Engineered Peptides for Targeting Breast Cancer Cells

Abstract

Tumor targeting ligands provide a promising solution to the problems associated with the selective delivery of conventional cancer chemotherapeutics and diagnostics to cancer cells. Therefore, numerous cancer cell surface targeting peptides have been identified and evaluated. These peptides have shown specificity for cancer cells and promising results for tumor-selective drug delivery. Kaurs group has reported on the development of analogues of p160 peptide that have shown increased affinity for breast cancer cell lines. An analogue of p160 (WxEAAYQkFL or 18-4DXK) when conjugated to doxorubicin showed specific targeting of breast tumors and demonstrated enhanced cytotoxicity against drug resistant cells as compared to free doxorubicin. In this thesis, the design and synthesis of four analogues based on lead decapeptide 18-4DXK was performed and the interaction with breast cancer cells (MDA-MB-231, MDA-MB-435, and MCF-7) was evaluated. Binding with noncancerous cells (HUVEC and MCF-10A) was studied to identify the peptides that specifically bind to breast cancer cells over normal cells. The design strategy involved replacement of either D-norleucine (x) and/or D-lysine (k) amino acid in the lead sequence with the corresponding L residues or cyclization of the sequence. The results show that cyclic (c18-4DK) peptide analogue displays higher (compared to other analogues) and more specific uptake by the breast cancer cells. This third generation analogue of p160 (Cyclic 18-4DK) cancer targeting peptide is a better candidate peptide for conjugation to drugs or drug carriers for targeted drug delivery in breast cancer treatment.