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  1. Article ; Online: Evaluation of the Biodistribution of Serinolamide-Derivatized C 60 Fullerene

    Nicholas G. Zaibaq / Alyssa C. Pollard / Michael J. Collins / Federica Pisaneschi / Mark D. Pagel / Lon J. Wilson

    Nanomaterials, Vol 10, Iss 1, p

    2020  Volume 143

    Abstract: Carbon nanoparticles have consistently been of great interest in medicine. However, there are currently no clinical materials based on carbon nanoparticles, due to inconsistent biodistribution and excretion data. In this work, we have synthesized a novel ...

    Abstract Carbon nanoparticles have consistently been of great interest in medicine. However, there are currently no clinical materials based on carbon nanoparticles, due to inconsistent biodistribution and excretion data. In this work, we have synthesized a novel C 60 derivative with a metal chelating agent (1,4,7-Triazacyclononane-1,4,7-triacetic acid; NOTA) covalently bound to the C 60 cage and radiolabeled with copper-64 (t 1/2 = 12.7 h). Biodistribution of the material was assessed in vivo using positron emission tomography (PET). Bingel-Hirsch chemistry was employed to functionalize the fullerene cage with highly water-soluble serinolamide groups allowing this new C 60 conjugate to clear quickly from mice almost exclusively through the kidneys. Comparing the present results to the larger context of reports of biocompatible fullerene derivatives, this work offers an important evaluation of the in vivo biodistribution, using experimental evidence to establish functionalization guidelines for future C 60 -based biomedical platforms.
    Keywords fullerene ; serinolamide ; biodistribution ; pharmacokinetics ; pet ; Chemistry ; QD1-999
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article: Combined therapies with nanostructured carbon materials: there is room still available at the bottom

    Biagiotti, Giacomo / Stefano Fedeli / Giulia Tuci / Lapo Luconi / Giuliano Giambastiani / Alberto Brandi / Federica Pisaneschi / Stefano Cicchi / Paolo Paoli

    Journal of materials chemistry. 2018 Apr. 4, v. 6, no. 14

    2018  

    Abstract: The progress of the chemistry of carbon nanotubes (CNT) and graphene derivatives [mainly graphene oxide (GO)] has produced a number of technologically advanced drug delivery systems (DDS) that have been used in the field of nanomedicine, mostly in ... ...

    Abstract The progress of the chemistry of carbon nanotubes (CNT) and graphene derivatives [mainly graphene oxide (GO)] has produced a number of technologically advanced drug delivery systems (DDS) that have been used in the field of nanomedicine, mostly in studies related to oncology. However, such a demanding field of research requires continuous improvements in terms of efficiency, selectivity and versatility. The loading of two, or more, bioactive components on the same nanoparticle offers new possibilities for treating cancer, efficiently addressing issues related both to biodistribution and pharmacokinetics. Nanostructured carbon materials (NCM), with their high surface area, their efficient cellular membrane crossing and their chemical versatility are ideal candidates for easy hetero-decoration and exploitation as advanced DDS. This review describes the achievements obtained in this area focusing on those studies in which two or more active components were loaded onto the DDS.
    Keywords bioactive compounds ; carbon nanotubes ; cell membranes ; drug delivery systems ; graphene ; graphene oxide ; nanomedicine ; nanoparticles ; neoplasms ; pharmacokinetics ; surface area
    Language English
    Dates of publication 2018-0404
    Size p. 2022-2035.
    Publishing place The Royal Society of Chemistry
    Document type Article
    ZDB-ID 2702241-9
    ISSN 2050-7518 ; 2050-750X
    ISSN (online) 2050-7518
    ISSN 2050-750X
    DOI 10.1039/c8tb00121a
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Positron Emission Tomographic Imaging of CXCR4 in Cancer

    Guillaume Pierre Charles George / Federica Pisaneschi / Quang-Dé Nguyen / Eric Ofori Aboagye

    Molecular Imaging, Vol

    Challenges and Promises

    2015  Volume 14

    Abstract: Molecular imaging is an attractive platform for noninvasive detection and assessment of cancer. In recent years, the targeted imaging of the C–X–C chemokine receptor 4 (CXCR4), a chemokine receptor that has been associated with tumor metastasis, has ... ...

