ORCID Profile
0000-0002-0066-219X
Current Organisation
University of Zurich
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Publisher: Wiley
Date: 27-06-2008
Abstract: Detailed chemical, spectroelectrochemical and computational studies have been used to investigate the mechanism of hypoxia selectivity of a range of copper radiopharmaceuticals. A revised mechanism involving a delicate balance between cellular uptake, intracellular reduction, reoxidation, protonation and ligand dissociation is proposed. This mechanism accounts for observed differences in the reported cellular uptake and washout of related copper bis(thiosemicarbazonato) complexes. Three copper and zinc complexes have been characterised by X-ray crystallography and the redox chemistry of a series of copper complexes has been investigated by using electronic absorption and EPR spectroelectrochemistry. Time-dependent density functional theory (TD-DFT) calculations have also been used to probe the electronic structures of intermediate species and assign the electronic absorption spectra. DFT calculations also show that one-electron oxidation is ligand-based, leading to the formation of cationic triplet species. In the absence of protons, metal-centred one-electron reduction gives the reduced anionic copper(I) species, [CuIATSM](-), and for the first time it is shown that molecular oxygen can reoxidise this anion to give the neutral, lipophilic parent complexes, which can wash out of cells. The electrochemistry is pH dependent and in the presence of stronger acids both chemical and electrochemical reduction leads to quantitative and rapid dissociation of copper(I) ions from the mono- or diprotonated complexes, [CuIATSMH] and [Cu(I)ATSMH2]+. In addition, a range of protonated intermediate species have been identified at lower acid concentrations. The one-electron reduction potential, rate of reoxidation of the copper(I) anionic species and ease of protonation are dependent on the structure of the ligand, which also governs their observed behaviour in vivo.
Publisher: Society of Nuclear Medicine
Date: 09-08-2012
DOI: 10.2967/JNUMED.112.105387
Abstract: In this era of systems biology, the tide of information derived from "omic" technologies (genomics, proteomics, etc.) has sparked a revolution in drug design, with many industrial and academic programs now embracing the concepts of molecular medicine (i.e., targeting changes in specific proteins or pathways) as measures of treatment efficacy and outcome. This approach has yielded a plethora of new preclinical therapeutics directed at novel targets within oncology. In many ways, the evolution of molecular imaging agents as diagnostic probes mirrors that of chemotherapeutics yet despite an increasing number of PET and SPECT radiotracers being evaluated in human trials, relatively few agents have found widespread use in clinical oncology. In light of this observation, is it time to reevaluate our strategies for radiopharmaceutical design and use? In this article, we argue that PET has enormous potential to deliver clinically relevant information on disease dynamics that extends beyond mapping the density and spatial distribution of a target. Recent developments in targeting pharmacodynamic biomarkers aim to exploit better the advantages of functional PET by detecting changes in signal transduction pathways, particularly in response to disease progression or treatment in cancer.
Publisher: American Chemical Society (ACS)
Date: 09-07-2009
DOI: 10.1021/IC900307F
Publisher: IOP Publishing
Date: 13-03-2009
DOI: 10.1088/0031-9155/54/7/017
Abstract: The development of hypoxia-selective radiopharmaceuticals for use as therapeutic and/or imaging agents is of vital importance for both early identification and treatment of cancer and in the design of new drugs. Radiotracers based on copper for use in positron emission tomography have received great attention due to the successful application of copper(II) bis(thiosemicarbazonato) complexes, such as [(60/62/64)Cu(II)ATSM] and [(60/62/64)Cu(II)PTSM], as markers for tumour hypoxia and blood perfusion, respectively. Recent work has led to the proposal of a revised mechanism of hypoxia-selective cellular uptake and retention of [Cu(II)ATSM]. The work presented here describes non-steady-state kinetic simulations in which the reported pO(2)-dependent in vitro cellular uptake and retention of [(64)Cu(II)ATSM] in EMT6 