The Development of a Novel Peptide-Drug Conjugate for Treating Triple-Negative Breast Cancer

<p>Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor prognosis and is difficult to treat. A diagnosis of TNBC means that the three most common types of receptors known to fuel most breast cancer growth–estrogen, progesterone, and HER2– are not present in the cancer tumors. Since the tumor cells lack necessary receptors, common treatments like hormone therapies and targeted HER2 drugs are ineffective. The use of chemotherapies in treating TNBC is an effective option instead. However, chemotherapies are not selective, thus they cause severe side effects such as cardiotoxicity, myelosuppression, alopecia and gastrointestinal problems. A peptide-drug conjugate (PDC) targeting overexpressed epidermal growth factor receptor (EGFR) in TNBC cells was synthesized to increase the uptake of drug by TNBC cells, thereby improving the safety and efficacy of chemotherapeutic doxorubicin (Dox) in TNBC treatment. This PDC includes a novel 13-mer linear peptide (sequence: CYHWYGYTPERVI) that was attached to Dox through a cleavable sulfo-SMCC linker. It was purified by reversed-phase HPLC and characterized by MALDI-TOF mass analysis. Its stability was studied in different conditions including aqueous-organic solvent mixture, human serum and mouse serum. The PDC was stable in aqueous-organic condition up to 10 days. In addition, its half-life in human serum was about 12 hours indicating that it is stable enough to reach the tumor sites for its activity. MTS assays were used to evaluate its cytotoxicity toward TNBC cells versus non-cancerous mammary epithelial cells. Initial evaluations of this PDC suggest that EGFR targeting PDC has the potential to improve the efficacy and reduce off- target side effects of chemotherapy.</p>

Name thesis:degree_name

Master of Science (MS)

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Year dc:date.available

2022

Author dc:creator

• Than, Phi-Phung

Contributors dc:contributor

• Kamaljit Kaur
• Sun Yang
• Surya Nauli

• Medicinal and Pharmaceutical Chemistry
• Other Pharmacy and Pharmaceutical Sciences
• Pharmaceutics and Drug Design

Repository record dc:identifier

https://digitalcommons.chapman.edu/pharmaceutical_sciences_theses/27

OAI identifier oai:identifier

oai:digitalcommons.chapman.edu:pharmaceutical_sciences_theses-1027