use of a microwave reactor, which allowed high input of energy into a pressurised system in a short period of time, was investigated for preparation of lipid nanoparticles (LNPs). The aim was to optimise the formulation process by reducing manufacturing time. Two types of LNPs were prepared; non-ionic surfactant vesicles (NISV) and bilosomes (modified NISV incorporating bile salts), with a model antigen (tetanus toxoid, TT) and the immune response induced after mucosal (nasal and oral, respectively) administration was assessed. The TT loaded LNPs were characterised in terms of particle size, size distribution, morphology, and entrapment efficiency. Immunisation was evaluated by lethal challenge with tetanus toxin in an animal model. The efficiency of vaccination was evaluated by measuring the anti-TT IgG antibody levels in the vaccinated animals. Bilosomes formed by this method showed an immunogen entrapment efficiency of ∼30% which was significantly (p < 0.05) higher than entrapment efficiency in the NISV. The percentage of animals that survived when challenged with tetanus toxin correlated with the level of IgG determined in the serum of mice immunised with LNPs by the mucosal route. Moreover, there were significant (p < 0.05) differences between orally and nasally immunised groups. Animal groups immunised bilosomes via the oral route showed the highest level of IgG (1.2 ± 0.13) compared to the positive control, LN + Xn, and no immunised group. Similarly, groups immunised via the nasal route showed significantly (p < 0.0001) higher titres compared with the control group. Mucosal TT was capable of inducing systemic specific IgG anti-TT responses that were higher than the parenteral vaccine.
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http://dx.doi.org/10.1016/j.ejpb.2021.12.014DOI Listing
February 2022

Potentiality of Melittin-Loaded Niosomal Vesicles Against Vancomycin-Intermediate and Staphylococcal Skin Infection.

Int J Nanomedicine 2021 16;16:7639-7661. Epub 2021 Nov 16.

Division of Clinical Microbiology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.

Background: is an important human pathogen, especially causing skin and soft tissue infections (SSTIs). Over the decades, the infections caused by antibiotic-resistant strains have often become life-threatening. Consequently, exploration and development of competent approaches to combat these serious circumstances are urgently required.

Methods: The antibacterial activity of melittin (Mel) on , methicillin-resistant (MRSA) and clinical isolates of vancomycin-intermediate (VISA) was investigated by minimum inhibitory concentration (MIC) and time-killing assays. The localization of Mel on the bacterial cell was visualized by confocal laser scanning microscopy and its effect on the membrane was indicated based on propidium iodide uptake. The non-ionic surfactant vesicle (NISV) or niosome nanocarrier was established for Mel loading (Mel-loaded NISV) by the thin-film hydration method. Physicochemical and in vitro biological properties of Mel-loaded NISVs were characterized. The cellular uptake of Mel-loaded NISVs was evaluated by holotomography analysis. In addition, an ex vivo study was conducted on a porcine ear skin model to assess the permeation ability of Mel-loaded NISVs and their potential to inhibit bacterial skin infection.

Results: The effective inhibitory activity of Mel on skin pathogens was demonstrated. Among the tested strains, VISA was most susceptible to Mel. Regarding to its function, Mel targeted the bacterial cell envelope and disrupted cell membrane integrity. Mel-loaded NISVs were successfully fabricated with a nano-size of 120-200 nm and entrapment efficiency of greater than 90%. Moreover, Mel-loaded NISVs were taken up and accumulated in the intracellular space. Meanwhile, Mel was released and distributed throughout the cytosol and nucleus. Mel-loaded NISVs efficiently inhibited the growth of bacteria, particularly MRSA and VISA. Importantly, they not only penetrated epidermal and dermal skin layers, but also reduced the bacterial growth in infected skin.

Conclusion: Mel-loaded NISVs have a great potential to exhibit antibacterial activity. Therapeutic application of Mel-loaded NISVs could be further developed as an alternative platform for the treatment of skin infection via dermal and transdermal delivery.
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http://dx.doi.org/10.2147/IJN.S325901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606986PMC
November 2021

Multiple myeloma: therapeutic delivery of antibodies and aptamers.

Ther Deliv 2021 10 27;12(10):705-722. Epub 2021 Sep 27.

Department of Chemical Engineering, University of Strathclyde, Glasgow, G1 1XL, UK.

Multiple myeloma is the second most common hematological malignancy in adults, accounting for 2% of all cancer-related deaths in the UK. Current chemotherapy-based regimes are insufficient, as most patients relapse and develop therapy resistance. This review focuses on current novel antibody- and aptamer-based therapies aiming to overcome current therapy limitations, as well as their respective limitations and areas of improvement. The use of computer modeling methods, as a tool to study and improve ligand-receptor alignments for the use of novel therapy development will also be discussed, as it has become a rapid, reliable and comparatively inexpensive method of investigation.
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http://dx.doi.org/10.4155/tde-2021-0041DOI Listing
October 2021

Biomolecular interactions with nanoparticles: applications for coronavirus disease 2019.

