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  • Journal article
    Wang C, Sun W, Zhang J, Zhang J, Guo Q, Zhou X, Fan D, Liu H, Qi M, Gao X, Xu H, Gao Z, Tian M, Zhang H, Wang J, Wei Z, Long NJ, Mao Y, Li Cet al., 2021,

    An electric-field-responsive paramagnetic contrast agent enhances the visualization of epileptic foci in mouse models of drug-resistant epilepsy

    , NATURE BIOMEDICAL ENGINEERING, Vol: 5, Pages: 278-289, ISSN: 2157-846X
  • Journal article
    Ismael A, Al-Jobory A, Wang X, Alshehab A, Almutlg A, Alshammari M, Grace I, Bennett TLR, Wilkinson LA, Robinson BJ, Long NJ, Lambert Cet al., 2021,

    Molecular-scale thermoelectricity: as simple as 'ABC' (vol 2, pg 5329, 2020)

    , NANOSCALE ADVANCES, Vol: 3, Pages: 619-619, ISSN: 2516-0230
  • Book chapter
    Blower PJ, Cusnir R, Darwesh A, Long NJ, Ma MT, Osborne BE, Price TW, Pellico J, Reid G, Southworth R, Stasiuk GJ, Terry SYA, de Rosales RTMet al., 2021,

    Gallium: New developments and applications in radiopharmaceutics

    , RECENT HIGHLIGHTS I, Editors: Hubbard, VanEldik, Publisher: ELSEVIER ACADEMIC PRESS INC, Pages: 1-35
  • Patent
    Boyle J, Long NJ, Walter ERH, Ge Y, Mason JCet al., 2020,

    COMPOUNDS FOR THE DETECTION OF HEME OXYGENASE 1 (HO-1), AND METHODS AND USES INVOLVING THE SAME

    , 2017871.1

    The present invention relates to compounds for the detection of heme oxygenase 1 (HO-1), in particular porphyrin, chlorin, bacteriochlorin or isobacteriochlorin compounds having a tetrapyrrole or reduced tetrapyrrole backbone and a fluorophore. Such compounds can be used in the detection of HO-1 in vivo, ex vivo and in vitro, and can also be used in methods of diagnosis and as research reagents.
  • Journal article
    Ismael A, Al-Jobory A, Wang X, Alshehab A, Almutlg A, Alshammari M, Grace I, Benett TLR, Wilkinson LA, Robinson BJ, Long NJ, Lambert Cet al., 2020,

    Molecular-scale thermoelectricity: as simple as 'ABC'

    , NANOSCALE ADVANCES, Vol: 2, Pages: 5329-5334, ISSN: 2516-0230
  • Journal article
    Morse SV, Boltersdorf T, Chan TG, Gavins FNE, Choi JJ, Long NJet al., 2020,

    In vivo delivery of a fluorescent FPR2/ALX-targeted probe using focused ultrasound and microbubbles to image activated microglia

    , RSC Chemical Biology, Vol: 1, Pages: 385-389, ISSN: 2633-0679

    To image activated microglia, a small-molecule FPR2/ALX-targeted fluorescent probe was locally delivered into the brain using focused ultrasound and microbubbles. The probe did not co-localise with neurons or astrocytes but accumulated in activated microglia, making this a potential imaging tool for future drug discovery programs focused on neurological disorders.
  • Journal article
    Seneviratne A, Han Y, Wong E, Walter E, Jiang L, Cave L, Long NJ, Carling D, Mason JC, Haskard DO, Boyle Jet al., 2020,

