School of Chemistry - Research Publications

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    An icosanuclear silver(I) cluster supported by bis (thiosemicarbazonato) ligands
    Paterson, BM ; White, JM ; Donnelly, PS ; Koutsantonis, G (CSIRO PUBLISHING, 2022-03-10)
    The synthesis and structural characterisation of an icosanuclear silver(I) cluster complex is reported here. The complex includes twenty silver(I) ions supported by eighteen bis(thiosemicarbazonato) ligands. The cluster of silver(I) ions involves several close Ag⋯Ag contacts suggesting some degree of argentophilic interactions and the bis(thiosemicarbazonato) ligands are present in three different conformations highlighting the ability of thiosemicarbazone ligands to coordinate to metal ions in different modes.
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    Imaging immunity in patients with cancer using positron emission tomography
    Hegi-Johnson, F ; Rudd, S ; Hicks, RJ ; De Ruysscher, D ; Trapani, JA ; John, T ; Donnelly, P ; Blyth, B ; Hanna, G ; Everitt, S ; Roselt, P ; MacManus, MP (NATURE PORTFOLIO, 2022-04-07)
    Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality.
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    Assessment of the epi-pericardial fibrotic substrate by collagen-targeted probes.
    Ezeani, M ; Noor, A ; Donnelly, PS ; Niego, B ; Hagemeyer, CE (Springer Science and Business Media LLC, 2022-04-05)
    The identification of the fibrotic arrhythmogenic substrate as a means of improving the diagnosis and prediction of atrial fibrillation has been a focus of research for many years. The relationship between the degree of atrial fibrosis as a major component of atrial cardiomyopathy and the recurrence of arrhythmia after AF ablation can correlate. While the focus in identification and characterisation of this substrate has been centred on the atrial wall and the evaluation of atrial scar and extracellular matrix (ECM) expansion by late gadolinium-enhancement (LGE) on cardiac magnetic resonance imaging (CMRI), LGE cannot visualise diffuse fibrosis and diffuse extravasation of gadolinium. The atrial pericardium is a fine avascular fibrous membranous sac that encloses the atrial wall, which can undergo remodelling leading to atrial disease and AF. Nevertheless, little attention has been given to the detection of its fibrocalcification, impact on arrhythmogenesis and, most importantly, on the potential prothrombotic role of epi-pericardial remodelling in generation of emboli. We have recently reported that tracers against collagen I and IV can provide a direct assessment of the ECM, and thus can estimate fibrotic burden with high sensitivity. Here, we show the ability of these optical tracers to identify epi-pericardial fibrosis, as well as to demonstrate subtle interstitial fibrosis of the atrial wall in a mouse model of beta-2-adrenergic receptor (β2-AR) cardiac overexpression.
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    CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1(G93A) mice with a C57BL/6 background
    Lum, JS ; Brown, ML ; Farrawell, NE ; McAlary, L ; Ly, D ; Chisholm, CG ; Snow, J ; Vine, KL ; Karl, T ; Kreilaus, F ; McInnes, LE ; Nikseresht, S ; Donnelly, PS ; Crouch, PJ ; Yerbury, JJ (NATURE PORTFOLIO, 2021-09-29)
    The synthetic copper-containing compound, CuATSM, has emerged as one of the most promising drug candidates developed for the treatment of amyotrophic lateral sclerosis (ALS). Multiple studies have reported CuATSM treatment provides therapeutic efficacy in various mouse models of ALS without any observable adverse effects. Moreover, recent results from an open label clinical study suggested that daily oral dosing with CuATSM slows disease progression in patients with both sporadic and familial ALS, providing encouraging support for CuATSM in the treatment of ALS. Here, we assessed CuATSM in high copy SOD1G93A mice on the congenic C57BL/6 background, treating at 100 mg/kg/day by gavage, starting at 70 days of age. This dose in this specific model has not been assessed previously. Unexpectedly, we report a subset of mice initially administered CuATSM exhibited signs of clinical toxicity, that necessitated euthanasia in extremis after 3-51 days of treatment. Following a 1-week washout period, the remaining mice resumed treatment at the reduced dose of 60 mg/kg/day. At this revised dose, treatment with CuATSM slowed disease progression and increased survival relative to vehicle-treated littermates. This work provides the first evidence that CuATSM produces positive disease-modifying outcomes in high copy SOD1G93A mice on a congenic C57BL/6 background. Furthermore, results from the 100 mg/kg/day phase of the study support dose escalation determination of tolerability as a prudent step when assessing treatments in previously unassessed models or genetic backgrounds.