Curr Opin Colloid Interface Sci 2021 Aug 23;54:101461. Epub 2021 Apr 23.

Department of Chemical and Process Engineering, University of Strathclyde, 75 Montrose Street, Glasgow, G1 1XJ, UK.

Nanoparticles are small particles sized 1-100 nm, which have a large surface-to-volume ratio, allowing efficient adsorption of drugs, proteins, and other chemical compounds. Consequently, functionalized nanoparticles have potential diagnostic and therapeutic applications. A variety of nanoparticles have been studied, including those constructed from inorganic materials, biopolymers, and lipids. In this review, we focus on recent work targeting the severe acute respiratory syndrome coronavirus 2 virus that causes coronavirus disease (COVID-19). Understanding the interactions between coronavirus-specific proteins (such as the spike protein and its host cell receptor angiotensin-converting enzyme 2) with different nanoparticles paves the way to the development of new therapeutics and diagnostics that are urgently needed for the fight against COVID-19, and indeed for related future viral threats that may emerge.
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http://dx.doi.org/10.1016/j.cocis.2021.101461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062422PMC
August 2021

Structural Analysis of Anti-Hapten Antibodies to Identify Long-Range Structural Movements Induced by Hapten Binding.

Front Mol Biosci 2021 24;8:633526. Epub 2021 Mar 24.

Department of Chemical and Process Engineering, University of Strathclyde, Glasgow, United Kingdom.

Antibodies are well known for their high specificity that has enabled them to be of significant use in both therapeutic and diagnostic applications. Antibodies can recognize different antigens, including proteins, carbohydrates, peptides, nucleic acids, lipids, and small molecular weight haptens that are abundantly available as hormones, pharmaceuticals, and pesticides. Here we focus on a structural analysis of hapten-antibody couples and identify potential structural movements originating from the hapten binding by comparison with unbound antibody, utilizing 40 crystal structures from the Protein Data Bank. Our analysis reveals three binding surface trends; S1 where a pocket forms to accommodate the hapten, S2 where a pocket is removed when the hapten binds, and S3 where no pockets changes are found. S1 and S2 are expected for induced-fit binding, whereas S3 indicates that a pre-existing population of optimal binding antibody conformation exists. The structural analysis reveals four classifications of structural reorganization, some of which correlate to S2 but not to the other binding surface changes. These observations demonstrate the complexity of the antibody-antigen interaction, where structural changes can be restricted to the binding sites, or extend through the constant domains to propagate structural changes. This highlights the importance of structural analysis to ensure successful and compatible transformation of small antibody fragments at the early discovery stage into full antibodies during the subsequent development stages, where long-range structural changes are required for an Fc effector response.
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http://dx.doi.org/10.3389/fmolb.2021.633526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044860PMC
March 2021

siRNA Delivery to Melanoma Cells with Cationic Niosomes.

Methods Mol Biol 2021 ;2265:621-634

Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, UK.

RNA interference (RNAi) is a posttranscriptional regulatory mechanism that employs siRNA. It typically results in the degradation of a target mRNA that encodes a particular protein. Treatment with siRNA therapeutics requires the use of an effective drug delivery system to assist in delivering these therapeutics into the cytoplasm of the transfected cells. Here we describe the transfection of melanoma cancer cells with siRNA using cationic niosome nanoparticles as a delivery system. The method of niosome preparation is first introduced and is followed by complex formation with siRNA and the transfection method.
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http://dx.doi.org/10.1007/978-1-0716-1205-7_42DOI Listing
April 2021

Use of Nanoparticles in Delivery of Nucleic Acids for Melanoma Treatment.

Methods Mol Biol 2021 ;2265:591-620

Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, UK.

Melanoma accounts for 4% of all skin cancer malignancies, with only 14% of diagnosed patients surviving for more than 5 years after diagnosis. Until now, there is no clear understanding of the detailed molecular contributors of melanoma pathogenesis. Accordingly, more research is needed to understand melanoma development and prognosis.All the treatment approaches that are currently applied have several significant limitations that prevent effective use in melanoma. One major limitation in the treatment of cancer is the acquisition of multidrug resistance (MDR). The MDR results in significant treatment failure and poor clinical outcomes in several cancers, including skin cancer. Treatment of melanoma is especially retarded by MDR. Despite the current advances in targeted and immune-mediated therapy, treatment arms of melanoma are severely limited and stand as a significant clinical challenge. Further, the poor pharmacokinetic profile of currently used chemotherapeutic agents is another reason for treatment failure. Therefore, more research is needed to develop novel drugs and carrier tools for more effective and targeted treatment.Nucleic acid therapy is based on nucleic acids or chemical compounds that are closely related, such as antisense oligonucleotides, aptamers, and small-interfering RNAs that are usually used in situations when a specific gene implicated in a disorder is deemed a therapeutically beneficial target for inhibition. However, the proper application for nucleic acid therapies is hampered by the development of an effective delivery system that can maintain their stability in the systemic circulation and enhance their uptake by the target cells. In this chapter, the prognosis of the different types of melanoma along with the currently used medications is highlighted, and the different types of nucleic acids along with the currently available nanoparticle systems for delivering these nucleic acids into melanoma cells are discussed. We also discuss recently conducted research on the use of different types of nanoparticles for nucleic acid delivery into melanoma cells and highlight the most significant outcomes.
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http://dx.doi.org/10.1007/978-1-0716-1205-7_41DOI Listing
April 2021

