KUKU

KU ScholarWorks

  • myKU
  • Email
  • Enroll & Pay
  • KU Directory
    • Login
    View Item 
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Targeting of nanoparticles to cell adhesion molecules for potential immune therapy

    Thumbnail
    View/Open
    Chittasupho_ku_0099D_11232_DATA_1.pdf (3.104Mb)
    Issue Date
    2010-12-10
    Author
    Chittasupho, Chuda
    Publisher
    University of Kansas
    Format
    208 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Pharmaceutical Chemistry
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
    Metadata
    Show full item record
    Abstract
    Cell adhesion molecules including leukocyte function associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) play an important role in regulating inflammatory responses. For circulating leukocytes to enter inflamed tissue or peripheral lymphoid organs, the cells must adhere to and transmigrate between endothelial cells lining blood vessel wall by binding of LFA-1 on leukocytes to ICAM-1 on endothelial cells. In addition, interaction of LFA-1 expressed on T cells and ICAM-1 expressed on antigen presenting cells (APCs) is crucial for immunological synapse formation and hence T cell activation. Clustering of LFA-1 and ICAM-1 by multivalent ligands increases binding avidity of these cell adhesion molecules. In this thesis, multivalent ICAM-1 or LFA-1 ligands were conjugated to the surface of polymeric nanoparticles (NPs) to target the clustering of these receptors and increase the avidity of binding to ICAM-1 or LFA-1. Polymeric nanoparticles possess some advantages over other multivalent ligands since drugs can be protected and released. This delivery system permits modification of the nanoparticle surface without compromising the activity of the drug carried. In chapter 2 of this thesis, a peptide ligand targeting ICAM-1 (cLABL) was conjugated to poly (DL-lactic-co-glycolic acid) (PLGA) nanoparticles. The cellular uptake of cLABL conjugated NPs (cLABL-NPs) by lung carcinoma epithelial cells upregulating ICAM-1 was significantly more rapid than control NPs. The specificity of ICAM-1 mediated internalization was confirmed by blocking the uptake of cLABL-NPs to ICAM-1 using free cLABL peptide. Cell studies suggested that cLABL-NPs targeted encapsulated doxorubicin to ICAM-1 expressing cells and provided sustained release of doxorubicin. In chapter 3, a peptide ligand targeting LFA-1 (cIBR) was conjugated to PLGA NPs to specifically target T cells expressing LFA-1. The specificity of NPs targeting LFA-1 was demonstrated by competitive inhibition using free cIBR peptide or by using the I domain of LFA-1 to inhibit the binding of cIBR-NPs. In addition, T-cell adhesion to epithelial cells was inhibited by cIBR-NPs. In chapter 4, nanoparticles capable of blocking LFA-1/ICAM-1 interaction were then studied as inhibitors of T cell conjugation to DCs. LABL-NPs and cIBR-NPs rapidly bound to DCs and inhibited T cell conjugation to DCs to a greater extent than the free peptides, unconjugated NPs, anti-ICAM-1 antibodies and anti-LFA-1 antibodies. In addition, DCs treated with NPs or with cIBR-NPs stimulated the proliferation of T cells, but DCs treated with LABL-NPs did not stimulate T cell proliferation. LABL-NPs and cIBR-NPs also altered cytokine production compared to free ligands suggesting these NPs may offer a unique tool for shaping T cell response. In chapter 5, multivalent ligands having both ovalbumin (OVA) antigen and LABL peptide grafted to hyaluronic acid (HA) were found to bind professional APCs and may offer an alternative targeting approach for inducing immune tolerance. Collectively, results verified that cyclic and linear LABL and cIBR peptides can target NPstoICAM-1 and LFA-1, respectively, to deliver encapsulated agent or to provide function as potent immune modulators.
    URI
    http://hdl.handle.net/1808/7010
    Collections
    • Dissertations [4472]
    • Pharmaceutical Chemistry Dissertations and Theses [141]

    Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.


    We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.


    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    Browse

    All of KU ScholarWorksCommunities & CollectionsThis Collection

    My Account

    LoginRegister

    Statistics

    View Usage Statistics

    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    The University of Kansas
      Contact KU ScholarWorks
    Lawrence, KS | Maps
     
    • Academics
    • Admission
    • Alumni
    • Athletics
    • Campuses
    • Giving
    • Jobs

    The University of Kansas prohibits discrimination on the basis of race, color, ethnicity, religion, sex, national origin, age, ancestry, disability, status as a veteran, sexual orientation, marital status, parental status, gender identity, gender expression and genetic information in the University’s programs and activities. The following person has been designated to handle inquiries regarding the non-discrimination policies: Director of the Office of Institutional Opportunity and Access, IOA@ku.edu, 1246 W. Campus Road, Room 153A, Lawrence, KS, 66045, (785)864-6414, 711 TTY.

     Contact KU
    Lawrence, KS | Maps