Abstract
Herceptin, a humanized monoclonal antibody that binds to human growth factor receptor-2(HER2), was covalently attached to a fifth-generation (G5) polyamidoamine dendrimercontaining the cytotoxic drug methotrexate. The specific binding and internalization of thisconjugate labeled with FITC was clearly demonstrated in cell lines overexpressing HER2by flow cytometry as well as confocal microscopic analysis. In addition, binding and uptakeof antibody conjugated dendrimers was completely blocked by excess non-conjugatedherceptin. The dendrimer conjugate was also shown to inhibit the dihydrofolate reductasewith similar activity to methotrexate. Co-localization experiments with lysotracker redindicate that antibody conjugate, although internalized efficiently into cells, has anunusually long residence time in the lysosome. Somewhat lower cytotoxicity ofthe conjugate in comparison to free methotrexate was attributed to the slowrelease of methotrexate from the conjugate and its long retention in the lysosomalpocket.
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