Antitrypanosomal and Antileishmanial Activity of Chalcones and Flavanones from .

Pathogens 2021 Feb 5;10(2). Epub 2021 Feb 5.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.

Trypanosomiasis and leishmaniasis are a group of neglected parasitic diseases caused by several species of parasites belonging to the family Trypansomatida. The present study investigated the antitrypanosomal and antileishmanial activity of chalcones and flavanones from , which grows in the wetlands of Iraq. The phytochemical evaluation of the plant yielded two chalcones, 2',4'-dimethoxy-6'-hydroxychalcone and 2',5'-dimethoxy-4',6'-dihydroxychalcone, and two flavanones, 5,7-dimethoxyflavanone and 5,8-dimethoxy-7-hydroxyflavanone. The chalcones showed a good antitrypanosomal and antileishmanial activity while the flavanones were inactive. The EC values for 2',4'-dimethoxy-6'-hydroxychalcone against (0.5 μg/mL), (2.5 μg/mL), and (5.2 μg/mL) indicated it was the most active of the compounds. None of the compounds displayed any toxicity against a human cell line, even at 100 µg/mL, or cross-resistance with first line clinical trypanocides, such as diamidines and melaminophenyl arsenicals. Taken together, our study provides significant data in relation to the activity of chalcones and flavanones from against both parasites in vitro. Further future research is suggested in order to investigate the mode of action of the extracted chalcones against the parasites.
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http://dx.doi.org/10.3390/pathogens10020175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915666PMC
February 2021

Antiparasitic and Cytotoxic Activity of Bokkosin, A Novel Diterpene-Substituted Chromanyl Benzoquinone From .

Front Chem 2020 17;8:574103. Epub 2020 Nov 17.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.

is a medicinal plant growing freely in Nigeria. It is used traditionally to treat tuberculosis, as an anthelmintic and an abortifacient. Phytochemical fractionation and screening of its root extracts has yielded a novel (5-hydroxy-7-methoxy-4-oxo-1-chromanyl)-4-methoxy-p-benzoquinone (breverin)-substituted cassane diterpene, which was designated bokkosin. It was obtained from column chromatography of the ethyl acetate extract of the roots. The compound was characterized using IR, NMR (1D and 2D) and mass spectral data. Promising antiparasitic activity was observed against the kinetoplastid parasite , as well as moderate activity against and and low toxicity in mammalian cells, with the best EC values against (0.69 μg/mL against a standard laboratory strain, and its multi-drug resistant clone (0.33 μg/mL). The effect on in culture was rapid and dose-dependent, leading to apparently irreversible growth arrest and cell death after an exposure of just 2 h at 2 × or 4 × EC. The identification of bokkosin constitutes the first isolation of this class of compound from any natural source and establishes the compound as a potential trypanocide that, considering its novelty, should now be tested for activity against other microorganisms as well.
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http://dx.doi.org/10.3389/fchem.2020.574103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705231PMC
November 2020

Antibody-protein binding and conformational changes: identifying allosteric signalling pathways to engineer a better effector response.

Sci Rep 2020 08 13;10(1):13696. Epub 2020 Aug 13.

Department of Chemical and Process Engineering, University of Strathclyde, Glasgow, G1 1XJ, UK.

Numerous monoclonal antibodies have been developed successfully for the treatment of various diseases. Nevertheless, the development of biotherapeutic antibodies is complex, expensive, and time-consuming, and to facilitate this process, careful structural analysis beyond the antibody binding site is required to develop a more efficacious antibody. In this work, we focused on protein antigens, since they induce the largest antibody changes, and provide interesting cases to compare and contrast. The structures of 15 anti-protein antibodies were analysed to compare the antigen-bound/unbound forms. Surprisingly, three different classes of binding-induced changes were identified. In class (B1), the antigen binding fragment distorted significantly, and we found changes in the loop region of the heavy chain's constant domain; this corresponds well with expected allosteric movements. In class (B2), we found changes in the same loop region without the overall distortion. In class (B3), these changes did not present, and only local changes at the complementarity determining regions were found. Consequently, structural analysis of antibodies is crucial for therapeutic development. Careful evaluation of allosteric movements must be undertaken to develop better effector responses, especially during the transformation of these antibodies from small fragments at the discovery stage to full antibodies at the subsequent development stages.
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http://dx.doi.org/10.1038/s41598-020-70680-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426963PMC
August 2020

Examination of the effect of niosome preparation methods in encapsulating model antigens on the vesicle characteristics and their ability to induce immune responses.

