Publications by authors named "Cinzia Imberti"

19 Publications

  • Page 1 of 1

Metallodrugs are unique: opportunities and challenges of discovery and development.

Chem Sci 2020 Nov 12;11(48):12888-12917. Epub 2020 Nov 12.

Department of Chemistry, University of Warwick Gibbet Hill Road Coventry CV4 7AL UK

Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs.
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http://dx.doi.org/10.1039/d0sc04082gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163330PMC
November 2020

DNA-Intercalative Platinum Anticancer Complexes Photoactivated by Visible Light.

Chemistry 2021 May 27. Epub 2021 May 27.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

Photoactivatable agents offer the prospect of highly selective cancer therapy with low side effects and novel mechanisms of action that can combat current drug resistance. 1,8-Naphthalimides with their extended π system can behave as light-harvesting groups, fluorescent probes and DNA intercalators. We conjugated N-(carboxymethyl)-1,8-naphthalimide (gly-R-Nap) with an R substituent on the naphthyl group to photoactive diazido Pt complexes to form t,t,t-[Pt(py) (N ) (OH)(gly-R-Nap)], R=H (1), 3-NO (2) or 4-NMe (3). They show enhanced photo-oxidation, cellular accumulation and promising photo-cytotoxicity in human A2780 ovarian, A549 lung and PC3 prostate cancer cells with visible light activation, and low dark cytotoxicity. Complexes 1 and 2 exhibit pre-intercalation into DNA, resulting in enhanced photo-induced DNA crosslinking. Complex 3 has a red-shifted absorption band at 450 nm, allowing photoactivation and photo-cytotoxicity with green light.
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http://dx.doi.org/10.1002/chem.202101168DOI Listing
May 2021

Methods and techniques for in vitro subcellular localization of radiopharmaceuticals and radionuclides.

Nucl Med Biol 2021 Jul-Aug;98-99:18-29. Epub 2021 Apr 22.

Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, King's College London, London SE1 7EH, United Kingdom. Electronic address:

In oncology, the holy grail of radiotherapy is specific radiation dose deposition in tumours with minimal healthy tissue toxicity. If used appropriately, injectable, systemic radionuclide therapies could meet these criteria, even for treatment of micrometastases and single circulating tumour cells. The clinical use of α and β particle-emitting molecular radionuclide therapies is rising, however clinical translation of Auger electron-emitting radionuclides is hampered by uncertainty around their exact subcellular localisation, which in turn affects the accuracy of dosimetry. This review aims to discuss and compare the advantages and disadvantages of various subcellular localisation methods available to localise radiopharmaceuticals and radionuclides for in vitro investigations.
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http://dx.doi.org/10.1016/j.nucmedbio.2021.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610823PMC
April 2021

Axial functionalisation of photoactive diazido platinum(iv) anticancer complexes.

Inorg Chem Front 2020 Oct 26;7(19):3533-3540. Epub 2020 Aug 26.

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.

Mono-axial functionalised octahedral diazido Pt(iv) complexes trans, trans, trans-[Pt(py)(N)(OR)(OR)] (OR = OH and OR = anticancer agent coumarin-3 carboxylate (cou, ), pyruvate dehydrogenase kinase (PDK) inhibitors 4-phenylbutyrate (PhB, ) or dichloroacetate (DCA, )), and their di-axial functionalised analogues with OR = DCA and OR = cou (), PhB (), or DCA () have been synthesised and characterised, including the X-ray crystal structures of complexes and . These complexes exhibit dark stability and have the potential to generate cytotoxic Pt(ii) species and free radicals selectively in cancer cells when irradiated. Mono-functionalised complexes showed higher aqueous solubility and more negative reduction potentials. Mono- and di-functionalised complexes displayed higher photocytotoxicity with blue light (1 h, 465 nm, 4.8 mW cm) than the parent dihydroxido complex 1 (OR = OR = OH) in A2780 human ovarian (IC 0.9-2.9 μM for ; 0.11-0.39 μM for ) and A549 human lung cancer cells (5.4-7.8 μM for ; 1.2-2.6 μM for ) with satisfactory dark stability. Notably, no apparent dark cytotoxicity was observed in healthy lung MRC-5 fibroblasts for all complexes (IC > 20 μM). Significantly higher platinum cellular accumulation and photo-generated ROS levels were observed for the di-functionalised complexes compared with their mono-functionalised analogues when cancer cells were treated under the same concentrations.
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http://dx.doi.org/10.1039/D0QI00685HDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610473PMC
October 2020

