MacHoll S.,Grove Center |
Morrison M.S.,Grove Center |
Iveson P.,Grove Center |
Arbo B.E.,General Electric |
And 3 more authors.
Molecular Imaging and Biology | Year: 2012
Purpose: A novel molecular imaging agent has been developed recently, which stains tissues of low extracellular pH [pH (low) insertion peptide, pHLIP®]. A pH-dependent process of peptide folding and insertion into cell membranes has been found in vitro. Targeting of acidic solid tumours has been demonstrated in vivo using fluorescence and PET labels. Here, we present proof of feasibility studies of pHLIP with a single-photon emission computed tomography (SPECT) label, 99mTc-AH114567, with focus on preclinical efficacy and imageability. Procedures: Lewis lung carcinoma, lymph node carcinoma of the prostate and prostate adenocarcinoma tumour xenografts were grown in mice and characterised by the angiogenesis marker 99mTc- NC100692 and by extracellular pH measurements with 31P-MRS of 3-aminopropyl phosphonate. Biodistribution was assessed and CT/SPECT imaging performed. Oral administration of bicarbonate served as control. Results and Conclusion: Tc-AH114567 can be obtained via a robust synthesis with good radiolabelling profile and improved formulation. The tracer retains the pH-dependent ability to insert into membranes and to target tumours with similar pharmacokinetics and efficacy that had been demonstrated earlier for pHLIP with optical or 64Cu PET labels. Despite the inherent challenges of SPECT compared to optical and PET imaging, e.g., in terms of lower sensitivity, 99mTc-AH114567 shows adequate image quality and contrast. The main development need for transitioning SPECT labelled pHLIP into the clinic is more rapid background signal reduction, which will be the focus of a subsequent optimisation study. © World Molecular Imaging Society, 2011.
Epidermal Growth Factor Receptor (EGFR) is overexpressed in high-grade dysplasia and adenocarcinoma of the esophagus and may represent a biomarker of histological progression in Barrett's Esophagus (BE)
Cronin J.,University of Swansea |
McAdam E.,University of Swansea |
Danikas A.,Grove Center |
Tselepis C.,University of Birmingham |
And 5 more authors.
American Journal of Gastroenterology | Year: 2011
Objectives: The assessment of cancer risk in patients with Barrett's esophagus (BE) is currently fraught with difficulty. The current gold standard method of assessing cancer risk is histological assessment, with the appearance of high-grade dysplasia (HGD) as the key event monitored. Sampling error during endoscopy limits the usefulness of this approach, and there has been much recent interest in supplementing histological assessment with molecular markers, which may aid in patient stratification. Methods: No molecular marker has been yet validated to accurately correlate with esophageal histological progression. Here, we assessed the suitability of several membranous proteins as biomarkers by correlating their abundance with histological progression. In all, 107 patient samples, from 100 patients, were arranged on a tissue microarray (TMA) and represented the various stages of histological progression in BE. This TMA was probed with antibodies for eight receptor proteins (mostly membranous). Results: Epidermal growth factor receptor (EGFR) staining was found to be the most promising biomarker identified with clear increases in staining accompanying histological progression. Further, immunohistochemistry was performed using the full-tissue sections from BE, HGD, and adenocarcinoma tissues, which confirmed the stepwise increase in EGFR abundance. Using a robust H-score analysis, EGFR abundance was shown to increase 13-fold in the adenocarcinoma tissues compared to the BE tissues. EGFR was overexpressed in 35% of HGD specimens and 80% of adenocarcinoma specimens when using the H-score of the BE patients (plus 3 s.d.) as the threshold to define overexpression. EGFR staining was also noted to be higher in BE tissues adjacent to HGD/adenocarcinoma. Western blotting, although showing more EGFR protein in the adenocarcinomas compared to the BE tissue, was highly variable. EGFR overexpression was accompanied by aneuploidy (gain) of chromosome 7, plus amplification of the EGFR locus. Finally, the bile acid deoxycholic acid (DCA) (at neutral and acidic pH) and acid alone was capable of upregulating EGFR mRNA in vitro, and in the case of neutral pH DCA, this was NF-B dependent. Conclusions: EGFR is overexpressed during the histological progression in BE tissues and hence may be useful as a biomarker of histological progression. Furthermore, as EGFR is a membranous protein expressed on the luminal surface of the esophageal mucosa, it may also be a useful target for biopsy guidance during endoscopy. © 2011 by the American College of Gastroenterology.
