• Login
    View Item 
    •   Home
    • Office of Sponsored Research (OSR)
    • KAUST Funded Research
    • Publications Acknowledging KAUST Support
    • View Item
    •   Home
    • Office of Sponsored Research (OSR)
    • KAUST Funded Research
    • Publications Acknowledging KAUST Support
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of KAUSTCommunitiesIssue DateSubmit DateThis CollectionIssue DateSubmit Date

    My Account

    Login

    Quick Links

    Open Access PolicyORCID LibguideTheses and Dissertations LibguideSubmit an Item

    Statistics

    Display statistics

    Conjugates of Superoxide Dismutase 1 with Amphiphilic Poly(2-oxazoline) Block Copolymers for Enhanced Brain Delivery: Synthesis, Characterization and Evaluation in Vitro and in Vivo

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Type
    Article
    Authors
    Tong, Jing
    Yi, Xiang
    Luxenhofer, Robert
    Banks, William A.
    Jordan, Rainer
    Zimmerman, Matthew C.
    Kabanov, Alexander V.
    KAUST Grant Number
    KUK-F1-029-32
    Date
    2012-12-17
    Online Publication Date
    2012-12-17
    Print Publication Date
    2013-01-07
    Permanent link to this record
    http://hdl.handle.net/10754/597837
    
    Metadata
    Show full item record
    Abstract
    Superoxide dismutase 1 (SOD1) efficiently catalyzes dismutation of superoxide, but its poor delivery to the target sites in the body, such as brain, hinders its use as a therapeutic agent for superoxide-associated disorders. Here to enhance the delivery of SOD1 across the blood-brain barrier (BBB) and in neurons the enzyme was conjugated with poly(2-oxazoline) (POx) block copolymers, P(MeOx-b-BuOx) or P(EtOx-b-BuOx), composed of (1) hydrophilic 2-methyl-2-oxazoline (MeOx) or 2-ethyl-2-oxazoline (EtOx) and (2) hydrophobic 2-butyl-2-oxazoline (BuOx) repeating units. The conjugates contained from 2 to 3 POx chains joining the protein amino groups via cleavable -(ss)- or noncleavable -(cc)- linkers at the BuOx block terminus. They retained 30% to 50% of initial SOD1 activity, were conformationally and thermally stable, and assembled in 8 or 20 nm aggregates in aqueous solution. They had little if any toxicity to CATH.a neurons and displayed enhanced uptake in these neurons as compared to native or PEGylated SOD1. Of the two conjugates, SOD1-(cc)-P(MeOx-b-BuOx) and SOD1-(cc)-P(EtOx-b-BuOx), compared, the latter was entering cells 4 to 7 times faster and at 6 h colocalized predominantly with endoplasmic reticulum (41 ± 3%) and mitochondria (21 ± 2%). Colocalization with endocytosis markers and pathway inhibition assays suggested that it was internalized through lipid raft/caveolae, also employed by the P(EtOx-b-BuOx) copolymer. The SOD activity in cell lysates and ability to attenuate angiotensin II (Ang II)-induced superoxide in live cells were increased for this conjugate compared to SOD1 and PEG-SOD1. Studies in mice showed that SOD1-POx had ca. 1.75 times longer half-life in blood than native SOD1 (28.4 vs 15.9 min) and after iv administration penetrated the BBB significantly faster than albumin to accumulate in brain parenchyma. The conjugate maintained high stability both in serum and in brain (77% vs 84% at 1 h postinjection). Its amount taken up by the brain reached a maximum value of 0.08% ID/g (percent of the injected dose taken up per gram of brain) 4 h postinjection. The entry of SOD1-(cc)-P(EtOx-b-BuOx) to the brain was mediated by a nonsaturable mechanism. Altogether, SOD1-POx conjugates are promising candidates as macromolecular antioxidant therapies for superoxide-associated diseases such as Ang II-induced neurocardiovascular diseases.
    Citation
    Tong J, Yi X, Luxenhofer R, Banks WA, Jordan R, et al. (2013) Conjugates of Superoxide Dismutase 1 with Amphiphilic Poly(2-oxazoline) Block Copolymers for Enhanced Brain Delivery: Synthesis, Characterization and Evaluation in Vitro and in Vivo. Molecular Pharmaceutics 10: 360–377. Available: http://dx.doi.org/10.1021/mp300496x.
    Sponsors
    This study was supported by the United States National Institute of Health RO1 Grant NS051334, the United States Department of Defense (DoD) USAMRMC 06108004, and the Nanomaterials Core Facility of the Nebraska Center of Nanomedicine supported by NIH COBRE Grant RR021937 (all awarded to A.V.K.). R.L. is also thankful to the King Abdullah University of Science and Technology (KAUST Award No. KUK-F1-029-32, partial salary support for R.L.). Likewise J.T. has been in part supported by the Program of Excellence Graduate Assistantship from UNMC. We also gratefully acknowledge Professor Luis Marky (College of Pharmacy, UNMC) for kind assistance in CD and DSC experiments, Daria Filonova (College of Pharmacy, UNC-Chapel Hill) for her assistance in preparation of the Table of Contents Graphic, and the assistance of UNMC CLSM, Cell Analysis and MS core facilities.
    Publisher
    American Chemical Society (ACS)
    Journal
    Molecular Pharmaceutics
    DOI
    10.1021/mp300496x
    PubMed ID
    23163230
    PubMed Central ID
    PMC3570234
    ae974a485f413a2113503eed53cd6c53
    10.1021/mp300496x
    Scopus Count
    Collections
    Publications Acknowledging KAUST Support

    entitlement

    Related articles

    • Pluronic-modified superoxide dismutase 1 attenuates angiotensin II-induced increase in intracellular superoxide in neurons.
    • Authors: Yi X, Zimmerman MC, Yang R, Tong J, Vinogradov S, Kabanov AV
    • Issue date: 2010 Aug 15
    • Neuronal uptake and intracellular superoxide scavenging of a fullerene (C60)-poly(2-oxazoline)s nanoformulation.
    • Authors: Tong J, Zimmerman MC, Li S, Yi X, Luxenhofer R, Jordan R, Kabanov AV
    • Issue date: 2011 May
    • Cross-linked antioxidant nanozymes for improved delivery to CNS.
    • Authors: Klyachko NL, Manickam DS, Brynskikh AM, Uglanova SV, Li S, Higginbotham SM, Bronich TK, Batrakova EV, Kabanov AV
    • Issue date: 2012 Jan
    • Neuronal uptake of nanoformulated superoxide dismutase and attenuation of angiotensin II-dependent hypertension after central administration.
    • Authors: Savalia K, Manickam DS, Rosenbaugh EG, Tian J, Ahmad IM, Kabanov AV, Zimmerman MC
    • Issue date: 2014 Aug
    • Protein modification with amphiphilic block copoly(2-oxazoline)s as a new platform for enhanced cellular delivery.
    • Authors: Tong J, Luxenhofer R, Yi X, Jordan R, Kabanov AV
    • Issue date: 2010 Aug 2
    DSpace software copyright © 2002-2022  DuraSpace
    Quick Guide | Contact Us | KAUST University Library
    Open Repository is a service hosted by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items. For anonymous users the allowed maximum amount is 50 search results.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.