| Reference | [1]. Antibiotics (Basel). 2020 Mar 27;9(4):144. doi: 10.3390/antibiotics9040144.<br />
The Iron-chelator, N,N'-bis (2-hydroxybenzyl) Ethylenediamine-N,N'-Diacetic acid is an Effective Colistin Adjunct against Clinical Strains of Biofilm-Dwelling Pseudomonas aeruginosa.<br />
Mettrick K(1), Hassan K(1), Lamont I(2), Reid D(3).<br />
Author information: (1)School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia. (2)Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand. (3)QIMR-Berghofer Institute of Medical Research, Herston, QLD 4029, Australia.<br />
Targeting the iron requirement of Pseudomonas aeruginosa may be an effective adjunctive for conventional antibiotic treatment against biofilm-dwelling P. aeruginosa. We, therefore, assessed the anti-biofilm activity of N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED), which is a synthetic hexadentate iron chelator. The effect of HBED was studied using short-term (microtitre plate) and longer-term (flow-cell) biofilm models, under aerobic, anaerobic, and microaerobic (flow-cell) conditions and in combination with the polymyxin antibiotic colistimethate sodium (colistin). HBED was assessed against strains of P. aeruginosa from patients with cystic fibrosis and the reference strain PAO1. HBED inhibited growth and biofilm formation of all clinical strains under aerobic and anaerobic conditions, but inhibitory effects against PAO1 were predominantly exerted under anaerobic conditions. PA605, which is a clinical strain with a robust biofilm-forming phenotype, was selected for flow-cell studies. HBED significantly reduced biomass and surface coverage of PA605, and, combined with colistin, HBED significantly enhanced the microcolony killing effects of colistin to result in almost complete removal of the biofilm. HBED combined with colistin is highly effective in vitro against biofilms formed by clinical strains of P. aeruginosa.<br />
DOI: 10.3390/antibiotics9040144 PMCID: PMC7235823 PMID: 32230813<br />
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[2]. (68)Ga-N,N’-bis[2-Hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N’-diacetic acid-polyethylene glycol-single-chain Cys-tagged vascular endothelial growth factor-121.<br />
Leung K(1).<br />
In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004–2013. 2010 Dec 18 [updated 2011 Feb 17].<br />
Author information: (1)National Center for Biotechnology Information, NLM, NIH, Bethesda, MD<br />
Vascular endothelial growth factor (VEGF) consists of at least six isoforms with various numbers of amino acids (121, 145, 165, 183, 189, and 206 amino acids) produced through alternative splicing (1). VEGF121, VEGF165, and VEGF189 are the forms secreted by most cell types and are active as homodimers linked by disulfide bonds. VEGF121 does not bind to heparin like the other VEGF species do (2). VEGF is a potent angiogenic factor that induces proliferation, sprouting, migration, and tube formation of endothelial cells. There are three high-affinity tyrosine kinase VEGF receptors (VEGFRs) on endothelial cells (VEGFR-1, Flt-1; VEGFR-2, KDR/Flt-1; and VEGFR-3, Flt-4). Several types of non-endothelial cells, such as hematopoietic stem cells, melanoma cells, monocytes, osteoblasts, and pancreatic β cells, also express VEGFRs (1). VEGFRs have been found to be overexpressed in various tumor cells and tumor-associated endothelial cells but are not detectable in quiescent endothelial cells (3). Inhibition of VEGFR function has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis (4, 5). Radiolabeled VEGF has been developed as a tracer for imaging solid tumors and angiogenesis in humans (6-8). A 15-amino-acid fusion tag (Cys-tag) was developed for site-specific conjugation via the free sulfhydryl group of Cys. Backer et al. (9) prepared a Cys-tagged vector of VEGF121 by cloning two single-chain 3–112 amino acid fragments of VEGF121 joining head-to-tail to express as scVEGF, which was labeled as 64Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-polyethylene glycol (PEG)-scVEGF (64Cu-DOTA-PEG-scVEGF), 99mTc-hydrazinonicotinic acid (HYNIC)-scVEGF (99mTc-HYNIC-scVEGF), and Cy5.5-scVEGF for imaging VEGFR expression to study tumor angiogenesis. In this chapter, 68Ga-N,N’-bis[2-Hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N’-diacetic acid-PEG-scVEGF (68Ga-HBED-CC-PEG-scVEGF) is being developed for positron emission tomography (PET) imaging of VEGFR-2 in tumor vasculature (10).<br />
