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Mechanistic studies of a peptidic GRP78 ligand for cancer cell-specific drug delivery

Academic Article
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Overview

related to degree

  • Kim, YoungSoo, Ph.D. in Chemistry, Scripps Research 2002 - 2006

authors

  • Liu, Y.
  • Steiniger, S. C. J.
  • Kim, YoungSoo
  • Kaufmann, Gunnar
  • Felding, Brunhilde
  • Janda, Kim

publication date

  • May 2007

journal

  • Molecular Pharmaceutics  Journal

abstract

  • Major obstacles in the development of new therapeutic anticancer drugs are the low bioavailability of hydrophilic substances and the nonspecific toxicity toward healthy tissues. As such, cell-targeting oligopeptides have emerged as attractive drug delivery vehicles for a variety of different types of cargo. The recently identified peptide Pep42 binds to the glucose-regulated protein 78 (GRP78), which is overexpressed on the cell surface of human cancer cells and internalizes into these cells. Herein, we demonstrate how Pep42 can be utilized as a carrier for different types of cytotoxic drugs to specifically target human cancer cell lines in vitro in a strictly GRP78-dependent manner. Furthermore, the mechanism of internalization of Pep42 was elucidated and found to involve clathrin-mediated endocytosis. Pep42 subsequently colocalizes within the lysosomal compartment. Importantly, we also provide evidence that Pep42-conjugated quantum dots have the ability to selectively enrich in tumor tissue in a xenograft mouse model. Our results suggest that the highly specific GRP78-Pep42 interaction can be utilized for the generation of Pep42-drug conjugates as a powerful anticancer drug delivery system that could substantially enhance the efficacy of chemotherapy by increasing the drug-tumor specificity, thus minimizing the adverse side effects associated with conventional cancer therapeutics.

subject areas

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents
  • Apoptosis
  • Cell Line, Tumor
  • Cell Membrane
  • Clathrin
  • Drug Delivery Systems
  • Endocytosis
  • Heat-Shock Proteins
  • Humans
  • Ligands
  • Lysosomes
  • Mice
  • Molecular Chaperones
  • Neoplasm Transplantation
  • Neoplasms, Experimental
  • Peptides, Cyclic
  • Photochemotherapy
  • Quantum Dots
  • RNA, Small Interfering
  • Transplantation, Heterologous
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Research

keywords

  • GRP78
  • cyclic peptide
  • drug delivery
  • heat shock protein
  • tumor targeting
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Identity

PubMed Central ID

  • PMC2533281

International Standard Serial Number (ISSN)

  • 1543-8384

Digital Object Identifier (DOI)

  • 10.1021/mp060122j

PubMed ID

  • 17373820
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Additional Document Info

start page

  • 435

end page

  • 447

volume

  • 4

issue

  • 3

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