J Liposome Res 2021 Jun 28;31(2):195-202. Epub 2020 May 28.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.

Niosome nanoparticles can be prepared using different methods, each of which can affect the size and homogeneity of the prepared particles. The aim of this study was to establish if the method of preparation impacted on the prepared vesicles when loaded with a model protein and the type of immune responses induced to the vaccine antigen. Niosomes were prepared using both the traditional thin film hydration (TFH) technique and the microfluidic mixing (MM) technique. Influenza antigen was then entrapped in the niosomes and formulations tested for their ability to induce in immune responses in immunised BALB/c mice. Niosomes prepared by MM had a mean size of 157 ± 1.8 nm and were significantly more uniform compared with the niosomes prepared using TFH (mean size 388 ± 10 nm). Niosomes play a key role as an adjuvant to help raise high antibody immune responses. This was confirmed in this study since animals treated with both types of niosomes and antigen were more responsive than unentrapped (free) antigen. Cytokine analysis showed that the TFH niosomes induced a Th1 immune response by raising IgG2a and high levels of IFN-ɣ, while the MM niosomes induced a Th2 immune response by inducing IgG1 ( < .05). These results confirmed that the method of preparation of the niosomes nanoparticles induced different immune responses and the average particle size of the niosomes differed depending on the method of manufacture. This indicates that particle size and uniformity are of importance and should be taken into consideration when designing an oral based delivery system for vaccine delivery.
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http://dx.doi.org/10.1080/08982104.2020.1768110DOI Listing
June 2021

Niosome-encapsulated balanocarpol: compound isolation, characterisation, and cytotoxicity evaluation against human breast and ovarian cancer cell lines.

Nanotechnology 2020 May 20;31(19):195101. Epub 2020 Jan 20.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan.

Natural products have been successfully used to treat various ailments since ancient times and currently several anticancer agents based on natural products are used as the main therapy to treat cancer patients, or as a complimentary treatment to chemotherapy or radiation. Balanocarpol, which is a promising natural product that has been isolated from Hopea dryobalanoides, has been studied as a potential anticancer agent but its application is limited due to its high toxicity, low water solubility, and poor bioavailability. Therefore, the aim of this study is to improve the characteristics of balanocarpol and increase its anticancer activity through its encapsulation in a bilayer structure of a lipid-based nanoparticle drug delivery system where the application of nanotechnology can help improve the limitations of balanocarpol. The compound was first extracted and isolated from H. dryobalanoides. Niosome nanoparticles composed of Span 80 (SP80) and cholesterol were formulated through an innovative microfluidic mixing method for the encapsulation and delivery of balanocarpol. The prepared particles were spherical, small, and uniform with an average particles size and polydispersity index ∼175 nm and 0.088, respectively. The encapsulation of balanocarpol into the SP80 niosomes resulted in an encapsulation efficiency of ∼40%. The niosomes formulation loaded with balanocarpol showed a superior anticancer effect over the free compound when tested in vitro on human ovarian carcinoma (A2780) and human breast carcinoma (ZR-75-1). This is the first study to report the use of SP80 niosomes for the successful encapsulation and delivery of balanocarpol into cancer cells.
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http://dx.doi.org/10.1088/1361-6528/ab6d9cDOI Listing
May 2020

Metabolomic Profiling of the Immune Stimulatory Effect of Eicosenoids on PMA-Differentiated THP-1 Cells.

Vaccines (Basel) 2019 Oct 9;7(4). Epub 2019 Oct 9.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.

Honey bee venom has been established to have significant effect in immunotherapy. In the present study, (Z)-11-eicosenol-a major constituent of bee venom, along with its derivations methyl cis-11-eicosenoate and cis-11-eicosenoic acid, were synthesised to investigate their immune stimulatory effect and possible use as vaccine adjuvants. Stimuli that prime and activate the immune system have exerted profound effects on immune cells, particularly macrophages; however, the effectiveness of bee venom constituents as immune stimulants has not yet been established. Here, the abilities of these compounds to act as pro-inflammatory stimuli were assessed, either alone or in combination with lipopolysaccharide (LPS), by examining the secretion of tumour necrosis factor-α (TNF-α) and the cytokines interleukin-1β (IL-1β), IL-6 and IL-10 by THP-1 macrophages. The compounds clearly increased the levels of IL-1β and decreased IL-10, whereas a decrease in IL-6 levels suggested a complex mechanism of action. A more in-depth profile of macrophage behaviour was therefore obtained by comprehensive untargeted metabolic profiling of the cells using liquid chromatography mass spectrometry (LC-MS) to confirm the ability of the eicosanoids to trigger the immune system. The level of 358 polar and 315 non-polar metabolites were changed significantly ( < 0.05) by all treatments. The LPS-stimulated production of most of the inflammatory metabolite biomarkers in glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, purine, pyrimidine and fatty acids metabolism were significantly enhanced by all three compounds, and particularly by methyl cis-11-eicosenoate and cis-11-eicosenoic acid. These findings support the proposed actions of (Z)-11-eicosenol, methyl cis-11-eicosenoate and cis-11-eicosenoic acid as immune system stimulators.
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http://dx.doi.org/10.3390/vaccines7040142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963534PMC
October 2019