    Abstract Molecular imaging is an attractive platform for noninvasive detection and assessment of cancer. In recent years, the targeted imaging of the C–X–C chemokine receptor 4 (CXCR4), a chemokine receptor that has been associated with tumor metastasis, has become an area of intensive research. This review article focuses on positron emission tomography (PET) and aims to provide useful and critical insights into the application of PET to characterize CXCR4 expression, including the chemical, radiosynthetic, and biological requirements for PET radiotracers. This discussion is informed by a summary of the different approaches taken so far and a comparison of their clinical translation. Finally, our expert opinions as to potential future advances in the field are expressed.
    Keywords Biology (General) ; QH301-705.5 ; Medical technology ; R855-855.5
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Hindawi - SAGE Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Development of a Potential Gallium-68-Labelled Radiotracer Based on DOTA-Curcumin for Colon-Rectal Carcinoma

    Giulia Orteca / Federica Pisaneschi / Sara Rubagotti / Tracy W. Liu / Giacomo Biagiotti / David Piwnica-Worms / Michele Iori / Pier Cesare Capponi / Erika Ferrari / Mattia Asti

    Molecules, Vol 24, Iss 3, p

    From Synthesis to In Vivo Studies

    2019  Volume 644

    Abstract: Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in ... ...

    Abstract Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell lines compared to normal human lymphocytes. In the present study, we report a new gallium-68-labelled curcumin derivative ( 68 Ga-DOTA-C21) and its initial validation as marker for early detection of colorectal cancer. The precursor and non-radioactive complexes were synthesized and deeply characterized by analytical methods then the curcuminoid was radiolabelled with gallium-68. The in vitro stability, cell uptake, internalization and efflux properties of the probe were studied in HT29 cells, and the in vivo targeting ability and biodistribution were investigated in mice bearing HT29 subcutaneous tumour model. 68 Ga-DOTA-C21 exhibits decent stability (57 ± 3% after 120 min of incubation) in physiological media and a curcumin-mediated cellular accumulation in colorectal cancer cell line (121 ± 4 KBq of radiotracer per mg of protein within 60 min of incubation). In HT29 tumour-bearing mice, the tumour uptake of 68 Ga-DOTA-C21 is 3.57 ± 0.3% of the injected dose per gram of tissue after 90 min post injection with a tumour to muscle ratio of 2.2 ± 0.2. High amount of activity (12.73 ± 1.9% ID/g) is recorded in blood and significant uptake of the radiotracer occurs in the intestine (13.56 ± 3.3% ID/g), lungs (8.42 ± 0.8% ID/g), liver (5.81 ± 0.5% ID/g) and heart (4.70 ± 0.4% ID/g). Further studies are needed to understand the mechanism of accumulation and clearance; however, 68 Ga-DOTA-C21 provides a productive base-structure to develop further radiotracers for imaging of colorectal cancer.
    Keywords gallium-68 ; radiotracers ; positron emission tomography ; curcuminoids ; colorectal cancer ; Organic chemistry ; QD241-441
    Subject code 610
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: The 3 S Enantiomer Drives Enolase Inhibitory Activity in SF2312 and Its Analogues

    Federica Pisaneschi / Yu-Hsi Lin / Paul G. Leonard / Nikunj Satani / Victoria C. Yan / Naima Hammoudi / Sudhir Raghavan / Todd M. Link / Dimitra K. Georgiou / Barbara Czako / Florian L. Muller

    Molecules, Vol 24, Iss 13, p

    2019  Volume 2510

    Abstract: We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with a previously unknown mode of action, is a potent inhibitor of the glycolytic enzyme, Enolase. SF2312 can only be synthesized as a ... ...

