Targeting Triple Negative Breast Cancer Cells with Novel Cytotoxic Peptide–Doxorubicin Conjugates

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In this study, we have designed and synthesized two novel peptide-drug conjugates (PDCs) where the drug, doxorubicin (Dox), is linked to the peptide via a succinimidyl thioether bond or a hydrazone linker. A highly specific and proteolytically stable breast cancer cell targeting peptide (WxEAAYQrFL) is conjugated to Dox to synthesize peptide-Dox thioether (1) or hydrazone (2) conjugate. The evaluation of the stability in water, media, and human serum showed that the conjugate 1 with the succinimidyl thioether linkage is more stable compared to the acid-sensitive hydrazone containing conjugate 2. The cytotoxicity studies showed that the two PDCs were as toxic as free Dox toward the triple negative breast cancer (TNBC) cells and were 7–30 times less toxic (IC50 1.2–4.7 μM for TNBC cells versus 15–39 μM for non-cancerous cells) toward the non-cancerous breast cells compared to the free doxorubicin (IC50 0.35–1.5 μM for TNBC cells versus 0.24 μM for non-cancerous cells). The results from the comparative study of the two PDCs suggest that both may have translational potential for TNBC treatment.


This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Bioconjugate Chemistry, volume 30, issue 12, in 2019. The definitive publisher-authenticated version is available online at


American Chemical Society