Microfluidic manufacturing of different niosomes nanoparticles for curcumin encapsulation: Physical characteristics, encapsulation efficacy, and drug release.

Beilstein J Nanotechnol 2019 5;10:1826-1832. Epub 2019 Sep 5.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, G4 0RE Glasgow, United Kingdom.

Curcumin, a natural chemical compound found in that has been used in antitumor and anti-inflammation applications, exhibits very limited water solubility and rapid in vivo degradation, which limits its clinical application. To overcome these limitations, niosome nanoparticles were prepared by microfluidic mixing for curcumin encapsulation. Niosome nanoparticles are lipid-based, and composed of non-ionic surfactants with cholesterol orientated into a membrane bilayer structure. Two different non-ionic surfactants were used and the mixing parameters were varied to optimize the characteristics of the prepared niosomes. The prepared niosomes had an average particle size of 70-230 nm depending on the type of non-ionic surfactant used and the mixing parameter. Moreover, all prepared niosomes were monodisperse with an average polydispersity index ranging from 0.07 to 0.3. All prepared niosomes were spherical as demonstrated by transmission electron microscopy. Curcumin was encapsulated with a maximum encapsulation efficiency of around 60% using Tween 85 as the non-ionic surfactant. Niosomes prepared by microfluidic mixing provided a controlled release of curcumin, as indicated by the release profile of curcumin, improving its therapeutic capability. These results demonstrate that niosomes prepared by microfluidic mixing to encapsulate curcumin are a promising delivery system to reach target cells.
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http://dx.doi.org/10.3762/bjnano.10.177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753676PMC
September 2019

Propolis Exerts an Anti-Inflammatory Effect on PMA-Differentiated THP-1 Cells via Inhibition of Purine Nucleoside Phosphorylase.

Metabolites 2019 Apr 16;9(4). Epub 2019 Apr 16.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.

Previous research has shown that propolis has immunomodulatory activity. Propolis extracts from different geographic origins were assessed for their anti-inflammatory activities by investigating their ability to alter the production of tumour necrosis factor-α (TNF-α) and the cytokines interleukin-1β (IL-1β), IL-6 and IL-10 in THP-1-derived macrophage cells co-stimulated with lipopolysaccharide (LPS). All the propolis extracts suppressed the TNF-α and IL-6 LPS-stimulated levels. Similar suppression effects were detected for IL-1β, but the release of this cytokine was synergised by propolis samples from Ghana and Indonesia when compared with LPS. Overall, the Cameroonian propolis extract (P-C) was the most active and this was evaluated for its effects on the metabolic profile of unstimulated macrophages or macrophages activated by LPS. The levels of 81 polar metabolites were identified by liquid chromatography (LC) coupled with mass spectrometry (MS) on a ZIC-pHILIC column. LPS altered the energy, amino acid and nucleotide metabolism in THP-1 cells, and interpretation of the metabolic pathways showed that P-C reversed some of the effects of LPS. Overall, the results showed that propolis extracts exert an anti-inflammatory effect by inhibition of pro-inflammatory cytokines and by metabolic reprogramming of LPS activity in macrophage cells, suggesting an immunomodulatory effect.
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http://dx.doi.org/10.3390/metabo9040075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523283PMC
April 2019

Exosomes: fighting cancer with cancer.

Ther Deliv 2019 01;10(1):37-61

Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, G4 0RE Glasgow, United Kingdom.

Exosomes are nanovesicles secreted by many cells, including cancer cells. Extensive research has been carried out to validate potential applications of exosomes and to evaluate their efficiency in a wide range of diseases, including cancer. The current knowledge on the origin, biogenesis and composition of exosomes is described. This review then focuses on the use of exosomes in cancer diagnostics and therapeutics.
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http://dx.doi.org/10.4155/tde-2018-0051DOI Listing
January 2019

Hibiscus acid from Hibiscus sabdariffa (Malvaceae) has a vasorelaxant effect on the rat aorta.