Ligand-Controlled Reactivity and Cytotoxicity of Cyclometalated Rhodium(III) Complexes.

Eur J Inorg Chem 2020 Mar 20;2020(11-12):1052-1060. Epub 2019 Nov 20.

Department of Chemistry, University of Warwick, CV4 7AL, Coventry, UK.

We report the synthesis, characterisation and cytotoxicity of six cyclometalated rhodium(III) complexes [CpRh(C^N)Z], in which Cp = Cp*, Cp, or Cp, C^N = benzo[h]quinoline, and Z = chloride or pyridine. Three x-ray crystal structures showing the expected "piano-stool" configurations have been determined. The chlorido complexes hydrolysed faster in aqueous solution, also reacted preferentially with 9-ethyl guanine or glutathione compared to their pyridine analogues. The 1-biphenyl-2,3,4,5,-tetramethylcyclopentadienyl complex [CpRh(benzo[h]quinoline)Cl] () was the most efficient catalyst in coenzyme reduced nicotinamide adenine dinucleotide (NADH) oxidation to NAD and induced an elevated level of reactive oxygen species (ROS) in A549 human lung cancer cells. The pyridine complex [CpRh(benzo[h]quinoline)py] () was the most potent against A549 lung and A2780 ovarian cancer cell lines, being 5-fold more active than cisplatin towards A549 cells, and acted as a ROS scavenger. This work highlights a ligand-controlled strategy to modulate the reactivity and cytotoxicity of cyclometalated rhodium anticancer complexes.
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http://dx.doi.org/10.1002/ejic.201901055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610438PMC
March 2020

Synthesis and in vivo evaluation of PEG-BP-BaYbF nanoparticles for computed tomography imaging and their toxicity.

J Mater Chem B 2020 09 29;8(34):7723-7732. Epub 2020 Jul 29.

Department of Imaging Chemistry & Biology, School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK.

Computed tomography (CT) is one of the most widespread imaging techniques in clinical use worldwide. CT contrast agents are administered to improve soft tissue contrast and highlight blood vessels. However, the range of CT contrast agents available in the clinic is limited and they suffer from short-circulation times and low k-edge values that result in the need for high doses for in vivo applications. Nanomaterials containing a mixture of electron-dense elements, such as BaYbF nanoparticles, have shown promise as more efficient CT contrast agents, but they require biocompatible coatings for biomedical applications. Here, we explore the use of a bifunctional PEG polymer (5 kDa) containing a terminal bisphosphonate (BP) anchor for efficient binding to the surface of BaYbF nanomaterials. The resulting PEG(5)-BP-BaYbF nanoparticles were synthesized and characterized using TEM, DLS, TGA, XRD and Z-potential measurements. Their in vitro stability was verified and their ability to produce CT contrast in a wide range of X-ray energies, covering preclinical and clinical scanners, was demonstrated. In vitro toxicity studies with PEG(5)-BP-BaYbF in the phagocytic pro-monocytic human cell line U937 did not identify toxic effects, even at high concentrations (30 mM). In vivo, PEG(5)-BP-BaYbF exhibited efficient CT contrast for angiography imaging, highlighting blood vessels and vascular organs, and long circulation times as expected from the PEG coating. However, at late time points (48 h), in vivo toxicity was observed. While the causes could not be completely elucidated, in vitro studies suggest that decomposition and release of Yb and/or Ba metal ions after decomposition of PEG(5)-BP-BaYbF may play a role. Overall, despite the promising CT contrast properties, our results suggest that BaYbF nanomaterials may suffer from significant long-term toxicities.
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http://dx.doi.org/10.1039/d0tb00969eDOI Listing
September 2020

Manipulating the In Vivo Behaviour of Ga with Tris(Hydroxypyridinone) Chelators: Pretargeting and Blood Clearance.