PMID: 21348057<br />
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[3]. (99m)Tc-Ethylenenediamine-N,N'-diacetic acid/hydrazinonicotinamide[Lys(3)]-bombesin.<br />
Cheng KT(1), Ferro-Flores G(2), Arteaga de Murphy C(3).<br />
In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004–2013. 2007 Aug 15 [updated 2007 Sep 19].<br />
Author information: (1)National Center for Biotechnology Information, NLM, NIH, [email protected] (2)Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, [email protected] (3)Departamento de Medicina Nuclear, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, [email protected]<br />
99mTc-Ethylenediamine-N,N’-diacetic acid/hydrazinonicotinamide-[Lys3]-bombesin (99mTc-EDDA/HYNIC-[Lys3]-BN) is a peptide analog of human gastrin-releasing peptide (GRP) conjugated with 99mTc, and it was developed for planar gamma and single-photon emission computed tomography (SPECT) imaging of tumors with overexpressed GRP receptors (GRP-R) (1). 99mTc is a gamma emitter with a physical half-life (t½) of 6.02 h. The amphibian bombesin (BBN or BN), a peptide of 14 amino acids, is an analog of human GRP, a peptide of 27 amino acids, that binds to GRP-R (BB2) with high affinity and specificity (2, 3). Both GRP and BN share an amidated C-terminus sequence homology of seven amino acids, -Trp-Ala-Val-Gly-His-Leu-Met-NH2. BN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system (CNS) and the gastrointestinal (GI) system (4, 5). They also act as potential growth factors for both normal and neoplastic tissues. Specific BN receptors (BN-R) have been identified in CNS and GI tissues and a number of tumor cell lines. The BN-R superfamily includes at least four different subtypes, namely the GRP-R subtype, the neuromedin B receptor subtype (BB1), the BB3 subtype, and the BB4 subtype (6). Overexpression of GRP-R in various human tumors (e.g., breast, prostate, lung, colon, ovarian, and pancreatic cancers) provides opportunities to image tumors with the use of specific molecular imaging agents designed to target the GRP-R (3, 7-10). There have been varying degrees of success in the current development of GRP-R–targeted radiopharmaceuticals for diagnostic or therapeutic applications (10). Various BN analogs have been labeled with 99mTc and 111In for SPECT imaging (1, 11-13). Baidoo et al. (12) synthesized and radiolabeled [Lys3]-BN (Pyr-Gln-Lys-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) with 99mTc through the diaminedithiol (DADT) bifunctional chelating agent. The 99mTc-DADT-[Lys3]-BN showed high in vitro affinity to the BN-R in rat brain membrane preparations. Because of its favorable physical properties, 99mTc is the radionuclide of choice for routine clinical applications of SPECT imaging (14). HYNIC is a bifunctional coupling agent for 99mTc-labeling of peptides that can achieve high specific activities without interfering with the amino acid sequence responsible for receptor binding (15-17). In this approach, 99mTc is bound to the hydrazine group, and other coordination sites are occupied by one or more coligands . The choice of coligand can influence the stability and hydrophilicity of the radiolabeled peptide (15, 18). Convenient freeze-dried kit formulations with HYNIC for labeling peptides with 99mTc have been achieved (19). Using the HYNIC labeling strategy and EDDA/N-tris(hydroxymethyl)-methylglycine (tricine) as the coligands, Ferro-Flores et al. (1) successfully prepared 99mTc-EDDA/HYNIC-[Lys3]-BN as a potential molecular imaging probe for GRP-R.<br />
PMID: 20641296<br />
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[4]. Medchemcomm. 2017 Feb 16;8(3):673-679. doi: 10.1039/c7md00006e. eCollection 2017 Mar 1.<br />
