Novel Peptide–Doxorubucin Conjugates for Targeting Breast Cancer Cells Including the Multidrug Resistant Cells

The efficacy of chemotherapeutic doxorubucin (Dox) in cancer treatment is limited by two main factors, nonspecific toxicity and the emergence of tumor resistance. To overcome these hurdles, in this study peptide-Dox conjugates were prepared. A decapeptide 18-4a (NH₂-WxEAAYQkFL-CONH₂) [corrected] with high specificity for breast cancer cells and improved proteolytic stability was conjugated to Dox to give peptide-Dox ester (1) and amide (2) conjugates. Cell uptake studies showed that the conjugates were 6-10 times selective for breast cancerous cells (MCF-7 and MDA-MB-435) over noncancerous cells (HUVECs and MCF-10A). Conjugate 1 displayed similar toxicity as free Dox toward the breast cancerous cells and was about 40 times less toxic toward the noncancerous cells and 4-fold more toxic toward the Dox resistant MDA-MB-435-MDR cells than the free Dox. These data suggest that conjugate 1 can be used as a potential prodrug for improving the therapeutic index of Dox and potentially many other cytotoxic drugs.