Int J Mol Sci 2020 Feb 22;21(4). Epub 2020 Feb 22.

School of Biomedical Engineering and Imaging Sciences, King's College London, Fourth Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, UK.

Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THP as a high-affinity pair capable of combining in vivo. After confirming the ability of THP to bind Ga in vivo at low concentrations, the bifunctional THP-NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 μg of THP-NCS-huA33, followed after 24 h by 8-10 MBq of Ga) with both a directly labelled radioimmunoconjugate (Zr-DFO-NCS-huA33, 88 μg, 7 MBq) and a Ga-only negative control (8-10 MBq of Ga). Imaging was performed 25 h after antibody administration (1 h after Ga administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of "unchelated" Ga in the tumour was found (12.9 %ID/g) even without prior administration of THP-NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the Ga-only experiment was repeated using THP (20 μg, 1 h after Ga administration) to clear circulating Ga, producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THP as a Ga clearing agent in imaging applications with gallium citrate.
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http://dx.doi.org/10.3390/ijms21041496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073083PMC
February 2020

Biotinylated photoactive Pt(iv) anticancer complexes.

Chem Commun (Camb) 2020 Feb 28;56(15):2320-2323. Epub 2020 Jan 28.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

Novel biotinylated diazido-Pt(iv) complexes exhibit high visible light photocytotoxicity while being stable in the dark. Photocytotoxicity and cellular accumulation of all-trans-[Pt(py)(N)(biotin)(OH)] (2a) were enhanced significantly when bound to avidin; irradiation induced dramatic cellular morphological changes in human ovarian cancer cells treated with 2a.
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http://dx.doi.org/10.1039/c9cc07845bDOI Listing
February 2020

In vitro cytotoxicity of Auger electron-emitting [Ga]Ga-trastuzumab.

Nucl Med Biol 2020 Jan - Feb;80-81:57-64. Epub 2019 Dec 13.

Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, St. Thomas' Hospital, London, SE1 7EH, United Kingdom. Electronic address:

Introduction: Molecular radiotherapy exploiting short-range Auger electron-emitting radionuclides has potential for targeted cancer treatment and, in particular, is an attractive option for managing micrometastatic disease. Here, an approach using chelator-trastuzumab conjugates to target radioactivity to breast cancer cells was evaluated as a proof-of-concept to assess the suitability of Ga as a therapeutic radionuclide.

Methods: THP-trastuzumab and DOTA-trastuzumab were synthesised and radiolabelled with Auger electron-emitters Ga and In, respectively. Radiopharmaceuticals were tested for HER2-specific binding and internalisation, and their effects on viability (dye exclusion) and clonogenicity of HER2-positive HCC1954 and HER2-negative MDA-MB-231 cell lines was measured. Labelled cell populations were studied by microautoradiography.