Macholl S.,Free University of Berlin |
Macholl S.,Grove Center |
Tietze D.,TU Darmstadt |
Buntkowsky G.,TU Darmstadt
CrystEngComm | Year: 2013
NMR crystallography, the combination of solid-state NMR techniques, chemical modelling, quantum chemical calculations and other characterization techniques, allows the determination of molecular and supramolecular structures which are not amenable to standard X-ray crystallography. The method is demonstrated on a set of application examples. First the principles and practical considerations of NMR crystallography based on dipolar NMR spectroscopy are outlined in conformational studies of polymorphs of N-octyl-gluconamide and of methoxycarbonyl urea. Then structural studies of two substrate-inhibitor complexes, human manganese superoxide dismutase with azide and nickel superoxide dismutase with cyanide, are reviewed. Finally an example of ongoing developments in the related field of EPR crystallography is reported. © 2013 The Royal Society of Chemistry.
Mizuta S.,University of Oxford |
Stenhagen I.S.R.,University of Oxford |
O'Duill M.,University of Oxford |
Wolstenhulme J.,University of Oxford |
And 10 more authors.
Organic Letters | Year: 2013
Treatment of readily available α,α-difluoro- and α-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [18F]labeling is demonstrated using [ 18F]Selectfluor bis(triflate), a reagent affording [ 18F]tri- and [18F]difluoromethylarenes not within reach with [18F]F2. © 2013 American Chemical Society.
Cant A.A.,University of Glasgow |
Bhalla R.,Grove Center |
Pimlott S.L.,West of Scotland Radionuclide Dispensary |
Sutherland A.,University of Glasgow
Chemical Communications | Year: 2012
A fast and efficient nickel-catalysed iodination reaction of aryl and heteroaryl bromides has been developed. The transformation was found to be general for a wide range of substrates and was used for the synthesis of iodo-PK11195, an imaging agent of Alzheimer's disease and iniparib, a compound used in the treatment of breast cancer. © 2012 The Royal Society of Chemistry.
Stasiuk G.J.,Imperial College London |
Smith H.,Imperial College London |
Wylezinska-Arridge M.,Imperial College London |
Tremoleda J.L.,Imperial College London |
And 5 more authors.
Chemical Communications | Year: 2013
Formyl Peptide Receptors (FPRs) are vital in the host inflammatory response, playing an important regulatory role in multiple diseases. A Gd(iii) DOTA conjugate of cFLFLFK has been synthesised which targets and visualises FPR1 upon leukocytes in the inflammatory response via magnetic resonance imaging for the first time. © 2013 The Royal Society of Chemistry.
Trousil S.,Imperial College London |
Hoppmann S.,Grove Center |
Nguyen Q.-D.,Imperial College London |
Kaliszczak M.,Imperial College London |
And 4 more authors.
Clinical Cancer Research | Year: 2014
Purpose: Expression of HER2 has profound implications on treatment strategies in various types of cancer. We investigated the specificity of radiolabeled HER2-targeting ZHER2:2891 Affibody, [18F]GE-226, for positron emission tomography (PET) imaging. Experimental Design: Intrinsic cellular [18F]GE-226 uptake and tumor-specific tracer binding were assessed in cells and xenografts with and without drug treatment. Specificity was further determined by comparing tumor localization of a fluorescently labeled analogue with DAKO HercepTest. Results: [18F]GE-226 uptake was 11- to 67-fold higher in 10 HER2-positive versus HER2-negative cell lines in vitro independent of lineage. Uptake in HER2-positive xenografts was rapid with net irreversible binding kinetics making possible the distinction of HER2-negative [MCF7 and MCF7-p95HER2: NUV60 (%ID/mL) 6.1 0.7; Ki (mL/cm3/min) 0.0069 0.0014] from HER2-positive tumors (NUV60 and Ki: MCF7-HER2, 10.91.5 and 0.015 0.0035; MDA-MB-361, 18.23.4 and 0.0250.0052; SKOV-3, 18.7 2.4 and 0.036 0.0065) within 1 hour. Tumor uptake correlated with HER2 expression determined by ELISA (r2 1/4 0.78), and a fluorophore-labeled tracer analogue colocalized with HER2 expression. Tracer uptake was not influenced by short-term or continuous treatment with trastuzumab in keeping with differential epitope binding, but reflected HER2 degradation by short-term NVP-AUY922 treatment in SKOV-3 xenografts (NUV60: 13.5 2.1 %ID/mL vs. 9.0 0.9 %ID/mL for vehicle or drug, respectively). Conclusions: [18F]GE-226 binds with high specificity to HER2 independent of cell lineage. The tracer has potential utility for HER2 detection, irrespective of prior trastuzumab treatment, and to discern HSP90 inhibitor-mediated HER2 degradation. © 2014 American Association for Cancer Research.
