title: Aminopeptidase P Mediated Targeting for Breast Tissue Specific Conjugate Delivery.
abstract: Cytotoxic chemotherapies are used to treat breast cancer, but are limited by systemic toxicity. The key to addressing this important issue is the development of a nontoxic, tissue selective, and molecular specific delivery system. In order to potentially increase the therapeutic index of clinical reagents, we designed an Aminopeptidase P (APaseP) targeting tissue-specific construct conjugated to a homing peptide for selective binding to human breast-derived cancer cells. 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 to APaseP in the vascular endothelium. 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 with the membrane-bound proline-specific APaseP (KD = 723 ± 3 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. Ultimately, tissue specific peptides and their conjugates can enhance drug delivery and treatment by their ability to discriminate between tissue types. Tissue specific conjugates as we have designed may be valuable tools for drug delivery and visualization, including the potential to treat breast cancer, while simultaneously minimizing systemic toxicity.
authors.affiliation: Center for Drug Discovery, Georgetown University Medical Center , 3970 Reservoir Road NW Washington, DC 20057, United States.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Cordova
authors.affiliation: Georgetown University Medical Center , 3900 Reservoir Road NW, Washington, DC 20057, United States.
authors.forename: Jordan
authors.initials: J
authors.lastname: Woodrick
authors.affiliation: Center for Drug Discovery, Georgetown University Medical Center , 3970 Reservoir Road NW Washington, DC 20057, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Grindrod
authors.affiliation: Center for Drug Discovery, Georgetown University Medical Center , 3970 Reservoir Road NW Washington, DC 20057, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Georgetown University Medical Center , 3900 Reservoir Road NW, Washington, DC 20057, United States.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Saygideger-Kont
authors.affiliation: Center for Drug Discovery, Georgetown University Medical Center , 3970 Reservoir Road NW Washington, DC 20057, United States.
authors.forename: Kan
authors.initials: K
authors.lastname: Wang
authors.affiliation: Georgetown University Medical Center , 3900 Reservoir Road NW, Washington, DC 20057, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: DeVito
authors.affiliation: Georgetown University Medical Center , 3900 Reservoir Road NW, Washington, DC 20057, United States.
authors.forename: Stefano G
authors.initials: SG
authors.lastname: Daniele
authors.affiliation: George Mason University , Department of Chemistry and Biochemistry, 10900 University Boulevard, Manassas, Virginia 20110, United States.
authors.forename: Mikell
authors.initials: M
authors.lastname: Paige
authors.affiliation: Center for Drug Discovery, Georgetown University Medical Center , 3970 Reservoir Road NW Washington, DC 20057, United States.
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D001940:Breast / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D009928:Organ Specificity
chemical_list: D004337:Drug Carriers; D005456:Fluorescent Dyes; D009842:Oligopeptides; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase