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

Area of Science:

• Oncology
• Drug Delivery
• Bioconjugation

Background:

• Selective chemotherapy delivery to tumors is crucial for improving cancer treatment efficacy and reducing systemic toxicity.
• Peptide-drug conjugates (PDCs) offer a promising strategy for targeted cancer therapy by leveraging the specific affinity of peptides for cancer cell receptors.
• Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to its aggressive nature and lack of targeted treatment options.

Purpose of the Study:

• To evaluate the in vivo anti-tumor activity and biodistribution of a novel peptide-drug conjugate (PDC) targeting triple-negative breast cancer (TNBC).
• To assess the therapeutic efficacy of the peptide 18-4-doxorubicin (Dox) conjugate in mice bearing orthotopic MDA-MB-231 tumors.
• To investigate the mechanism of selective tumor uptake mediated by the keratin 1 (K1) receptor.

Main Methods:

• Design and synthesis of a peptide-drug conjugate (PDC) using a 10-mer linear peptide (18-4) targeting breast cancer cells and doxorubicin (Dox) as the payload.
• In vivo efficacy studies in mice with orthotopic MDA-MB-231 tumors, comparing the PDC with free Dox and saline treatments.
• Immunohistochemical (IHC) analysis to assess tumor proliferation (PCNA, Ki-67), apoptosis (caspase-3), and receptor expression (K1); biodistribution studies of Dox accumulation in tumors and healthy organs.

Main Results:

• The peptide 18-4-Dox conjugate significantly reduced tumor volumes in mice compared to free Dox at equivalent doses.
• PDC treatment led to decreased proliferation markers (PCNA, Ki-67) and increased apoptosis (caspase-3) in tumors, with minimal impact at equivalent free Dox doses.
• Tumor accumulation of Dox was significantly higher (7-fold) in PDC-treated mice, while levels in healthy organs (liver, heart, lungs) were lower (up to 3-fold less) compared to free Dox treatment.
• Upregulation of the K1 receptor in tumors and low expression in normal tissues suggest K1-mediated, tumor-selective uptake of the PDC.

Conclusions:

• The peptide 18-4-Dox conjugate demonstrates potent and tumor-selective anti-cancer activity in vivo against TNBC.
• This PDC approach effectively delivers chemotherapy to the tumor site, enhancing efficacy and reducing systemic toxicity.
• The findings support the potential of K1 receptor-targeted PDCs as a promising therapeutic strategy for TNBC.