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

  • Bioconjug Chem. 2019 Dec 18;30(12):3098-3106. doi: 10.1021/acs.bioconjchem.9b00755.
Elmira Ziaei  1 ,  Azam Saghaeidehkordi  1 ,  Cassandra Dill  1 ,  Innokentiy Maslennikov  1 ,  Shiuan Chen  2 ,  Kamaljit Kaur  1
Affiliations
  • 1. Chapman University School of Pharmacy (CUSP), Harry and Diane Rinker Health Science Campus , Chapman University , Irvine , California 92618-1908 , United States.
  • 2. Department of Cancer Biology , Beckman Research Institute of the City of Hope , Duarte , California 91010 , United States.
PMID: 31715102 DOI: 10.1021/acs.bioconjchem.9b00755
Abstract

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 noncancerous cells) toward the noncancerous breast cells compared to the free doxorubicin (IC50 0.35-1.5 μM for TNBC cells versus 0.24 μM for noncancerous cells). The results from the comparative study of the two PDCs suggest that both may have translational potential for TNBC treatment.

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