Cytotoxic and antitumor activities of doxorubicin conjugates with the epidermal growth factor and its receptor-binding fragment.

The epidermal growth factor (EGF) receptor is expressed at high levels on many types of tumor cells, such as squamous carcinoma, breast cancer and endothelial cells. We studied targeted delivery of the anticancer drug doxorubicin (DOX) using EGF and its receptor-binding fragment (EGFfr) to cells able to overexpress EGF receptors. EGF-DOX and EGFfr-DOX conjugates were synthesized via a glutaraldehyde bridge. The cytotoxic activities (CTA) of the conjugates were studied in vitro in different tumor cell lines (MCF-7Wt, MCF-7AdrR, B16) and endothelial cells using MTT-test. The antitumor effects of the conjugates were examined in vivo in mice with a subcutaneous B16 model. In the case of MCF-7Wt cells, CTA of EGF-DOX and EGFfr-DOX conjugates exceeded 7.7- and 68-fold that of free DOX. Besides, the conjugates effectively decreased the drug resistance of MCF-7AdrR cells. CTA of the conjugates against endothelial cell cultures markedly exceeded that of free DOX. It is of note that proliferating endothelial cells were much more sensitive to the effects of the conjugates than confluent endothelial cells. Administration of EGF-DOX and EGFfr-DOX conjugates significantly inhibited tumor growth and increased the mean life span of experimental animals by 46 and 48.5%, respectively.