Results: Labelling efficiencies for [Ga]Ga-THP-trastuzumab and [In]In-DOTA-trastuzumab were 90% and 98%, respectively, giving specific activities 0.52 ± 0.16 and 0.61 ± 0.11 MBq/μg (78-92 GBq/μmol). At 4 nM total antibody concentration and 200 × 10 cells/mL, [Ga]Ga-THP-trastuzumab showed higher percentage of cell association (10.7 ± 1.3%) than [In]In-DOTA-trastuzumab (6.2 ± 1.6%; p = 0.01). The proportion of bound activity that was internalised did not differ significantly for the two tracers (62.1 ± 1.4% and 60.8 ± 15.5%, respectively). At 100 nM, percentage cell binding of both radiopharmaceuticals was greatly reduced compared to 4 nM and did not differ significantly between the two (1.2 ± 1.0% [Ga]Ga-THP-trastuzumab and 0.8 ± 0.9% for [In]In-DOTA-trastuzumab). Viability and clonogenicity of HER2-positive cells decreased when each radionuclide was incorporated into cells by conjugation with trastuzumab, but not when the same level of radioactivity was confined to the medium by omitting the antibody conjugation, suggesting that Ga needs to be cell-bound or internalised for a therapeutic effect. Microautoradiography showed that radioactivity bound to individual cells varied considerably within the population.

Conclusions: [Ga]Ga-THP-trastuzumab reduced cell viability and clonogenicity only when cell-bound, suggesting Ga holds promise as a therapeutic radionuclide as part of a targeted radiopharmaceutical. The causes and consequences of non-homogeneous uptake among the cell population should be explored.
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http://dx.doi.org/10.1016/j.nucmedbio.2019.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099941PMC
January 2021

Strategies for conjugating iridium(III) anticancer complexes to targeting peptides via copper-free click chemistry.

Inorganica Chim Acta 2020 Apr 23;503:119396. Epub 2019 Dec 23.

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.

We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged 'piano-stool' configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes.
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http://dx.doi.org/10.1016/j.ica.2019.119396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610455PMC
April 2020

New Designs for Phototherapeutic Transition Metal Complexes.

Angew Chem Int Ed Engl 2020 01 24;59(1):61-73. Epub 2019 Sep 24.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

In this Minireview, we highlight recent advances in the design of transition metal complexes for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT), and discuss the challenges and opportunities for the translation of such agents into clinical use. New designs for light-activated transition metal complexes offer photoactivatable prodrugs with novel targeted mechanisms of action. Light irradiation can provide spatial and temporal control of drug activation, increasing selectivity and reducing side-effects. The photophysical and photochemical properties of transition metal complexes can be controlled by the appropriate choice of the metal, its oxidation state, the number and types of ligands, and the coordination geometry.
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http://dx.doi.org/10.1002/anie.201905171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973108PMC
January 2020

Tuning the properties of tris(hydroxypyridinone) ligands: efficient Ga chelators for PET imaging.

Dalton Trans 2019 Mar;48(13):4299-4313

King's College London, School of Biomedical Engineering and Imaging Sciences, St Thomas' Hospital, London SE1 7EH, UK.

The prototype tris(1,6-dimethyl-3-hydroxypyridin-4-one) chelator for gallium-68, THPMe, has shown great promise for rapid and efficient kit-based 68Ga labelling of PET radiopharmaceuticals. Peptide derivatives of THPMe have been used to image expression of their target receptors in vivo in preclinical and clinical studies. Herein we describe new synthetic routes to the THP platform including replacing the 1,6-dimethyl-3-hydroxypyridin-4-one N1-CH3 group of THPMe with O (tris(6-methyl-3-hydroxypyran-4-one, THPO) and N1-H (tris(6-methyl-3-hydroxypyridin-4-one), THPH) groups. The effect of these structural modifications on lipophilicity, gallium binding and metal ion selectivity was investigated. THPH was able to bind 68Ga in extremely mild conditions (5 min, room temperature, pH 6, 1 μM ligand concentration) and, notably, in vivo, when administered to a mouse previously injected with 68Ga acetate. The 67Ga radiolabelled complex was stable in serum for more than 7 days. [68Ga(THPH)] displayed a log P value of -2.40 ± 0.02, less negative than the log P = -3.33 ± 0.02 measured for [68Ga(THPMe)], potentially due to an increase in intramolecular hydrogen bonding attributable to the N1-H pyridinone units. Spectrophotometric determination of the Ga3+/Fe3+ complex formation constants for both THPMe and THPH revealed their preference for binding Ga3+ over Fe3+, which enabled selective labelling with 68Ga3+ in the presence of a large excess of Fe3+ in both cases. Compared to THPMe, THPH showed significantly reduced affinity for Fe3+, increased affinity for Ga3+ and improved radiolabelling efficiency. THPO was inferior to both THPH and THPMe in terms of labelling efficiency, but its benzylated precursor Bn-THPO (tris(6-methyl-3-benzyloxypyran-4-one)) provides a potential platform for the synthesis of a library of THP compounds with tunable chemical properties and metal preferences.
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http://dx.doi.org/10.1039/c8dt04454fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469224PMC
March 2019

