Publications by authors named "Craig Irving"

8 Publications

  • Page 1 of 1

Octadecyl chain-bearing PEGylated poly(propyleneimine)-based dendrimersomes: physicochemical studies, redox-responsiveness, DNA condensation, cytotoxicity and gene delivery to cancer cells.

Biomater Sci 2021 Feb 6;9(4):1431-1448. Epub 2021 Jan 6.

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

Stimuli-responsive nanocarriers have become increasingly important for nucleic acid and drug delivery in cancer therapy. Here, we report the synthesis, characterization and evaluation of disulphide-linked, octadecyl (C18 alkyl) chain-bearing PEGylated generation 3-diaminobutyric polypropylenimine dendrimer-based vesicles (or dendrimersomes) for gene delivery. The lipid-bearing PEGylated dendrimer was successfully synthesized through in situ two-step reaction. It was able to spontaneously self-assemble into stable, cationic, nanosized vesicles, with low critical aggregation concentration value, and also showed redox-responsiveness in presence of a glutathione concentration similar to that of the cytosolic reducing environment. In addition, it was able to condense more than 70% of DNA at dendrimer: DNA weight ratios of 5 : 1 and higher. This dendriplex resulted in an enhanced cellular uptake of DNA at dendrimer: DNA weight ratios of 10 : 1 and 20 : 1, by up to 16-fold and by up to 28-fold compared with naked DNA in PC-3 and DU145 prostate cancer cell lines respectively. At a dendrimer: DNA weight ratio of 20 : 1, it led to an increase in gene expression in PC-3 and DU145 cells, compared with DAB dendriplex. These octadecyl chain-bearing, PEGylated dendrimer-based vesicles are therefore promising redox-sensitive drug and gene delivery systems for potential applications in combination cancer therapy.
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http://dx.doi.org/10.1039/d0bm01441aDOI Listing
February 2021

Anti-Tumor Activity of Intravenously Administered Plumbagin Entrapped in Targeted Nanoparticles.

J Biomed Nanotechnol 2020 Jan;16(1):85-100

Plumbagin, a natural naphthoquinone from the officinal leadwort, has recently been shown to exert promising anti-cancer effects. However, its therapeutic use is hampered by its failure to specifically reach tumors after intravenous administration, without secondary effects on normal tissues. Its poor solubility in water and rapid elimination following administration further limit its potential use. We hypothesize that the entrapment of plumbagin within PEGylated PLGA nanoparticles conjugated with transferrin, whose receptors are overexpressed on many types of cancer cells, could lead to a selective delivery of the drug to tumors following intravenous administration and enhance its chemotherapeutic effects. The objectives of this study were therefore to prepare and characterize transferrin-conjugated, PEGylated PLGA nanoparticles entrapping plumbagin, and to assess their anti-cancer efficacy as well as in tumor-bearing mice. The intravenous administration of transferrin-conjugated PEGylated PLGA nanoparticles resulted in the complete suppression of 10% of B16-F10 tumors and regression of 30% of the tumors, with improvement of the animal survival compared to controls. The treatment was well tolerated by the animals. Transferrin-bearing PEGylated PLGA nanoparticles entrapping plumbagin are therefore highly promising therapeutic systems, able to lead to tumor regression and even suppression after intravenous administration without visible toxicity.
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http://dx.doi.org/10.1166/jbn.2020.2874DOI Listing
January 2020

Camptothecin-based dendrimersomes for gene delivery and redox-responsive drug delivery to cancer cells.

Nanoscale 2019 Nov 15;11(42):20058-20071. Epub 2019 Oct 15.

