Evaluation of a Keratin 1 Targeting Peptide-Doxorubicin Conjugate in a Mouse Model of Triple-Negative Breast Cancer
Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), a subtype of breast cancer that is aggressive with a poor prognosis. While chemotherapeutics are potent, these agents lack specificity and are equally toxic to cancer and nonmalignant cells and tissues. Targeted therapies for TNBC treatment could lead to more safe and efficacious drugs. We previously engineered a breast cancer cell targeting peptide 18-4 that specifically binds cell surface receptor keratin 1 (K1) on breast cancer cells. A conjugate of peptide 18-4 and doxorubicin (Dox) containing an acid-sensitive hydrazone linker showed specific toxicity toward TNBC cells. Here, we report the in vivo evaluation of the K1 targeting peptide-Dox conjugate (PDC) in a TNBC cell-derived xenograft mouse model. Mice treated with the conjugate show significantly improved antitumor efficacy and reduced off-target toxicity compared to mice treated with Dox or saline. After six weekly treatments, on day 35, the mice treated with PDC (2.5 mg Dox equivalent/kg) showed significant reduction (1.5 times) in tumor volume compared to mice treated with Dox (2.5 mg/kg). The mice treated with the conjugate showed significantly higher (1.4 times) levels of Dox in tumors and lower (1.3–2.2 times) levels of Dox in other organs compared to mice treated with Dox. Blood collected at 15 min showed 3.6 times higher concentration of the drug (PDC and Dox) in mice injected with PDC compared to the drug (Dox) in mice injected with Dox. The study shows that the K1 targeting PDC is a promising novel modality for treatment of TNBC, with a favorable safety profile, and warrants further investigation of K1 targeting conjugates as TNBC therapeutics.
Saghaeidehkordi A, Chen S, Yang S, Kaur K. Evaluation of a keratin 1 targeting peptide- doxorubicin conjugate in a mouse model of triple-negative breast cancer. Pharmaceutics 2021;13(5):661. https://doi.org/10.3390/pharmaceutics13050661
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This article was originally published in Pharmaceutics, volume 13, issue 5, in 2021. https://doi.org/10.3390/pharmaceutics13050661