Nucleus-Targeted Organoiridium-Albumin Conjugate for Photodynamic Cancer Therapy.

Angew Chem Int Ed Engl 2019 02 21;58(8):2350-2354. Epub 2019 Jan 21.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

An organoiridium-albumin bioconjugate (Ir1-HSA) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1-HSA was enhanced significantly compared to parent complex Ir1. The long phosphorescence lifetime and high O quantum yield of Ir1-HSA are highly favorable properties for photodynamic therapy. Ir1-HSA mainly accumulated in the nucleus of living cancer cells and showed remarkable photocytotoxicity against a range of cancer cell lines and tumor spheroids (light IC ; 0.8-5 μm, photo-cytotoxicity index PI=40-60), while remaining non-toxic to normal cells and normal cell spheroids, even after photo-irradiation. This nucleus-targeting organoiridium-albumin is a strong candidate photosensitizer for anticancer photodynamic therapy.
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http://dx.doi.org/10.1002/anie.201813002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468315PMC
February 2019

Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling.

RSC Adv 2017 Oct 25;7(78):49586-49599. Epub 2017 Oct 25.

King's College London, Division of Imaging Sciences and Biomedical Engineering, St Thomas' Hospital, London SE1 7EH, UK. Email:

Gallium-68 (Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression. Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting biomolecules tethered to chelators that complex Ga. Ideally, the chelator will rapidly, quantitatively and stably coordinate Ga at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation. Identification of chelators that fulfil these requirements will facilitate development of kit-based Ga radiopharmaceuticals. Herein the reaction of a range of widely used macrocyclic and acyclic chelators with Ga is reported. Radiochemical yields have been measured under conditions of varying chelator concentrations, pH (3.5 and 6.5) and temperature (25 and 90 °C). These chelators are: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane macrocycles substituted with phosphonic (NOTP) and phosphinic (TRAP) groups at the amine, bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), a tris(hydroxypyridinone) containing three 1,6-dimethyl-3-hydroxypyridin-4-one groups (THP) and the hexadentate tris(hydroxamate) siderophore desferrioxamine-B (DFO). Competition studies have also been undertaken to assess relative complexation efficiencies of each chelator for Ga under different pH and temperature conditions. Performing radiolabelling reactions at pH 6.5, 25 °C and 5-50 μM chelator concentration resulted in near quantitative radiochemical yields for all chelators, except DOTA. Radiochemical yields either decreased or were not substantially improved when the reactions were undertaken at lower pH or at higher temperature, except in the case of DOTA. THP and DFO were the most effective Ga chelators at near-neutral pH and 25 °C, rapidly providing near-quantitative radiochemical yields at very low chelator concentrations. NOTP and HBED were only slightly less effective under these conditions. In competition studies with all other chelators, THP demonstrated highest reactivity for Ga complexation under all conditions. These data point to THP possessing ideal properties for rapid, one-step kit-based syntheses of Ga-biomolecules for molecular PET imaging. LC-MS and H, C{H} and Ga NMR studies of HBED complexes of Ga showed that under the analytical conditions employed in this study, multiple HBED-bound Ga complexes exist. X-ray diffraction data indicated that crystals isolated from these solutions contained octahedral [Ga(HBED)(HO)], with HBED coordinated in a pentadentate NO mode, with only one phenolic group coordinated to Ga, and the remaining coordination site occupied by a water molecule.
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http://dx.doi.org/10.1039/c7ra09076eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708347PMC
October 2017

Ga-THP-PSMA: A PET Imaging Agent for Prostate Cancer Offering Rapid, Room-Temperature, 1-Step Kit-Based Radiolabeling.

