School of Chemistry - Research Publications
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ItemCopper bis(thiosemicarbazone) complexes modulate P-glycoprotein expression and function in human brain microvascular endothelial cells(WILEY, 2022-08)P-glycoprotein (P-gp) is an efflux transporter at the blood-brain barrier (BBB) that hinders brain access of substrate drugs and clears endogenous molecules such as amyloid beta (Aβ) from the brain. As biometals such as copper (Cu) modulate many neuronal signalling pathways linked to P-gp regulation, it was hypothesised that the bis(thiosemicarbazone) (BTSC) Cu-releasing complex, copper II glyoxal bis(4-methyl-3-thiosemicarbazone) (CuII [GTSM]), would enhance P-gp expression and function at the BBB, while copper II diacetyl bis(4-methyl-3-thiosemicarbazone) (CuII [ATSM]), which only releases Cu under hypoxic conditions, would not modulate P-gp expression. Following treatment with 25-250 nM CuII (BTSC)s for 8-48 h, expression of P-gp mRNA and protein in human brain endothelial (hCMEC/D3) cells was assessed by RT-qPCR and Western blot, respectively. P-gp function was assessed by measuring accumulation of the fluorescent P-gp substrate, rhodamine 123 and intracellular Cu levels were quantified by inductively coupled plasma mass spectrometry. Interestingly, CuII (ATSM) significantly enhanced P-gp expression and function 2-fold and 1.3-fold, respectively, whereas CuII (GTSM) reduced P-gp expression 0.5-fold and function by 200%. As both compounds increased intracellular Cu levels, the effect of different BTSC backbones, independent of Cu, on P-gp expression was assessed. However, only the Cu-ATSM complex enhanced P-gp expression and this was mediated partly through activation (1.4-fold) of the extracellular signal-regulated kinase 1 and 2, an outcome that was significantly attenuated in the presence of an inhibitor of the mitogen-activated protein kinase regulatory pathway. Our findings suggest that CuII (ATSM) and CuII (GTSM) have the potential to modulate the expression and function of P-gp at the BBB to impact brain drug delivery and clearance of Aβ.
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ItemImmunoPET: IMaging of cancer imMUNOtherapy targets with positron Emission Tomography: a phase 0/1 study characterising PD-L1 with 89Zr-durvalumab (MEDI4736) PET/CT in stage III NSCLC patients receiving chemoradiation study protocol.(BMJ Publishing Group, 2022-11-18)BACKGROUND: ImmunoPET is a multicentre, single arm, phase 0-1 study that aims to establish if 89Zr-durvalumab PET/CT can be used to interrogate the expression of PD-L1 in larger, multicentre clinical trials. METHODS: The phase 0 study recruited 5 PD-L1+ patients with metastatic non-small cell lung cancer (NSCLC). Patients received 60MBq/70 kg 89Zr-durva up to a maximum of 74 MBq, with scan acquisition at days 0, 1, 3 or 5±1 day. Data on (1) Percentage of injected 89Zr-durva dose found in organs of interest (2) Absorbed organ doses (µSv/MBq of administered 89Zr-durva) and (3) whole-body dose expressed as mSv/100MBq of administered dose was collected to characterise biodistribution.The phase 1 study will recruit 20 patients undergoing concurrent chemoradiotherapy for stage III NSCLC. Patients will have 89Zr-durva and FDG-PET/CT before, during and after chemoradiation. In order to establish the feasibility of 89Zr-durva PET/CT for larger multicentre trials, we will collect both imaging and toxicity data. Feasibility will be deemed to have been met if more than 80% of patients are able complete all trial requirements with no significant toxicity. ETHICS AND DISSEMINATION: This phase 0 study has ethics approval (HREC/65450/PMCC 20/100) and is registered on the Australian Clinical Trials Network (ACTRN12621000171819). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and must be submitted to the approving HREC for review and approval. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Network ACTRN12621000171819.
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ItemNo Preview AvailableSynthesis of acyloin natural products by Mukaiyama hydration(ROYAL SOC CHEMISTRY, 2022-05-18)The acyloin natural products are a family of bioactive compounds isolated from fungi and myxobacteria. The total synthesis of 7 members of the acyloin family was achieved via a HWE reaction followed by Mukaiyama-Isayama hydration, using novel Co(II) and Co(III) Schiff base SALPN complexes as catalysts for the key enone hydration step. Furthermore, we have shown that a mild acyloin rearrangement is possible under Mukaiyama hydration conditions, which was crucial in the success of this approach.
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ItemNo Preview AvailableHexadentate technetium-99m bis(thiosemicarbazonato) complexes: synthesis, characterisation and biodistribution(ROYAL SOC CHEMISTRY, 2022-09-26)The syntheses of non-oxido/non-nitrido bis(thiosemicarbazonato)technetium(V) complexes featuring a series of alkyl and ether substituents is presented. The bis(thiosemicarbazones) were radiolabelled with technetium-99m using an optimised one-pot synthesis from [99mTc][TcO4]-. Mass spectrometry and computational chemistry data suggested a distorted trigonal prismatic coordination environment for the bis(thiosemicarbazonato)technetium(V) complexes by way of a bis(thiosemicarbazone)technetium(V)-oxido intermediate complex. The lipophilicities of the complexes were estimated using distribution ratios and three of the new complexes were investigated in mice using kinetic planar imaging and ex vivo biodistribution experiments and were compared to [99mTc][TcO4]-. Modification of the technetium complexes with various lipophilic functional groups altered the biodistributions of the complexes in mice despite evidence suggesting limited stability of the complexes to biologically relevant conditions. The most hydrophilic complex had higher uptake in the kidneys compared to the most lipophilic, which had higher liver uptake, suggesting modification of the excretion pathways.
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ItemNovel Anti-Neuroinflammatory Properties of a Thiosemicarbazone-Pyridylhydrazone Copper(II) Complex(MDPI, 2022-09)Neuroinflammation has a major role in several brain disorders including Alzheimer's disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (CuII(gtsm) and CuII(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with CuII(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo. These findings suggest that copper(II) complexes could be harnessed as a new approach to modulate immune function in neurodegenerative diseases. In this study, we examined the anti-neuroinflammatory action of several low-molecular-weight, charge-neutral and lipophilic copper(II) complexes. Our analysis revealed that one compound, a thiosemicarbazone-pyridylhydrazone copper(II) complex (CuL5), delivered copper into cells in vitro and increased the concentration of copper in the brain in vivo. In a primary murine microglia culture, CuL5 was shown to decrease secretion of pro-inflammatory cytokine macrophage chemoattractant protein 1 (MCP-1) and expression of tumor necrosis factor alpha (Tnf), increase expression of metallothionein (Mt1), and modulate expression of Alzheimer's disease-associated risk genes, Trem2 and Cd33. CuL5 also improved the phagocytic function of microglia in vitro. In 5xFAD model AD mice, treatment with CuL5 led to an improved performance in a spatial working memory test, while, interestingly, increased accumulation of amyloid plaques in treated mice. These findings demonstrate that CuL5 can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases.
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ItemNo Preview AvailableAn icosanuclear silver(I) cluster supported by bis (thiosemicarbazonato) ligands(CSIRO PUBLISHING, 2022)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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ItemImaging immunity in patients with cancer using positron emission tomography(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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ItemAssessment of the epi-pericardial fibrotic substrate by collagen-targeted probes(NATURE PORTFOLIO, 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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ItemCuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1G93A mice with a C57BL/6 background(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.