A cornerstone of pancreatic cancer treatment is the surgical resection of the primary tissues infected with cancerous cells. Without surgery, the American Cancer Society reports a five year survival rate of 6%. However when the tumor tissue can be completely removed by surgical resection, the five year survival rate has been shown to be as high as 20 – 25%. Toll-like Receptor 2 (TLR2) is a type I transmembrane glycoprotein that plays a role in the activation and regulation of the innate immune system, and is overexpressed on pancreatic tumor cells. By taking advantage of TLR2 as a biomarker of pancreatic cancer, there is a potential to monitor the removal of pancreatic tumors in the operating suite. Additionally, structure activity relationship research has already developed hit motifs with agonistic binding activities for TLR2 (EC50 = 674 nM, Ki = 22 nM). This project was designed to elucidate a peptidomimetic ligand for TLR2 incorporating a fluorescent molecular tag meant to improve the distinction between cancerous pancreatic cells and normal cells. The first challenge was to optimize our synthetic strategy for the monoacylated PAM monomer of the ligand. This building block was a L-cysteine amino acid analog with a palmitic acid like motif. It was subsequently incorporated into the polypeptide using conventional N<sup>α</sup>-Fmoc solid phase peptide synthesis technique. Because this peptide was being designed for pancreatic cancer imaging, a fluorescent dye (IRDye780CW) conjugate was prepared using a Suzuki coupling reaction, and then attached to the N-terminus of the TLR2 ligand using typical peptide coupling reagents. The ligand was prepared with high yield and purity levels. Future work will characterize the importance of this fluorescent ligand in imaging pancreatic cancer through cell binding assay, functional bioassay, and fluorescence imaging of murine tumors.

Synthesis of new toll-like receptors 2 (TLR2) ligands for pancreatic cancer imaging

249th National Meeting (2015)

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