murine carcinoma cells has been modelled by using the revised mechanistic scheme. Non-steady-state (NSS) kinetic analysis reveals that the model is in very good agreement with the reported experimental data with a root-mean-squared error of less than 6% between the simulated and experimental cellular uptake profiles. Estimated rate constants are derived for the cellular uptake and washout (k(1) = 9.8 +/- 0.59 x 10(-4) s(-1) and k(2) = 2.9 +/- 0.17 x 10(-3) s(-1)), intracellular reduction (k(3) = 5.2 +/- 0.31 x 10(-2) s(-1)), reoxidation (k(4) = 2.2 +/- 0.13 mol(-1) dm(3) s(-1)) and proton-mediated ligand dissociation (k(5) = 9.0 +/- 0.54 x 10(-5) s(-1)). Previous mechanisms focused on the reduction and reoxidation steps. However, the data suggest that the origins of hypoxia-selective retention may reside with the stability of the copper(I) anion with respect to protonation and ligand dissociation. In vitro kinetic studies using the nicotimamide adenine dinucleotide (NADH)-dependent ferredoxin reductase enzyme PuR isolated from the bacterium Rhodopseudomonas palustris have also been conducted. NADH turnover frequencies are found to be dependent on the structure of the ligand and the results confirm that the proposed reduction step in the mechanism of hypoxia selectivity is likely to be mediated by NADH-dependent enzymes. Further understanding of the mechanism of hypoxia selectivity may facilitate the development of new imaging and radiotherapeutic agents with increased specificity for tumour hypoxia.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9DT02506E
Abstract: Multifunctional cyclopentadiene ligands are used to prepare difunctional and monofunctional, PSMA-targeting Re( i ) and 99m Tc( i ) complexes. The difunctional rhenium complex is shown to bind the PSMA with an order of magnitude lower K D .
Publisher: Wiley
Date: 15-10-2008
Publisher: Wiley
Date: 17-07-2008
Publisher: International Union of Crystallography (IUCr)
Date: 03-05-2008
Publisher: Wiley
Date: 04-2008
Publisher: American Chemical Society (ACS)
Date: 05-06-2019
DOI: 10.1021/ACS.INORGCHEM.9B00878
Abstract: An expedited synthesis of
Publisher: Society of Nuclear Medicine
Date: 16-10-2008
DOI: 10.2967/JNUMED.108.054015
Abstract: A water-soluble glucose conjugate of the hypoxia tracer 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) was synthesized and radiolabeled (64Cu-ATSE/A-G). Here we report our initial biological experiments with 64Cu-ATSE/A-G and compare the results with those obtained for 64Cu-ATSM and 18F-FDG. The uptake of 64Cu-ATSE/A-G and 64Cu-ATSM into HeLa cells in vitro was investigated at a range of dissolved oxygen concentrations representing normoxia, hypoxia, and anoxia. Small-animal PET with 64Cu-ATSE/A-G was performed in male BDIX rats implanted with P22 syngeneic carcinosarcomas. Images of 64Cu-ATSM and 18F-FDG were obtained in the same model for comparison. 64CuATSE/A-G showed oxygen concentration-dependent uptake in vitro and, under anoxic conditions, showed slightly lower levels of cellular uptake than 64Cu-ATSM uptake levels under hypoxic conditions were also lower. Whereas the normoxic uptake of 64Cu-ATSM increased linearly over time, 64Cu-ATSE/A-G uptake remained at low levels over the entire time course. In the PET study, 64CuATSE/A-G showed good tumor uptake and a biodistribution pattern substantially different from that of each of the controls. In marked contrast to the findings for 64Cu-ATSM, renal clearance and accumulation in the bladder were observed. 64Cu-ATSE/A-G did not display the characteristic brain and heart uptake of 18F-FDG. The in vitro cell uptake studies demonstrated that 64Cu-ATSE/A-G retained hypoxia selectivity and had improved characteristics when compared with 64Cu-ATSM. The in vivo PET results indicated a difference in the excretion pathways, with a shift from primarily hepatointestinal for 64Cu-ATSM to partially renal with 64Cu-ATSE/A-G. This finding is consistent with the hydrophilic nature of the glucose conjugate. A comparison with 18F-FDG PET results revealed that 64Cu-ATSE/A-G was not a surrogate for glucose metabolism. We have demonstrated that our method for the modification of Cu-bis(thiosemicarbazonato) complexes allows their biodistribution to be modified without negating their hypoxia selectivity or tumor uptake properties.
Publisher: Elsevier BV
Date: 2009
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jason Holland.