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    TISSUE SPECIFIC PEPTIDE CONJUGATES FOR DRUG DELIVERY

    Cover for TISSUE SPECIFIC PEPTIDE CONJUGATES FOR DRUG DELIVERY
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    View/Open: Cordova_georgetown_0076D_13111.pdf (12.MB) Bookview

    Creator
    Cordova, Antoinette
    Advisor
    Brown, Milton L
    Abstract
    Cytotoxic agents and targeted small molecules are used to treat cancer and disease, but are limited by systemic toxicity. The key to addressing this important issue is the development of a non-toxic, selective and specific delivery system. The goal of our studies is to potentially increase the therapeutic index of clinical reagents to treat and efficaciously deliver therapies to pathological tissues. To address these concerns we designed two targeting tissue-specific constructs comprised of a homing peptide for selective binding to human breast-derived cancer cells, and brain tissue. Homing peptides are short amino acid sequences derived from phage display libraries that have the unique property of localizing to specific organs. Our molecular construct allows for tissue specific drug delivery by binding the vascular endothelium of the tissue of interest. In Part I of this work the breast homing peptide evaluated in our studies is a cyclic nine amino acid peptide with the sequence CPGPEGAGC, referred to as PEGA. We show by confocal microscopy, that the PEGA peptide and similar peptide conjugates distribute to human breast tissue xenograft specifically, and evaluate the interaction of PEGA with the membrane-bound proline-specific APaseP (KD = 723 nM) by binding studies. To achieve intracellular breast cancer cell delivery, the incorporation of the Tat sequence, a cell-penetrating motif derived from HIV, was conjugated with the fluorescently labeled PEGA peptide sequence. In Part II of our work, we show that a cyclic eleven amino acid peptide with the sequence ACTTPHAWLCG, referred to as the brain homing peptide distributes in the brain after intranasal administration. The fluorescently labeled brain homing peptide was shown to localize into the olfactory nerve and bulb of C57BL/6 models, the primary route of intranasal administration to the brain. Ultimately, tissue specific peptides and their conjugates can enhance drug delivery and treatment, via their ability to discriminate between tissue types. The tissue specific conjugates we have designed may be valuable tools for drug delivery and visualization, including the potential to treat cancer and other disease, while minimizing systemic toxicity.
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/1029915
    Date Published
    2015
    Subject
    Drug Deilvery; Drug Discovery; Peptide; Peptide Conjugates; Small Molecule; Tissue-Specific; Chemistry; Biology; Nanotechnology; Chemistry; Biology; Nanotechnology;
    Type
    thesis
    Embargo Lift Date
    2017-12-19
    Publisher
    Georgetown University
    Extent
    108 leaves
    Collections
    • Graduate Theses and Dissertations - Tumor Biology
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility