Peptide-Drug Conjugate Targeting Keratin 1 Inhibits Triple-Negative Breast Cancer in Mice.

Elmira Ziaei, Igor Moura de Paiva, Shih-Jing Yao, Nasim Sarrami, Parnian Mehinrad, Justine Lai, Afsaneh Lavasanifar, Kamaljit Kaur

Molecular pharmaceutics 2023 Jul 03

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Selective delivery of chemotherapy to the tumor site while sparing healthy cells and tissues is an attractive approach for cancer treatment. Carriers such as peptides can facilitate selective tumor targeting and payload delivery. Peptides with specific affinity for the overexpressed cell-surface receptors in cancer cells are conjugated to chemotherapy to afford peptide-drug conjugates (PDCs) that show selective uptake by cancer cells. Using a 10-mer linear peptide (WxEAAYQrFL) called 18-4 that targets and binds breast cancer cells, we designed a peptide 18-4-doxorubicin (Dox) conjugate with high specific toxicity toward triple-negative breast cancer (TNBC) MDA-MB-231 cells and 30-fold lower toxicity to normal breast MCF10A epithelial cells. Here, we elucidate the in vivo activity of this potent and tumor-selective peptide 18-4-Dox conjugate in mice bearing orthotopic MDA-MB-231 tumors. Mice treated with four weekly injections of the conjugate showed significantly lower tumor volumes compared to mice treated with free Dox at an equivalent Dox dose. Immunohistochemical (IHC) analysis of mice tissues revealed that treatment with a low dose of PDC (2.5 mg/kg of Dox equiv) reduced the expression of proliferation markers (PCNA and Ki-67) and increased apoptosis (evidenced by increased caspase-3 expression). At the same dose of free Dox (2.5 mg/kg), the expression of these markers was similar to that of saline treatment. Accordingly, significantly more Dox accumulated in tumors of conjugate-treated mice (7-fold) compared to the Dox-treated mice, while lower levels of Dox were observed in the liver, heart, and lungs of peptide-Dox conjugate-treated mice (up to 3-fold less) than Dox-treated mice. The IHC analysis of keratin 1 (K1), the receptor for peptide 18-4, revealed K1 upregulation in tumors and low levels in normal mammary fat pad and liver tissues from mice, suggesting preferential uptake of PDCs by TNBC to be K1 receptor-mediated. Taken together, our data support the use of a PDC approach to deliver chemotherapy selectively to the TNBC to inhibit tumor growth.

Citation

Elmira Ziaei, Igor Moura de Paiva, Shih-Jing Yao, Nasim Sarrami, Parnian Mehinrad, Justine Lai, Afsaneh Lavasanifar, Kamaljit Kaur. Peptide-Drug Conjugate Targeting Keratin 1 Inhibits Triple-Negative Breast Cancer in Mice. Molecular pharmaceutics. 2023 Jul 03;20(7):3570-3577