    Abstract We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with a previously unknown mode of action, is a potent inhibitor of the glycolytic enzyme, Enolase. SF2312 can only be synthesized as a racemic-diastereomeric mixture. However, co-crystal structures with Enolase 2 (ENO2) have consistently shown that only the (3 S ,5 S )-enantiomer binds to the active site. The acidity of the alpha proton at C-3, which deprotonates under mildly alkaline conditions, results in racemization; thus while the separation of four enantiomeric intermediates was achieved via chiral High Performance Liquid Chromatography (HPLC) of the fully protected intermediate, deprotection inevitably nullified enantiopurity. To prevent epimerization of the C-3, we designed and synthesized MethylSF2312, ((1,5-dihydroxy-3-methyl-2-oxopyrrolidin-3-yl)phosphonic acid), which contains a fully-substituted C-3 alpha carbon. As a racemic-diastereomeric mixture, MethylSF2312 is equipotent to SF2312 in enzymatic and cellular systems against Enolase. Chiral HPLC separation of a protected MethylSF2312 precursor resulted in the efficient separation of the four enantiomers. After deprotection and inevitable re-equilibration of the anomeric C-5, (3 S )-MethylSF2312 was up to 2000-fold more potent than (3 R )-MethylSF2312 in an isolated enzymatic assay. This observation strongly correlates with biological activity in both human cancer cells and bacteria for the 3 S enantiomer of SF2312. Novel X-ray structures of human ENO2 with chiral and racemic MethylSF2312 show that only (3 S, 5 S) -enantiomer occupies the active site. Enolase inhibition is thus a direct result of binding by the (3 S, 5 S) -enantiomer of MethylSF2312. Concurrent with these results for MethylSF2312, we contend that the (3 S ,5 S )-SF2312 is the single active enantiomer of inhibitor SF2312.
    Keywords glycolysis ; enolase ; chiral ; phosphonate ; hydroxamate ; E. coli ; enzyme inhibitor ; enzyme structure ; natural product ; X-ray crystallography ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Identification of ABC Transporter Interaction of a Novel Cyanoquinoline Radiotracer and Implications for Tumour Imaging by Positron Emission Tomography.

    Rozanna L Slade / Federica Pisaneschi / Quang-De Nguyen / Graham Smith / Laurence Carroll / Alice Beckley / Maciej A Kaliszczak / Eric O Aboagye

    PLoS ONE, Vol 11, Iss 8, p e

    2016  Volume 0161427

    Abstract: Background The epidermal growth factor receptor (EGFR) is overexpressed in many cancers including lung, ovarian, breast, head and neck and brain. Mutation of this receptor has been shown to play a crucial role in the response of non-small cell lung ... ...

    Abstract Background The epidermal growth factor receptor (EGFR) is overexpressed in many cancers including lung, ovarian, breast, head and neck and brain. Mutation of this receptor has been shown to play a crucial role in the response of non-small cell lung carcinoma (NSCLC) to EGFR-targeted therapies. It is envisaged that imaging of EGFR using positron emission tomography (PET) could aid in selection of patients for treatment with novel inhibitors. We recognised multi-drug resistant phenotype as a threat to development of successful imaging agents. In this report, we describe discovery of a novel cyanoquinoline radiotracer that lacks ABC transporter activity. Methods Cellular retention of the prototype cyanoquinoline [18F](2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxyquinolin-6-yl}-4-({[1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl]methyl}amino)-but-2-enamide ([18F]FED6) and [18F](2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxyquinolin-6-yl}-4-[({1-[(2R,5S)-3-fluoro-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]-1H-1,2,3-triazol-4-yl}methyl)amino]but-2-enamide ([18F]FED20) were evaluated to establish potential for imaging specificity. The substrate specificity of a number of cyanoquinolines towards ABC transporters was investigated in cell lines proficient or deficient in ABCB1 or ABCG2. Results FED6 demonstrated substrate specificity for both ABCG2 and ABCB1, a property that was not observed for all cyanoquinolines tested, suggesting scope for designing novel probes. ABC transporter activity was confirmed by attenuating the activity of transporters with drug inhibitors or siRNA. We synthesized a more hydrophilic compound [18F]FED20 to overcome ABC transporter activity. FED20 lacked substrate specificity for both ABCB1 and ABCG2, and maintained a strong affinity for EGFR. Furthermore, FED20 showed higher inhibitory affinity for active mutant EGFR versus wild-type or resistant mutant EGFR; this property resulted in higher [18F]FED20 cellular retention in active mutant EGFR expressing NSCLC. Conclusion ...
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2016-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Mechanism-Specific Pharmacodynamics of a Novel Complex-I Inhibitor Quantified by Imaging Reversal of Consumptive Hypoxia with [ 18 F]FAZA PET In Vivo