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

Combination therapy involving chemotherapeutic drugs and genes is emerging as a promising strategy to provide a synergistic therapeutic effect, to overcome drug resistance while reducing the severe side effects associated with conventional chemotherapeutic drugs. However, the lack of nanomedicines able to simultaneously carry anti-cancer drugs and nucleic acids limits the application of this therapeutic strategy. To overcome this issue, we proposed to synthesize a pro-drug dendrimer by conjugating the PEGylated, positively charged generation 3-diaminobutyric polypropylenimine dendrimer to the anti-cancer drug camptothecin with a redox-sensitive disulphide linkage, and evaluate its efficacy to co-deliver the complexed DNA and camptothecin to cancer cells. This PEGylated pro-drug dendrimer was found to spontaneously self-assemble into cationic (∼3-5 mV) vesicles at pH 7.4, at a critical aggregation concentration of about 200 μg mL. These vesicles (dendrimersomes) became smaller (150-200 nm) with increasing dendrimer concentration and remained stable over 7 days. They were able to release about 70% of the conjugated camptothecin in presence of 50 mM glutathione (equivalent to the intracellular environment of tumor tissue). They could also condense more than 85% of the DNA at dendrimer : DNA weight ratios of 5 : 1 and higher. DNA condensation occurred instantly and was found to be stable for at least 24 h. This led to an enhanced cellular uptake of DNA (by up to 1.6-fold) and increased gene transfection (by up to 2.4-fold) in prostate cancer cells in comparison with the unmodified dendrimer. These novel dendrimersomes are therefore promising for single carrier-based combination cancer therapy.
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http://dx.doi.org/10.1039/c9nr07254cDOI Listing
November 2019

The differential actions of clozapine and other antipsychotic drugs on the translocation of dopamine D2 receptors to the cell surface.

J Biol Chem 2019 04 22;294(14):5604-5615. Epub 2019 Jan 22.

From the Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881,

Most clinically available antipsychotic drugs (APDs) bind dopamine D2 receptors (D2R) at therapeutic concentrations, and it is thought that they suppress psychotic symptoms by serving as competitive antagonists of dopamine at D2R. Here, we present data that demonstrate that APDs act independently of dopamine at an intracellular pool of D2R to enhance transport of D2R to the cell surface and suggest that APDs can act as pharmacological chaperones at D2R. Among the first- and second-generation APDs that we tested, clozapine exhibited the lowest efficacy for translocating D2R to the cell surface. Thus, our observations could provide a cellular explanation for some of the distinct therapeutic characteristics of clozapine in schizophrenia. They also suggest that differential intracellular actions of APDs at their common G protein-coupled receptor (GPCR) target, D2R, could contribute to differences in their clinical profiles.
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http://dx.doi.org/10.1074/jbc.RA118.004682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462534PMC
April 2019

PEGylation of polypropylenimine dendrimers: effects on cytotoxicity, DNA condensation, gene delivery and expression in cancer cells.

Sci Rep 2018 06 20;8(1):9410. Epub 2018 Jun 20.

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

Diaminobutyric polypropylenimine (DAB) dendrimers have been shown to be highly efficient non-viral gene delivery systems for cancer therapy. However, their cytotoxicity currently limits their applications. To overcome this issue, PEGylation of DAB dendrimer, using various PEG molecular weights and dendrimer generations, has been attempted to decrease the cytotoxicity and enhance the DNA condensation, size and zeta potential, cellular uptake and transfection efficacy of these dendriplexes. Among all the PEGylated dendrimers synthesized, generation 3- and generation 4-DAB conjugated to low molecular weight PEG (2 kDa) at a dendrimer: DNA ratio of 20:1 and 10:1 resulted in an increase in gene expression on almost all tested cancer cells lines (by up to 3.2-fold compared to unmodified dendrimer in A431 cells). The highest level of β-galactosidase gene expression (10.07 × 10 ± 0.09 × 10 U/mL) was obtained following treatment of B16F10-Luc cells with G4-dendrimer PEGylated with PEG2K at a dendrimer: DNA ratio of 20:1. These delivery systems significantly decreased cytotoxicity on B16F10-Luc cells, by more than 3.4-fold compared to unmodified dendrimer. PEGylated generations 3- and 4-DAB dendrimers are therefore promising gene delivery systems for cancer therapy, combining low cytotoxicity and high transfection efficacy.
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http://dx.doi.org/10.1038/s41598-018-27400-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010408PMC
June 2018

Chemoselective oxidation of aryl organoboron systems enabled by boronic acid-selective phase transfer.

Chem Sci 2017 Feb 27;8(2):1551-1559. Epub 2016 Oct 27.

