Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), a subtype of breast cancer that is aggressive with poor prognosis. While chemotherapeutics are potent, these agents suffer from a lack of specificity and are equally toxic to cancer and nonmalignant cells and tissues. Targeted therapies for TNBC treatment are not available at this point, largely due to the absence of well-established clinical molecular targets. In recent years several cell surface receptors on TNBC cells have been identified that are being targeted using engineered antibodies and tumor homing/targeting peptides for site-specific delivery of chemotherapeutics. We engineered TNBC cell targeting peptides, such as cyclic <b>cy18-4</b> and linear<b> GE11-31</b>, that specifically bind cell surface receptors keratin 1 (K1) and epidermal growth factor receptor (EGFR), respectively, on TNBC cells. We used different chemistries to link the targeting peptide to cytotoxic doxorubicin (payload) to form peptide-drug conjugates (PDCs). In this talk, conjugate syntheses with different linkers, and recent in vitro and in vivo findings with the conjugates will be presented. In vitro cytotoxicity evaluation with TNBC cells as well as in vivo efficacy studies using MDA-MB-231 xenograft in NOD-SCID mice tumor models show that linker chemistry plays an important role in improving the efficacy of the drug. The linker should allow sufficient circulation time for the conjugate to reach its target tumor site before releasing the drug. The implications of the peptide, linker, and the cytotoxic payload for improved efficacy in TNBC treatment will be discussed.

Peptide-drug conjugates: A novel modality for triple-negative breast cancer treatment

ACS Spring 2022

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