    Seth T. Gammon / Federica Pisaneschi / Madhavi L. Bandi / Melinda G. Smith / Yuting Sun / Yi Rao / Florian Muller / Franklin Wong / John De Groot / Jeffrey Ackroyd / Osama Mawlawi / Michael A. Davies / Y.N. Vashisht Gopal / M. Emilia Di Francesco / Joseph R. Marszalek / Mark Dewhirst / David Piwnica-Worms

    Cells, Vol 8, Iss 12, p

    2019  Volume 1487

    Abstract: Tumors lack a well-regulated vascular supply of O 2 and often fail to balance O 2 supply and demand. Net O 2 tension within many tumors may not only depend on O 2 delivery but also depend strongly on O 2 demand. Thus, tumor O 2 consumption rates may ... ...

    Abstract Tumors lack a well-regulated vascular supply of O 2 and often fail to balance O 2 supply and demand. Net O 2 tension within many tumors may not only depend on O 2 delivery but also depend strongly on O 2 demand. Thus, tumor O 2 consumption rates may influence tumor hypoxia up to true anoxia. Recent reports have shown that many human tumors in vivo depend primarily on oxidative phosphorylation (OxPhos), not glycolysis, for energy generation, providing a driver for consumptive hypoxia and an exploitable vulnerability. In this regard, IACS-010759 is a novel high affinity inhibitor of OxPhos targeting mitochondrial complex-I that has recently completed a Phase-I clinical trial in leukemia. However, in solid tumors, the effective translation of OxPhos inhibitors requires methods to monitor pharmacodynamics in vivo. Herein, 18 F-fluoroazomycin arabinoside ([ 18 F]FAZA), a 2-nitroimidazole-based hypoxia PET imaging agent, was combined with a rigorous test-retest imaging method for non-invasive quantification of the reversal of consumptive hypoxia in vivo as a mechanism-specific pharmacodynamic (PD) biomarker of target engagement for IACS-010759. Neither cell death nor loss of perfusion could account for the IACS-010759-induced decrease in [ 18 F]FAZA retention. Notably, in an OxPhos-reliant melanoma tumor, a titration curve using [ 18 F]FAZA PET retention in vivo yielded an IC 50 for IACS-010759 (1.4 mg/kg) equivalent to analysis ex vivo. Pilot [ 18 F]FAZA PET scans of a patient with grade IV glioblastoma yielded highly reproducible, high‐contrast images of hypoxia in vivo as validated by CA-IX and GLUT-1 IHC ex vivo. Thus, [ 18 F]FAZA PET imaging provided direct evidence for the presence of consumptive hypoxia in vivo, the capacity for targeted reversal of consumptive hypoxia through the inhibition of OxPhos, and a highly-coupled mechanism-specific PD biomarker ready for translation.
    Keywords hypoxia ; [18f]faza ; pet ; iacs-010759 ; mitochondrial complex i ; metabolism ; pharmacodynamics ; oxidative phosphorylation ; collateral lethality ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2019-11-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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