Department of Pure and Applied Chemistry , WestCHEM , University of Strathclyde , 295 Cathedral Street , Glasgow , G1 1XL , UK . Email:

We report the direct chemoselective Brown-type oxidation of aryl organoboron systems containing two oxidizable boron groups. Basic biphasic reaction conditions enable selective formation and phase transfer of a boronic acid trihydroxyboronate in the presence of boronic acid pinacol (BPin) esters, while avoiding speciation equilibria. Spectroscopic investigations validate a base-promoted phase-selective discrimination of organoboron species. This phenomenon is general across a broad range of organoboron compounds and can also be used to invert conventional protecting group strategies, enabling chemoselective oxidation of BMIDA species over normally more reactive BPin substrates. We also demonstrate the selective oxidation of diboronic acid systems with chemoselectivity predictable . The utility of this method is exemplified through the development of a chemoselective oxidative nucleophile coupling.
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http://dx.doi.org/10.1039/c6sc04014dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452267PMC
February 2017

Forensic electrochemistry: the electroanalytical sensing of synthetic cathinone-derivatives and their accompanying adulterants in "legal high" products.

Analyst 2014 Jan;139(2):389-400

Faculty of Science and Engineering, School of Chemistry and the Environment, Division of Chemistry and Environmental Science, Manchester Metropolitan University, Chester Street, Manchester M1 5GD, Lancs, UK.

The production and abuse of new psychoactive substances, known as "legal highs" which mimic traditional drugs of abuse is becoming a global epidemic. Traditional analytical methodologies exist which can provide confirmatory analysis but there is a requirement for an on-the-spot analytical screening tool that could be used to determine whether a substance, or sample matrix contains such legal, or formally "legal highs". In this paper the electrochemical sensing of (±)-methcathinone and related compounds at a range of commercially available electrode substrates is explored. We demonstrate for the first time that this class of "legal highs" are electrochemically active providing a novel sensing protocol based upon their electrochemical oxidation. Screen-printed graphite sensing platforms are favoured due to their proven ability to be mass-produced providing large numbers of reliable and reproducible electrode sensing platforms that preclude the requirement of surface pre-treatment such as mechanical polishing as is the case in the use of solid/re-usable electrode substrates. Additionally they hold potential to be used on-site potentially being the basis of an on-site legal high screening device. Consequently the electroanalytical sensing of (±)-methcathinone (3a), (±)-4′-methylmethcathinone [3b, 4-MMC, (±)-mephedrone] and (±)-4′-methyl-N-ethylcathinone (3c, 4-MEC) is explored using screen-printed sensing platforms with the effect of pH explored upon the analytical response with their analytical efficiency evaluated towards the target legal highs. Interesting at pH values below 6 the voltammetric response quantitatively changes from that of an electrochemically irreversible response to that of a quasi-reversible signature which can be used analytically. It is demonstrated for the first time that the electroanalytical sensing of (±)-methcathinone (3a), (±)-mephedrone (3b) and 4-MEC (3c) are possible with accessible linear ranges found to correspond to 16–200 μg mL(−1) for 3a (at pH 12) and 16–350 μg mL(−1) for both 3b and 3c in pH 2, with limits of detection (3σ) found to correspond to 44.5, 39.8 and 84.2 μg mL(−1) respectively. Additionally adulterants that are commonly incorporated into cathinone legal highs are electrochemically explored at both pH 2 and 12.
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http://dx.doi.org/10.1039/c3an01985cDOI Listing
January 2014

Synthesis, full chemical characterisation and development of validated methods for the quantification of the components found in the evolved "legal high" NRG-2.

J Pharm Biomed Anal 2012 Mar 11;61:122-35. Epub 2011 Nov 11.

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

The recent global increase in the abuse of 4'-methylmethcathinone (mephedrone) and related compounds has developed a requirement for full chemical characterisation of these products. This work presents full synthetic and chemical characterisation data for the hydrobromide salts of two mephedrone derivatives: 4'-methyl-N-ethylcathinone (4-MEC) and 4'-methyl-N-benzylcathinone (4-MBC) which have been identified in samples of the "legal high" NRG-2. The first fully validated chromatographic methods for the detection and quantitative analysis of these substances both in their pure form and in the presence of a number of common adulterants used in illicit drug manufacture is also reported.
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http://dx.doi.org/10.1016/j.jpba.2011.11.004DOI Listing
March 2012