UCSF

ABSTRACT: IDENTIFICATION OF ORAL CANCER SPECIFIC LIGANDS FROM ONE-BEAD ONE-COMPOUND COMBINATERIAL LIBRARIES TO DEVELOP THERANOSTIC AGENTS AGAINST ORAL SQUAMOUS CELL CARCINOMA

Fan Yang

Background: Oral squamous cell carcinoma (OSCC) is one of the most prevalent disease worldwide. One-bead one-compound (OBOC) combinatorial technology is a powerful method to identify peptidomimetic ligands against a variety of receptors on cell surfaces. We therefore hypothesized that cancer specific ligands against OSCC might be identified and can be conjugated to optical dyes or nanocarriers to develop theranostic agents against OSCC. Material and methods: Different OSCC cell lines were incubated with OBOC libraries and beads with cell binding were sorted and then screened with normal human cells to identify peptide-beads binding to different OSCC cell lines but not binding to normal human cells. The molecular probes of OSCC were developed by biotinylating the carboxyl end of the ligands. OSCC theranostic agents were developed by decorating LLY13 with NPs and evaluated by using orthotopic bioluminescent oral cancer model. Results: Six OSCC specific ligands were discovered. Initial peptide-histochemistry study indicated that LLY12 and LLY13 were able to specifically detect OSCC cells grown on chamber slides at the concentration of 1 µM. In addition, LLY13 was found to penetrate into the OSCC cells and accumulate in the cytoplasm, and nucleus. After screened with a panel of integrin antibodies, only anti-α3 antibody was able to block most of OSCC cells binding to the LLY13 beads. OSCC theranostic agents developed using targeting LLY13 micelles (25± 4nm in diameter) were more efficient in binding to HSC-3 cancer cells compared to non-targeting micelles. Ex vivo images demonstrated that xenografts from the mice with targeting micelles appeared to have higher signals than the non-targeting groups. Conclusion: LLY13 has promising in vitro and in vivo targeting activity against OSCC. In addition, LLY13 is also able to penetrate into cancer cells via endocytosis. Initial study indicated that α3 integrin might partially be the corresponding receptor involved for LLY13’s binding to oral cancer cells. OSCC ligands developed from this study may become potential candidates for the development of OSCC targeted theranostic agents.