    Hematoma resolution in vivo is directed by Activating Transcription Factor 1

    , Circulation Research, Vol: 127, Pages: 928-944, ISSN: 0009-7330

    Rationale: The efficient resolution of tissue hemorrhage is an important homeostatic function. In human macrophages in vitro, heme activates an adenosine monophosphate activated protein kinase / activating transcription factor 1 (AMPK/ATF1) pathway that directs Mhem macrophages through coregulation of heme oxygenase 1 (HMOX1, HO-1) and lipid homeostasis genes.Objective: We asked whether this pathway had an in vivo role in mice.Methods and Results: Perifemoral hematomas were used as a model of hematoma resolution. In mouse bone marrow derived macrophages (mBMM), heme induced HO-1, lipid regulatory genes including LXR, the growth factor IGF1, and the splenic red pulp macrophage gene Spic. This response was lost in mBMM from mice deficient in AMPK (Prkab1-/-) or ATF1 (Atf1-/-). In vivo, femoral hematomas resolved completely between day 8 and day 9 in littermate control mice (n=12), but were still present at day 9 in mice deficient in either AMPK (Prkab1-/-) or ATF1 (Atf1-/-) (n=6 each). Residual hematomas were accompanied by increased macrophage infiltration, inflammatory activation and oxidative stress. We also found that fluorescent lipids and a fluorescent iron-analog were trafficked to lipid-laden and iron-laden macrophages respectively. Moreover erythrocyte iron and lipid abnormally colocalized in the same macrophages in Atf1-/- mice. Therefore, iron-lipid separation was Atf1-dependent.Conclusions: Taken together, these data demonstrate that both AMPK and ATF1 are required for normal hematoma resolution.
  • Journal article
    Evans RJ, Lavin B, Phinikaridou A, Chooi KY, Mohri Z, Wong E, Boyle JJ, Krams R, Botnar R, Long NJet al., 2020,

    Targeted molecular iron oxide contrast agents for imaging atherosclerotic plaque

    , Nanotheranostics, Vol: 4, Pages: 184-194, ISSN: 2206-7418

    Overview: Cardiovascular disease remains a leading cause of death worldwide, with vulnerable plaque rupture the underlying cause of many heart attacks and strokes. Much research is focused on identifying an imaging biomarker to differentiate stable and vulnerable plaque. Magnetic Resonance Imaging (MRI) is a non-ionising and non-invasive imaging modality with excellent soft tissue contrast. However, MRI has relatively low sensitivity (micromolar) for contrast agent detection compared to nuclear imaging techniques. There is also an increasing emphasis on developing MRI probes that are not based on gadolinium chelates because of increasing concerns over associated systemic toxicity and deposits1. To address the sensitivity and safety concerns of gadolinium this project focused on the development of a high relaxivity probe based on superparamagnetic iron oxide nanoparticles for the imaging of atherosclerotic plaque with MRI. With development, this may facilitate differentiating stable and vulnerable plaque in vivo.Aim: To develop a range of MRI contrast agents based on superparamagnetic iron oxide nanoparticles (SPIONs), and test them in a murine model of advanced atherosclerosis.Methods: Nanoparticles of four core sizes were synthesised by thermal decomposition and coated with poly(maleicanhydride-alt-1-octadecene) (PMAO), poly(ethyleneimine) (PEI) or alendronate, then characterised for core size, hydrodynamic size, surface potential and relaxivity. On the basis of these results, one candidate was selected for further studies. In vivo studies using 10 nm PMAO-coated SPIONs were performed in ApoE-/- mice fed a western diet and instrumented with a perivascular cuff on the left carotid artery. Control ApoE-/- mice were fed a normal chow diet and were not instrumented. Mice were scanned on a 3T MR scanner (Philips Achieva) with the novel SPION contrast agent, and an elastin-targeted gadolinium agent that was shown previously to enable visualisation of plaque burden. Histo
  • Journal article
    Cohen L, 2020,

    Tuning the thermoelectrical properties of anthracene-based self-assembled monolayers

    , Chemical Science, Vol: 11, Pages: 6836-6841, ISSN: 2041-6520

    It is known that the electrical conductance of single molecules can be controlled in a deterministic manner by chemically varying their anchor groups to external electrodes. Here, by employing synthetic methodologies to vary the terminal anchor groups around aromatic anthracene cores, and by forming self-assembled monolayers (SAMs) of the resulting molecules, we demonstrate that this method of control can be translated into cross-plane SAM-on-gold molecular films. The cross-plane conductance of SAMs formed from anthracene-based molecules with four different combinations of anchors are measured to differ by a factor of approximately 3 in agreement with theoretical predictions. We also demonstrate that the Seebeck coefficient of such films can be boosted by more than an order of magnitude by an appropriate choice of anchor groups and that both positive and negative Seebeck coefficients can be realised. This demonstration that the thermoelectric properties of SAMs are controlled by their anchor groups represents a critical step towards functional ultra-thin-film devices for future molecular-scale electronics.
  • Conference paper
    Long NJ, 2020,