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    Tunable Porous Coordination Polymers for the Capture, Recovery and Storage of Inhalation Anesthetics
    Abrahams, BF ; Dharma, AD ; Donnelly, PS ; Hudson, TA ; Kepert, CJ ; Robson, R ; Southon, PD ; White, KF (Wiley, 2017-06-12)
    The uptake of inhalation anesthetics by three topologically identical frameworks is described. The 3D network materials, which possess square channels of different dimensions, are formed from the relatively simple combination of ZnII centres and dianionic ligands that contain a phenolate and a carboxylate group at opposite ends. All three framework materials are able to adsorb N2O, Xe and isoflurane. Whereas the framework with the widest channels is able to adsorb large quantities of the various guests from the gas phase, the frameworks with the narrower channels have superior binding enthalpies and exhibit higher levels of retention. The use of ligands in which substituents are bound to the aromatic rings of the bridging ligands offers great scope for tuning the adsorption properties of the framework materials.
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    Guest‐induced Assembly of Bis(thiosemicarbazonato) Zinc(II) Coordination Nanotubes
    Paterson, BM ; White, KF ; White, JM ; Abrahams, BF ; Donnelly, PS (Wiley, 2017-07-10)
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    Guest-induced Assembly of Bis(thiosemicarbazonato) Zinc(II) Coordination Nanotubes
    Paterson, BM ; White, KF ; White, JM ; Abrahams, BF ; Donnelly, PS (Wiley, 2017-07-10)
    A ZnII complex of the dianionic tetradentate ligand formed by deprotonation of glyoxal‐bis(4‐phenyl‐3‐thiosemicarbazone) (H2gtsp) is a [3+3] trinuclear triangular prism. Recrystallization of this complex in the presence of either CO2, CS2, or CH3CN leads to the formation of [4+4] open‐ended charge‐neutral tetranuclear coordination nanotubes, approximately 2 nm in length and with internal dimensions large enough to accommodate linear guest molecules, which serve to template their formation. Upon removal of the templating molecules the nanotubes demonstrated reversible sorption of CO2 with an isosteric enthalpy of sorption of 28 kJ mol−1 at low loading.
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    Synthesis of Homochiral Co-III- and Mn-IV-[2.2]Paracyclophane Schiff Base Complexes with Predetermined Chirality at the Metal Centre
    Loits, D ; Braese, S ; North, AJ ; White, JM ; Donnelly, PS ; Rizzacasa, MA (WILEY-V C H VERLAG GMBH, 2016-08-01)
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    Collagen-Targeted Peptides for Molecular Imaging of Diffuse Cardiac Fibrosis
    Ezeani, M ; Noor, A ; Alt, K ; Lal, S ; Donnelly, PS ; Hagemeyer, CE ; Niego, B (WILEY, 2021-09-21)
    Background Cardiac fibrosis is the excessive deposition of extracellular matrix in the heart, triggered by a cardiac insult, aging, genetics, or environmental factors. Molecular imaging of the cardiac extracellular matrix with targeted probes could improve diagnosis and treatment of heart disease. However, although this technology has been used to demonstrate focal scarring arising from myocardial infarction, its capacity to demonstrate extracellular matrix expansion and diffuse cardiac fibrosis has not been assessed. Methods and Results Here, we report the use of collagen-targeted peptides labeled with near-infrared fluorophores for the detection of diffuse cardiac fibrosis in the β2-AR (β-2-adrenergic receptor) overexpressing mouse model and in ischemic human hearts. Two approaches were evaluated, the first based on a T peptide that binds matrix metalloproteinase-2-proteolyzed collagen IV, and the second on the cyclic peptide EP-3533, which targets collagen I. The systemic and cardiac uptakes of both peptides (intravenously administered) were quantified ex vivo by near-infrared imaging of whole organs, tissue sections, and heart lysates. The peptide accumulation profiles corresponded to an immunohistochemically-validated increase in collagen types I and IV in hearts of transgenic mice versus littermate controls. The T peptide could encouragingly demonstrate both the intermediate (7 months old) and severe (11 months old) cardiomyopathic phenotypes. Co-immunostainings of fluorescent peptides and collagens, as well as reduced collagen binding of a control peptide, confirmed the collagen specificity of the tracers. Qualitative analysis of heart samples from patients with ischemic cardiomyopathy compared with nondiseased donors supported the collagen-enhancement capabilities of these peptides also in the clinical settings. Conclusions Together, these observations demonstrate the feasibility and translation potential of molecular imaging with collagen-binding peptides for noninvasive imaging of diffuse cardiac fibrosis.
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    A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention
    Zia, NA ; Cullinane, C ; Van Zuylekom, JK ; Waldeck, K ; McInnes, LE ; Buncic, G ; Haskali, MB ; Roselt, PD ; Hicks, RJ ; Donnelly, PS (WILEY-V C H VERLAG GMBH, 2019-09-05)
    Molecules containing lysine-ureido-glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine-ureido-glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron-emitting copper-64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper-67 variant.