The exploitation of differential endocytic pathways in normal and tumor cells in the selective targeting of nanoparticulate chemotherapeutic agents.
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.
Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, 68198-5830, USA.
Gaurav
G
Sahay
Jong Oh
JO
Kim
Alexander V
AV
Kabanov
Tatiana K
TK
Bronich
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis; D006801:Humans; D053758:Nanoparticles; D009369:Neoplasms / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D004317:Doxorubicin