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Mechanistic Studies of a Peptidic GRP78 Ligand for Cancer Cell-Specific Drug Delivery

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journal contribution
posted on 04.06.2007, 00:00 by Ying Liu, Sebastian C. J. Steiniger, YoungSoo Kim, Gunnar F. Kaufmann, Brunhilde Felding-Habermann, Kim D. Janda
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. Keywords: Drug delivery; tumor targeting; GRP78; heat shock protein; cyclic peptide

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