Fitoterapia 2019 Apr 25;134:5-13. Epub 2019 Jan 25.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, Scotland, UK. Electronic address:

Hibiscus sabdariffa (Malvaceae) is a plant that is widely recognised for its antihypertensive properties; however the constituent(s) responsible for this biological activity are presently unknown. The aim of this study was to identify the potential compounds that are responsible for the vasorelaxant activity of H. sabdariffa. Thereafter, the mechanisms involved in producing the vasorelaxation were investigated. The plant was extracted consecutively with hexane, ethyl acetate and methanol. The methanolic extract was subjected to bioassay-guided fractionation in order to isolate pure compounds that possessed vasorelaxant activity. The vascular effects of the pure compounds were studied on the rat aorta in vitro using myography techniques. Hibiscus acid produced a concentration-dependent relaxation of the rat aorta pre-contracted with either phenylephrine (3 μM) or KCl (60 mM), irrespective of the presence of the endothelium. When the tissue was pre-contracted with phenylephrine, the concentration required to produce 50% relaxation (IC), was 0.09 ± 0.01 mg/ml. Hibiscus acid had no effect on the phasic contraction induced by phenylephrine in Ca-free physiological solution; but it did affect the component of the contraction that is due to Ca influx. In parallel studies, garcinia acid, a diastereoisomer of hibiscus acid, was found to have an almost identical vasorelaxant effect. The vasorelaxant action of both compounds is most likely due to the inhibition of Ca influx via voltage-dependent Ca channels.
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http://dx.doi.org/10.1016/j.fitote.2019.01.012DOI Listing
April 2019

Rationalising drug delivery using nanoparticles: a combined simulation and immunology study of GnRH adsorbed to silica nanoparticles.

Sci Rep 2018 11 20;8(1):17115. Epub 2018 Nov 20.

Department of Chemical and Process Engineering, University of Strathclyde, 75 Montrose Street, Glasgow, G1 1XJ, UK.

Silica nanoparticles (SiNPs) have been shown to have significant potential for drug delivery and as adjuvants for vaccines. We have simulated the adsorption of GnRH-I (gonadotrophin releasing hormone I) and a cysteine-tagged modification (cys-GnRH-I) to model silica surfaces, as well as its conjugation to the widely-used carrier protein bovine serum albumin (BSA). Our subsequent immunological studies revealed no significant antibody production was caused by the peptide-SiNP systems, indicating that the treatment was not effective. However, the testosterone response with the native peptide-SiNPs indicated a drug effect not found with cys-GnRH-I-SiNPs; this behaviour is explained by the specific orientation of the peptides at the silica surface found in the simulations. With the BSA systems, we found significant testosterone reduction, particularly for the BSA-native conjugates, and an antibody response that was notably higher with the SiNPs acting as an adjuvant; this behaviour again correlates well with the epitope presentation predicted by the simulations. The range of immunological and hormone response can therefore be interpreted and understood by the simulation results and the presentation of the peptides to solution, paving the way for the future rational design of drug delivery and vaccine systems guided by biomolecular simulation.
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http://dx.doi.org/10.1038/s41598-018-35143-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244087PMC
November 2018

Effect of Melittin on Metabolomic Profile and Cytokine Production in PMA-Differentiated THP-1 Cells.

Vaccines (Basel) 2018 Oct 13;6(4). Epub 2018 Oct 13.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.

Melittin, the major active peptide of honeybee venom (BV), has potential for use in adjuvant immunotherapy. The immune system response to different stimuli depends on the secretion of different metabolites from macrophages. One potent stimulus is lipopolysaccharide (LPS), a component isolated from gram-negative bacteria, which induces the secretion of pro-inflammatory cytokines in macrophage cell cultures. This secretion is amplified when LPS is combined with melittin. In the present study, pure melittin was isolated from whole BV by flash chromatography to obtain pure melittin. The ability of melittin to enhance the release of tumour necrosis factor-α (TNF-α), Interleukin (IL-1β, IL-6, and IL-10) cytokines from a macrophage cell line (THP-1) was then assessed. The response to melittin and LPS, applied alone or in combination, was characterised by metabolic profiling, and the metabolomics results were used to evaluate the potential of melittin as an immune adjuvant therapy. The addition of melittin enhanced the release of inflammatory cytokines induced by LPS. Effective chromatographic separation of metabolites was obtained by liquid chromatography-mass spectrometry (LC-MS) using a ZIC-pHILIC column and an ACE C4 column. The levels of 108 polar and non-polar metabolites were significantly changed ( ˂ 0.05) following cell activation by the combination of LPS and melittin when compared to untreated control cells. Overall, the findings of this study suggested that melittin might have a potential application as a vaccine adjuvant.
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http://dx.doi.org/10.3390/vaccines6040072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313865PMC
October 2018

Proof of concept studies for siRNA delivery by nonionic surfactant vesicles: and evaluation of protein knockdown.