    Inorganic chemistry for PET radiolabelling: <SUP>68</SUP>Ga- and <SUP>18</SUP>F-based probes for mitochondria imaging

    , Publisher: WILEY, Pages: 359-359, ISSN: 0362-4803
  • Journal article
    Boltersdorf T, Ansari J, Senchenkova EY, Groeper J, Pajonczyk D, Vital SA, Kaur G, Alexander JS, Vogl T, Rescher U, Long NJ, Gavins FNEet al., 2020,

    Targeting of formyl peptide receptor 2 for in vivo imaging of acute vascular inflammation

    , Theranostics, Vol: 10, Pages: 6599-6614, ISSN: 1838-7640

    Inflammatory conditions are associated with a variety of diseases and can significantly contribute to their pathophysiology. Neutrophils are recognised as key players in driving vascular inflammation and promoting inflammation resolution. As a result, neutrophils, and specifically their surface formyl peptide receptors (FPRs), are attractive targets for non-invasive visualization of inflammatory disease states and studying mechanistic details of the process.Methods: A small-molecule Formyl Peptide Receptor 2 (FPR2/ALX)-targeted compound was combined with two rhodamine-derived fluorescent tags to form firstly, a targeted probe (Rho-pip-C1) and secondly a targeted, pH-responsive probe (Rho-NH-C1) for in vivo applications. We tested internalization, toxicity and functional interactions with neutrophils in vitro for both compounds, as well as the fluorescence switching response of Rho-NH-C1 to neutrophil activation. Finally, in vivo imaging (fluorescent intravital microscopy [IVM]) and therapeutic efficacy studies were performed in an inflammatory mouse model.Results: In vitro studies showed that the compounds bound to human neutrophils via FPR2/ALX without causing internalization at relevant concentrations. Additionally, the compounds did not cause toxicity or affect neutrophil functional responses (e.g. chemotaxis or transmigration). In vivo studies using IVM showed Rho-pip-C1 bound to activated neutrophils in a model of vascular inflammation. The pH-sensitive (“switchable”) version termed Rho-NH-C1 validated these findings, showing fluorescent activity only in inflammatory conditions.Conclusions: These results indicate a viable design of fluorescent probes that have the ability to detect inflammatory events by targeting activated neutrophils.
  • Journal article
    Wang X, Bennett TLR, Ismael A, Wilkinson LA, Hamill J, White AJP, Grace IM, Kolosov OV, Albrecht T, Robinson BJ, Long NJ, Cohen LF, Lambert CJet al., 2020,

    Scale-up of room-temperature constructive quantum interference from single molecules to self-assembled molecular-electronic films

    , Journal of the American Chemical Society, Vol: 142, Pages: 8555-8560, ISSN: 0002-7863

    The realization of self-assembled molecular-electronic films, whose room-temperature transport properties are controlled by quantum interference (QI), is an essential step in the scale-up of QI effects from single molecules to parallel arrays of molecules. Recently, the effect of destructive QI (DQI) on the electrical conductance of self-assembled monolayers (SAMs) has been investigated. Here, through a combined experimental and theoretical investigation, we demonstrate chemical control of different forms of constructive QI (CQI) in cross-plane transport through SAMs and assess its influence on cross-plane thermoelectricity in SAMs. It is known that the electrical conductance of single molecules can be controlled in a deterministic manner, by chemically varying their connectivity to external electrodes. Here, by employing synthetic methodologies to vary the connectivity of terminal anchor groups around aromatic anthracene cores, and by forming SAMs of the resulting molecules, we clearly demonstrate that this signature of CQI can be translated into SAM-on-gold molecular films. We show that the conductance of vertical molecular junctions formed from anthracene-based molecules with two different connectivities differ by a factor of approximately 16, in agreement with theoretical predictions for their conductance ratio based on CQI effects within the core. We also demonstrate that for molecules with thioether anchor groups, the Seebeck coefficient of such films is connectivity dependent and with an appropriate choice of connectivity can be boosted by ∼50%. This demonstration of QI and its influence on thermoelectricity in SAMs represents a critical step toward functional ultra-thin-film devices for future thermoelectric and molecular-scale electronics applications.
  • Journal article
    Clough TJ, Baxan N, Coakley EJ, Rivas C, Zhao L, Leclerc I, Martinez-Sanchez A, Rutter GA, Long NJet al., 2020,

    Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of beta-cell-dependent contrast enhancement in the pancreas

    , Dalton Transactions: an international journal of inorganic chemistry, Vol: 49, Pages: 4732-4740, ISSN: 1477-9226

    Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in β-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(III) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in β-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]−, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of β-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.
  • Journal article
    Jiang L, Lung HL, Huang T, Lan R, Zha S, Chan LS, Thor W, Tsoi T-H, Chau H-F, Borestrom C, Cobb SL, Tsao SW, Bian Z-X, Law G-L, Wong W-T, Tai WC-S, Chau WY, Du Y, Tang LHX, Chiang AKS, Middeldorp JM, Lo K-W, Mak NK, Long NJ, Wong K-Let al., 2020,

    Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn<SUP>2+</SUP>-chelating function (vol 116, pg 26614, 2019)

    , PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 5542-5542, ISSN: 0027-8424
  • Journal article
    Gawne PJ, Clarke F, Turjeman K, Cope AP, Long NJ, Barenholz Y, Terry SYA, de Rosales RTMet al., 2020,

    PET imaging of liposomal glucocorticoids using Zr-89-oxine: theranostic applications in inflammatory arthritis

    , Theranostics, Vol: 10, Pages: 3867-3879, ISSN: 1838-7640

    The encapsulation of Glucocorticoids (GCs) into long-circulating liposomes (LCLs) is a proven strategy to reduce the side effects of glucocorticoids and improve the treatment of inflammatory diseases, such as rheumatoid arthritis (RA). With the aim of supporting the development of GC-loaded LCLs, and potentially predict patient response to therapy clinically, we evaluated a direct PET imaging radiolabelling approach for preformed GC-LCLs in an animal model of human inflammatory arthritis.Methods: A preformed PEGylated liposomal methylprednisolone hemisuccinate (NSSL-MPS) nanomedicine was radiolabelled using [89Zr]Zr(oxinate)4 (89Zr-oxine), characterised and tracked in vivo using PET imaging in a K/BxN serum-transfer arthritis (STA) mouse model of inflammatory arthritis and non-inflamed controls. Histology and joint size measurements were used to confirm inflammation. The biodistribution of 89Zr-NSSL-MPS was compared to that of free 89Zr in the same model. A therapeutic study using NSSL-MPS using the same time points as the PET/CT imaging was carried out.Results: The radiolabelling efficiency of NSSL-MPS with [89Zr]Zr(oxinate)4 was 69 ± 8 %. PET/CT imaging of 89Zr-NSSL-MPS showed high uptake (3.6 ± 1.5 % ID; 17.4 ± 9.3 % ID/mL) at inflamed joints, with low activity present in non-inflamed joints (0.5 ± 0.1 % ID; 2.7 ± 1.1 % ID/mL). Importantly, a clear correlation between joint swelling and high 89Zr-NSSL-MPS uptake was observed, which was not observed with free 89Zr. STA mice receiving a therapeutic dose of NSSL-MPS showed a reduction in inflammation at the time points used for the PET/CT imaging compared with the control group.Conclusions: PET imaging was used for the first time to track a liposomal glucocorticoid, showing high uptake at visible and occult inflamed sites and a good correlation with the degree of inflammation. A subsequent therapeutic response matching imaging time points in the same model demonstrated the potentia

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