J Nucl Med 2017 08 13;58(8):1270-1277. Epub 2017 Apr 13.

Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom; and

The clinical impact and accessibility of Ga tracers for the prostate-specific membrane antigen (PSMA) and other targets would be greatly enhanced by the availability of a simple, 1-step kit-based labeling process. Radiopharmacy staff are accustomed to such procedures in the daily preparation of Tc radiopharmaceuticals. Currently, chelating agents used in Ga radiopharmaceuticals do not meet this ideal. The aim of this study was to develop and evaluate preclinically a Ga radiotracer for imaging PSMA expression that could be radiolabeled simply by addition of Ga generator eluate to a cold kit. A conjugate of a tris(hydroxypyridinone) (THP) chelator with the established urea-based PSMA inhibitor was synthesized and radiolabeled with Ga by adding generator eluate directly to a vial containing the cold precursors THP-PSMA and sodium bicarbonate, with no further manipulation. It was analyzed after 5 min by instant thin-layer chromatography and high-performance liquid chromatography. The product was subjected to in vitro studies to determine PSMA affinity using PSMA-expressing DU145-PSMA cells, with their nonexpressing analog DU145 as a control. In vivo PET imaging and ex vivo biodistribution studies were performed in mice bearing xenografts of the same cell lines, comparing Ga-THP-PSMA with Ga-HBED-CC-PSMA. Radiolabeling was complete (>95%) within 5 min at room temperature, showing a single radioactive species by high-performance liquid chromatography that was stable in human serum for more than 6 h and showed specific binding to PSMA-expressing cells (concentration giving 50% inhibition of 361 ± 60 nM). In vivo PET imaging showed specific uptake in PSMA-expressing tumors, reaching 5.6 ± 1.2 percentage injected dose per cubic centimeter at 40-60 min and rapid clearance from blood to kidney and bladder. The tumor uptake, biodistribution, and pharmacokinetics were not significantly different from those of Ga-HBED-CC-PSMA except for reduced uptake in the spleen. Ga-THP-PSMA has equivalent imaging properties but greatly simplified radiolabeling compared with other Ga-PSMA conjugates. THP offers the prospect of rapid, simple, 1-step, room-temperature syringe-and-vial radiolabeling of Ga radiopharmaceuticals.
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http://dx.doi.org/10.2967/jnumed.117.191882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175039PMC
August 2017

Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68.

Int J Mol Sci 2017 Jan 8;18(1). Epub 2017 Jan 8.

Division of Imaging Sciences and Biomedical Engineering, King's College London, Fourth Floor Lambeth Wing, St. Thomas' Hospital, London SE1 7EH, UK.

Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal, Ga, which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex Ga at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of Ga PET radiopharmaceuticals. Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images.
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http://dx.doi.org/10.3390/ijms18010116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297750PMC
January 2017

Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(hydroxypyridinone) Conjugates for Molecular Imaging of αβ Integrin Expression with Gallium-68.

Bioconjug Chem 2017 02 14;28(2):481-495. Epub 2016 Dec 14.

King's College London , Division of Imaging Sciences and Biomedical Engineering, Fourth Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.

