Evaluation of a Keratin 1 Targeting Peptide-Doxorubicin Conjugate in a Mouse Model of Triple-Negative Breast Cancer.

Azam Saghaeidehkordi,Sun Yang,Shiuan Chen,Kamaljit Kaur

doi:10.3390/pharmaceutics13050661

Azam Saghaeidehkordi, Sun Yang + Show 2 more

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https://doi.org/10.3390/pharmaceutics13050661

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Journal: Pharmaceutics	Publication Date: May 5, 2021
Citations: 14	License type: CC BY 4.0

Affiliation: Chapman University, City of Hope

Abstract

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.

Highlights

Triple-negative breast cancer (TNBC) is an important subtype of breast cancer as it is aggressive and has a poor prognosis [1,2]
We showed that keratin 1 (K1) is present on the surface of MCF-7 breast cancer cells, and a comparison of the total K1 levels in cell lysates using Western blot showed that cancer cells (MCF-7 and MDA-MB-435) have a much higher expression of
Using cell-derived xenograft (CDX) mice models, we show significantly improved efficacy of peptide-Dox conjugate (PDC) in reducing tumor volume compared to free Dox (Figure 4a)

Summary

Introduction

Triple-negative breast cancer (TNBC) is an important subtype of breast cancer as it is aggressive and has a poor prognosis [1,2]. TNBC is a heterogeneous disease with ≈80% of TNBC cells with basal-like gene expression characteristics, such as KRT5, KRT14, KRT17, and EGFR [1,3]. Lehmann et al defined TNBC into four molecular subtypes, namely basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M) and, luminal androgen receptor (LAR) [3]. Several potential pathways with deletion (such as PTEN) and mutation/amplification (PIK3CA, KRAS, BRAF, EGFR, and MET) of genes have been identified as druggable molecular alterations in TNBC, but these have not proven to be clinically successful yet [1]. Some success has been seen with the recent approval of poly-ADP ribose-polymerase (PARP)

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