The exploitation of differential endocytic pathways in normal and tumor cells in the selective targeting of nanoparticulate chemotherapeutic agents.

Abstract

Polymeric micelles with cross-linked ionic cores of poly(methacrylic acid) and nonionic shell of poly(ethylene oxide) (cl-micelles) are shown here to readily internalize in epithelial cancer cells but not in normal epithelial cells that form tight junctions (TJ). The internalization of such cl-micelles in the cancer cells proceeded mainly through caveolae-mediated endocytosis. In confluent normal epithelial cells this endocytosis route was absent at the apical side and the cl-micelles sequestered in TJ regions of the cell membrane without entering the cells for at least 24h. Disruption of the TJ by calcium deprivation resulted in redistribution of cl-micelles inside the cells. In cancer cells following initial cellular entry the cl-micelles bypassed the early endosomes and reached the lysosomes within 30min. This allowed designing cl-micelles with cytotoxic drug, doxorubicin, linked via pH-sensitive hydrazone bonds, which were cleaved in the acidic environment of lysosomes resulting in accumulation of the drug in the nucleus after 5h. Such pH-sensitive cl-micelles displayed selective toxicity to cancer cells but were non-toxic to normal epithelial cells. In conclusion, we describe major difference in interactions of cl-micelles with cancer and normal cells that can lead to development of novel drug delivery system with reduced side effects and higher efficacy in cancer chemotherapy.

• Authors: Gaurav Sahay, Jong Oh Kim, Alexander V Kabanov, Tatiana K Bronich
• Journal: Biomaterials (Biomaterials) Vol. 31 Issue 5 Pg. 923-33 (Feb 2010) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 19853293 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Doxorubicin

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics)
• Cell Line, Tumor
• Doxorubicin (pharmacokinetics)
• Drug Delivery Systems (methods)
• Endocytosis
• Humans
• Nanoparticles
• Neoplasms (metabolism)
• Signal Transduction