Tris(hydroxypyridinone) chelators conjugated to peptides can rapidly complex the positron-emitting isotope gallium-68 (Ga) under mild conditions, and the resulting radiotracers can delineate peptide receptor expression at sites of diseased tissue in vivo. We have synthesized a dendritic bifunctional chelator containing nine 1,6-dimethyl-3-hydroxypyridin-4-one groups (SCN-HP) that can coordinate up to three Ga ions. This derivative has been conjugated to a trimeric peptide (RGD) containing three peptide groups that target the αβ integrin receptor. The resulting dendritic compound, HP-RGD, can be radiolabeled in 97% radiochemical yield at a 3-fold higher specific activity than its homologues HP-RGD and HP-RGD that contain only a single metal binding site. PET scanning and biodistribution studies show that [Ga(HP-RGD)] demonstrates higher receptor-mediated tumor uptake in animals bearing U87MG tumors that overexpress αβ integrin than [Ga(HP-RGD)] and [Ga(HP-RGD)]. However, concomitant nontarget organ retention of [Ga(HP-RGD)] results in low tumor to nontarget organ contrast in PET images. On the other hand, the trimeric peptide homologue containing a single tris(hydroxypyridinone) chelator, [Ga(HP-RGD)], clears nontarget organs and exhibits receptor-mediated uptake in mice bearing tumors and in mice with induced rheumatoid arthritis. PET imaging with [Ga(HP-RGD)] enables clear delineation of αβ integrin receptor expression in vivo.
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http://dx.doi.org/10.1021/acs.bioconjchem.6b00621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314429PMC
February 2017

Opportunities and challenges for metal chemistry in molecular imaging: from gamma camera imaging to PET and multimodality imaging.

Adv Inorg Chem 2016 16;68:1-41. Epub 2015 Nov 16.

King's College London, Division of Imaging Sciences and Biomedical Engineering, St Thomas' Hospital, London, UK.

The development of medical imaging is a highly multidisciplinary endeavor requiring the close cooperation of clinicians, physicists, engineers, biologists and chemists to identify capabilities, conceive challenges and solutions and apply them in the clinic. The chemistry described in this article illustrates how synergistic advances in these areas drive the technology and its applications forward, with each discipline producing innovations that in turn drive innovations in the others. The main thread running through the article is the shift from single photon radionuclide imaging towards PET, and in turn the emerging shift from PET/CT towards PET/MRI and further, combination of these with optical imaging. Chemistry to support these transitions is exemplified by building on a summary of the status quo, and recent developments, in technetium-99m chemistry for SPECT imaging, followed by a report of recent developments to support clinical application of short lived (Ga-68) and long-lived (Zr-89) positron emitting isotopes, copper isotopes for PET imaging, and combined modality imaging agents based on radiolabelled iron oxide based nanoparticles.
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http://dx.doi.org/10.1016/bs.adioch.2015.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205628PMC
November 2015

New Tris(hydroxypyridinone) Bifunctional Chelators Containing Isothiocyanate Groups Provide a Versatile Platform for Rapid One-Step Labeling and PET Imaging with (68)Ga(3.).

Bioconjug Chem 2016 Feb 2;27(2):309-18. Epub 2015 Sep 2.

King's College London , Division of Imaging Sciences and Biomedical Engineering, Fourth Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.

Two new bifunctional tris(hydroxypyridinone) (THP) chelators designed specifically for rapid labeling with (68)Ga have been synthesized, each with pendant isothiocyanate groups and three 1,6-dimethyl-3-hydroxypyridin-4-one groups. Both compounds have been conjugated with the primary amine group of a cyclic integrin targeting peptide, RGD. Each conjugate can be radiolabeled and formulated by treatment with generator-produced (68)Ga(3+) in over 95% radiochemical yield under ambient conditions in less than 5 min, with specific activities of 60-80 MBq nmol(-1). Competitive binding assays and in vivo biodistribution in mice bearing U87MG tumors demonstrate that the new (68)Ga(3+)-labeled THP peptide conjugates retain affinity for the αvβ3 integrin receptor, clear within 1-2 h from circulation, and undergo receptor-mediated tumor uptake in vivo. We conclude that bifunctional THP chelators can be used for simple, efficient labeling of (68)Ga biomolecules under mild conditions suitable for peptides and proteins.
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http://dx.doi.org/10.1021/acs.bioconjchem.5b00335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759618PMC
February 2016