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

Mol Pharm. May-Jun 2007;4(3):435-47. doi: 10.1021/mp060122j. Epub 2007 Mar 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics
  • Apoptosis
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Clathrin / metabolism
  • Drug Delivery Systems*
  • Endocytosis
  • Heat-Shock Proteins / antagonists & inhibitors
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Ligands
  • Lysosomes / metabolism
  • Mice
  • Molecular Chaperones / antagonists & inhibitors
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / metabolism*
  • Photochemotherapy
  • Quantum Dots
  • RNA, Small Interfering / genetics
  • Transplantation, Heterologous


  • Antineoplastic Agents
  • Clathrin
  • Heat-Shock Proteins
  • Ligands
  • Molecular Chaperones
  • Pep42 peptide
  • Peptides, Cyclic
  • RNA, Small Interfering
  • molecular chaperone GRP78