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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Cell surface-mediated cytotoxicity of polymer-bound Adriamycin against drug-resistant hepatocytes.

Growth inhibition properties of Adriamycin-coupled polyglutaraldehyde microspheres have been assessed using a highly resistant rat liver cell line, RLC. Covalent attachment of Adriamycin to microspheres increased the cytostatic activity of the drug 1000-fold for this cell line as measured by 50% inhibitory concentration determinations. The effects of Adriamycin-polymer complexes were investigated and compared to free drug, using trypan blue dye exclusion and 51Cr release as indicators of cell viability. When carcinogen-altered drug-resistant rat hepatocytes were tested at an Adriamycin concentration of 10(-6) M, the polymer-bound drug killed 32% of the cells, while the free drug had no detectable cytotoxic effect. However, with normal rat hepatocytes at the same drug concentration, the Adriamycin-coupled microspheres were shown to be less toxic than free drug at 24 hr. It was demonstrated that greater than 99.5% of the drug remains covalently coupled to the microspheres throughout the experiments. Scanning electron micrographs are presented for both cell types, which demonstrate the effects of free and bound Adriamycin on the ultrastructure of the cell surface. The cells lose their microvilli, exhibit numerous blebs, and develop holes and pits in the surface. Transmission electron microscopy demonstrates that less than 1% of the microspheres is internalized by either cell type. Multiple interactions of the drug-polymer complexes with the cell surface are presented as the most probable explanation for the results.[1]


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