J Liposome Res 2019 Sep 1;29(3):229-238. Epub 2019 Jan 1.

b Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , Glasgow , UK.

RNA interference is an effective and naturally occurring post-transcriptional gene regulatory mechanism. This mechanism involves the degradation of a target messenger RNA (mRNA) through the introduction of short interfering RNA (siRNA) that is complementary to the target mRNA. The application of siRNA-based therapeutics is limited by the development of an effective delivery system, as naked siRNA is unstable and cannot penetrate the cell membrane. In this study, we investigated the use of cationic niosomes (CN) prepared by microfluidic mixing for siRNA delivery. In an model, these vesicles were able to deliver anti-luciferase siRNA and effectively suppress luciferase expression in B16-F10 mouse melanoma cells. More importantly, in an mouse model, intratumoral administration of CN-carrying anti-luciferase siRNA led to significant suppression of luciferase expression compared with naked siRNA. Thus, we have established a novel and effective system for the delivery of siRNA both and which shows high potential for future application of gene therapeutics.
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http://dx.doi.org/10.1080/08982104.2018.1531424DOI Listing
September 2019

Delivering natural products and biotherapeutics to improve drug efficacy.

Ther Deliv 2017 11;8(11):947-956

Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, UK.

Due to the increasing problem of drug resistance, new and improved medicines are required. Natural products and biotherapeutics offer a vast resource for new drugs; however, challenges, including the cost and time taken for traditional drug discovery processes and the subsequent lack of investment from the pharmaceutical industry, are associated with these areas. New techniques are producing compounds with appropriate activity at a faster rate. While the formulation of these combined with drug-delivery systems offers a promising approach for expanding the drug developments available to modern medicine. Here, various classes of drug-delivery systems are described and the advantages they bring to small molecule and biotherapeutic targeting are highlighted. This is an attractive approach to the pharmaceutical industry and the rising trend in research in this area is examined in brief. [Formula: see text].
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http://dx.doi.org/10.4155/tde-2017-0060DOI Listing
November 2017

Crystal structures of hibiscus acid and hibiscus acid dimethyl ester isolated from (Malvaceae).

Acta Crystallogr E Crystallogr Commun 2017 Sep 21;73(Pt 9):1368-1371. Epub 2017 Aug 21.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, Scotland.

The biologically active title compounds have been isolated from plants, hibiscus acid as a dimethyl sulfoxide monosolvate [systematic name: (2,3)-3-hy-droxy-5-oxo-2,3,4,5-tetra-hydro-furan-2,3-di-carb-oxy-lic acid dimethyl sulfoxide monosolvate], CHO·CHOS, (I), and hibiscus acid dimethyl ester [systematic name: dimethyl (2,3)-3-hy-droxy-5-oxo-2,3,4,5-tetra-hydro-furan-2,3-di-carboxyl-ate], CHO, (II). Compound (I) forms a layered structure with alternating layers of lactone and solvent mol-ecules, that include a two-dimensional hydrogen-bonding construct. Compound (II) has two crystallographically independent and conformationally similar mol-ecules per asymmetric unit and forms a one-dimensional hydrogen-bonding construct. The known absolute configuration for both compounds has been confirmed.
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http://dx.doi.org/10.1107/S2056989017011902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588582PMC
September 2017

Formulation of Nonionic Surfactant Vesicles (NISV) Prepared by Microfluidics for Therapeutic Delivery of siRNA into Cancer Cells.

Mol Pharm 2017 07 8;14(7):2450-2458. Epub 2017 Jun 8.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, G4 0RE Glasgow, United Kingdom.

Small interfering RNAs (siRNA) have a broad potential as therapeutic agents to reversibly silence any target gene of interest. The clinical application of siRNA requires the use of safe and effective delivery systems. In this study, we investigated the use of nonionic surfactant vesicles (NISV) for the delivery of siRNA. Different types of NISV formulations were synthesized by microfluidic mixing and then evaluated for their physiochemical properties and cytotoxicity. The ability of the NISV to carry and transfect siRNA targeting green fluorescent protein (GFP) into A549 that stably express GFP (copGFP-A549) was evaluated. Flow cytometry and Western blotting were used to study the GFP expression knockdown, and significant knockdown was observed as a result of siRNA delivery to the cells by NISV. This occurred in particular when using Tween 85, which was able to achieve more than 70% GFP knockdown. NISV were thus demonstrated to provide a promising and effective platform for therapeutic delivery of siRNA.
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http://dx.doi.org/10.1021/acs.molpharmaceut.7b00352DOI Listing
July 2017

Metabolomic Profiling of the Synergistic Effects of Melittin in Combination with Cisplatin on Ovarian Cancer Cells.

Metabolites 2017 Apr 14;7(2). Epub 2017 Apr 14.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.

