Discovery of Targeting Ligands for Breast Cancer Cells Using the One-Bead One-Compound Combinatorial Method

Four one-bead one-compound (OBOC combinatorial libraries were designed, synthesized, and screened against MDA-MB-231 breast cancer cells. A novel cyclic peptide 1 (LXY1) with high binding specificity C) C to 0 integrin was identified. Molecular interactions between 0 integrin and I were characterized by using a series of K562 cells transfected with various mutant alpha 3 integrins. Using analytic flow cytometry, the binding affinity (K-d) of 1 to alpha 3 integrin on MDA-MB-231 breast cancer cells was determined to be approximately 0.4 mu M. Based on the established structure-activity relationship (SAR) study, two highly focused cyclic peptide libraries were further designed, synthesized, and screened against MDA-MB-231 breast cancer cells under stringent conditions. A novel cyclic peptide 2 (LXY3) with a high binding affinity (IC50 = 57 nM) was identified. Moreover, the targeting efficiency and specificity of 2 to the breast adenocarcinoma tumors in mouse xenografts were further confirmed by in vivo and ex vivo near-infrared fluorescence optical imaging.