(68)Ga-Chelation and comparative evaluation of N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) conjugated NGR and RGD peptides as tumor targeted molecular imaging probes.<br />
Satpati D(1), Sharma R(1), Kumar C(1), Sarma HD(2), Dash A(1).<br />
Author information: (1)Radiopharmaceuticals Division , Bhabha Atomic Research Centre , Mumbai , India . Email: [email protected] ; ; Tel: +91 22 25590748. (2)Radiation Biology and Health Science Division , Bhabha Atomic Research Centre , Mumbai , India.<br />
Peptides containing RGD and NGR motifs display high affinity towards tumor vasculature molecular markers, integrin αvβ3 and CD13 receptors, respectively. In the present study, RGD and NGR peptides were conjugated with the novel acyclic chelator N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) for radiolabeling with 68Ga. The radiotracers [68Ga-HBED-CC-c(NGR)] and [68Ga-HBED-CC-c(RGD)] were quite hydrophilic with respective log P values being -2.8 ± 0.14 and -2.1 ± 0.17. 68Ga-HBED-CC-c(RGD) displayed a significantly higher (p < 0.05) uptake in murine melanoma B16F10 tumors as compared to 68Ga-HBED-CC-c(NGR) indicating its higher specificity towards integrin αvβ3-positive tumors. The two radiotracers showed similar uptake in CD13-positive human fibrosarcoma HT-1080 tumor xenografts (∼1.5 ± 0.2% ID g-1). The tumor uptake of the two radiotracers was significantly reduced (p < 0.05) in both animal models during blocking studies. The tumor-to-blood ratio was observed to be ∼2-2.5 for the two radiotracers, whereas the tumor-to-muscle ratio was significantly higher (p < 0.005) for 68Ga-HBED-CC-c(RGD) in the two animal models. The two radiotracers 68Ga-HBED-CC-c(NGR) and 68Ga-HBED-CC-c(RGD) exhibited renal excretion with rapid clearance from blood and other non-target organs. Thus, 68Ga-chelated HBED-CC conjugated NGR and RGD peptides expressed features conducive towards development as tumor targeted molecular imaging probes. This study further opens avenues for the successful conjugation of different peptides with the acyclic chelator HBED-CC and expansion of 68Ga-based radiopharmaceuticals.<br />
DOI: 10.1039/c7md00006e PMCID: PMC6071919 PMID: 30108785<br />
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[5]. Inorg Chem. 2016 Mar 21;55(6):2977-85. doi: 10.1021/acs.inorgchem.5b02865. Epub 2016 Mar 1.<br />
Thermodynamic and Spectroscopic Studies of Trivalent f-element Complexation with Ethylenediamine-N,N'-di(acetylglycine)-N,N'-diacetic Acid.<br />
Heathman CR(1), Grimes TS(1), Zalupski PR(1).<br />
Author information: (1)Aqueous Separations and Radiochemistry, Idaho National Laboratory , Idaho Falls, Idaho 83415, United States.<br />
The coordination behavior and thermodynamic features of complexation of trivalent lanthanides and americium by ethylenediamine-N,N'-di(acetylglycine)-N,N'-diacetic acid (EDDAG-DA) (bisamide-substituted-EDTA) were investigated by potentiometric and spectroscopic techniques. Acid dissociation constants (K(a)) and complexation constants (β) of lanthanides (except Pm) were determined by potentiometric analysis. Absorption spectroscopy was used to determine stability constants for the binding of trivalent americium and neodymium by EDDAG-DA under similar conditions. The potentiometry revealed 5 discernible protonation constants and 3 distinct metal-ligand complexes (identified as ML(-), MHL, and MH2L(+)). Time-resolved fluorescence studies of Eu-(EDDAG-DA) solutions (at varying pH) identified a constant inner-sphere hydration number of 3, suggesting that glycine functionalities contained in the amide pendant arms are not involved in metal complexation and are protonated under more acidic conditions. The thermodynamic studies identified that f-element coordination by EDDAG-DA is similar to that observed for ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA). However, coordination via two amidic oxygens of EDDAG-DA lowers its trivalent f-element complex stability by roughly 3 orders of magnitude relative to EDTA.<br />
DOI: 10.1021/acs.inorgchem.5b02865 PMID: 26930023
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