Melittin, the main peptide present in bee venom, has been proposed as having potential for anticancer therapy; the addition of melittin to cisplatin, a first line treatment for ovarian cancer, may increase the therapeutic response in cancer treatment via synergy, resulting in improved tolerability, reduced relapse, and decreased drug resistance. Thus, this study was designed to compare the metabolomic effects of melittin in combination with cisplatin in cisplatin-sensitive (A2780) and resistant (A2780CR) ovarian cancer cells. Liquid chromatography (LC) coupled with mass spectrometry (MS) was applied to identify metabolic changes in A2780 (combination treatment 5 μg/mL melittin + 2 μg/mL cisplatin) and A2780CR (combination treatment 2 μg/mL melittin + 10 μg/mL cisplatin) cells. Principal components analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) multivariate data analysis models were produced using SIMCA-P software. All models displayed good separation between experimental groups and high-quality goodness of fit (R²) and goodness of prediction (Q²), respectively. The combination treatment induced significant changes in both cell lines involving reduction in the levels of metabolites in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, purine and pyrimidine metabolism, and the arginine/proline pathway. The combination of melittin with cisplatin that targets these pathways had a synergistic effect. The melittin-cisplatin combination had a stronger effect on the A2780 cell line in comparison with the A2780CR cell line. The metabolic effects of melittin and cisplatin in combination were very different from those of each agent alone.
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http://dx.doi.org/10.3390/metabo7020014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487985PMC
April 2017

Comparison of the physical characteristics of monodisperse non-ionic surfactant vesicles (NISV) prepared using different manufacturing methods.

Int J Pharm 2017 Apr 3;521(1-2):54-60. Epub 2017 Feb 3.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, G4 0RE Glasgow, United Kingdom. Electronic address:

Non-ionic surfactant vesicles (NISV) are synthetic membrane vesicles formed by self-assembly of a non-ionic surfactant, often in a mixture with cholesterol and a charged chemical species. Different methods can be used to manufacture NISV, with the majority of these requiring bulk mixing of two phases. This mixing process is time-consuming and leads to the preparation of large and highly dispersed vesicles, which affects the consistency of the final product and could hinder subsequent regulatory approval. In this study, we have compared the physical characteristics of NISV prepared using two conventional methods (thin-film hydration method and heating method) with a recently introduced microfluidic method. The resulting particles from these methods were assessed for their physical characteristics and in vitro cytotoxicity. Through microfluidics, nano-sized NISV were prepared in seconds, through rapid and controlled mixing of two miscible phases (lipids dissolved in alcohol and an aqueous medium) in a microchannel, without the need of a size reduction step, as required for the conventional methods. Stability studies over two months showed the particles were stable regardless of the method of preparation and there were no differences in terms of EC50 on A375 and A2780 cell lines. However, this work demonstrates the flexibility and ease of applying lab-on-chip microfluidics for the preparation of NISV that could be used to significantly improve formulation research and development, by enabling the rapid manufacture of a consistent end-product, under controlled conditions.
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http://dx.doi.org/10.1016/j.ijpharm.2017.02.007DOI Listing
April 2017

Analysis of the binding loops configuration and surface adaptation of different crystallized single-domain antibodies in response to various antigens.

J Mol Recognit 2017 04 16;30(4). Epub 2016 Nov 16.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK.

Monoclonal antibodies have revolutionized the biomedical field through their ubiquitous utilization in different diagnostics and therapeutic applications. Despite this widespread use, their large size and structural complexity have limited their versatility in specific applications. The antibody variable region that is responsible for binding antigen is embodied within domains that can be rescued individually as single-domain antibody (sdAb) fragments. Because of the unique characteristics of sdAbs, such as low molecular weight, high physicochemical stability, and the ability to bind antigens inaccessible to conventional antibodies, they represent a viable alternative to full-length antibodies. Consequently, 149 crystal structures of sdAbs, originating from human (VH), camelids (VHH), or sharks (VNAR), were retrieved from the Protein Data Bank, and their structures were compared. The 3 types of sdAbs displayed complementarity determining regions (CDRs) with different lengths and configurations. CDR3 of the VHH and VNAR domains were dominated by pleated and extended orientations, respectively. Although VNAR showed the smallest average molecular weight and molecular surface area compared with VHH and VH antibodies. However, the solvent accessible surface area measurements of the 3 tested sdAbs types were very similar. All the antihapten VHH antibodies showed pleated CDR3, which were sufficient to create a binding pocket to accommodate haptens (methotrexate and azo dyes) in terms of shape and electrostatic potential. The sdAbs that recognized lysozyme showed more diversity in their CDR3 orientation to enable them to recognize various topographies of lysozyme. Subsequently, the three sdAb classes were different in size and surface area and have shown distinguishable ability to optimize their CDR length and orientation to recognize different antigen classes.
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http://dx.doi.org/10.1002/jmr.2592DOI Listing
April 2017
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