Cant A.A.,University of Glasgow |
Champion S.,University of Glasgow |
Bhalla R.,Grove Center |
Pimlott S.L.,University of Glasgow |
Sutherland A.,University of Glasgow
Angewandte Chemie - International Edition | Year: 2013
Rapid and efficient radioiodination of aryl and heteroaryl bromides has been achieved using a nickel(0)-mediated halogen-exchange reaction. This transformation gives direct access to [123I]- and [ 125I]-imaging agents for single photon emission computed tomography (SPECT), such as 5-[123I]-A85380 (see scheme, Boc=tert- butyloxycarbonyl, cod=1,5-cyclooctadiene, TFA=trifluoroacetic acid). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
MacHoll S.,Grove Center |
Johannesson H.,Grove Center |
Ardenkjaer-Larsen J.H.,Grove Center
Physical Chemistry Chemical Physics | Year: 2010
The objective of this study is to investigate if trityl biradicals could lead to more efficient dynamic nuclear polarization (DNP) for low gamma nuclear spins at low temperature (≈1 K) than a trityl monoradical. Three novel trityl biradicals of different size are synthesized, characterized and employed for hyperpolarization of [1-13C]pyruvic acid at 3.35 T and 4.64 T. Intramolecular electron-electron distances are obtained via dipolar couplings from electron paramagnetic resonance (EPR) spectroscopy at X-band and W-band that match well with calculated molecular structures. Steady-state DNP levels and build-up times are measured as function of radical concentration, magnetic field strength and microwave frequency for each biradical. Similar maximal DNP is obtained with all studied biradicals whereas a twice as high polarization is achievable with the monoradical. Both the biradicals and the monoradical show approximately a doubling of the polarization when increasing the field strength from 3.35 T to 4.64 T. Biradical concentrations at maximum polarization are several times lower than the optimum monoradical concentration, but the penalty is a much longer build-up time. Adding a small amount of Gd3+ to the samples (molar fraction of typically 100 ppm) has the same effect on DNP with the biradicals as with the monoradical. The electron longitudinal relaxation time T1e is found to be independent of the radical type and the field strength in this study. The same dependence of T1e on the trityl concentration is observed for all radicals. A considerable shortening of the 13C longitudinal relaxation time is observed for biradicals which agrees with the shortened build-up time compared to the monoradical at the same trityl concentration. This is probably the reason for lower DNP levels with trityl biradicals. © 2010 the Owner Societies.
Kaushik S.S.,Duke University |
Cleveland Z.I.,Duke University |
Cofer G.P.,Duke University |
Metz G.,Duke University |
And 7 more authors.
Magnetic Resonance in Medicine | Year: 2011
Given its greater availability and lower cost, 129Xe apparent diffusion coefficient (ADC) MRI offers an alternative to 3He ADC MRI. To demonstrate the feasibility of hyperpolarized 129Xe ADC MRI, we present results from healthy volunteers (HV), chronic obstructive pulmonary disease (COPD) subjects, and age-matched healthy controls (AMC). The mean parenchymal ADC was 0.036 ± 0.003 cm2 sec-1 for HV, 0.043 ± 0.006 cm2 sec-1 for AMC, and 0.056 ± 0.008 cm2 sec-1 for COPD subjects with emphysema. In healthy individuals, but not the COPD group, ADC decreased significantly in the anterior-posterior direction by ∼22% (P = 0.006, AMC; 0.0059, HV), likely because of gravity-induced tissue compression. The COPD group exhibited a significantly larger superior-inferior ADC reduction (∼28%) than the healthy groups (∼24%) (P = 0.00018, HV; P = 3.45 × 10-5, AMC), consistent with smoking-related tissue destruction in the superior lung. Superior-inferior gradients in healthy subjects may result from regional differences in xenon concentration. ADC was significantly correlated with pulmonary function tests (forced expiratory volume in 1 sec, r = -0.77, P = 0.0002; forced expiratory volume in 1 sec/forced vital capacity, r = -0.77, P = 0.0002; diffusing capacity of carbon monoxide in the lung/alveolar volume (VA), r = -0.77, P = 0.0002). In healthy groups, ADC increased with age by 0.0002 cm2 sec-1 year-1 (r = 0.56, P = 0.02). This study shows that 129Xe ADC MRI is clinically feasible, sufficiently sensitive to distinguish HV from subjects with emphysema, and detects age- and posture-dependent changes. Copyright © 2010 Wiley-Liss, Inc.