title: Discovery of targeting ligands for breast cancer cells using the one-bead one-compound combinatorial method.
abstract: 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 to alpha3 integrin was identified. Molecular interactions between alpha3 integrin and 1 were characterized by using a series of K562 cells transfected with various mutant alpha3 integrins. Using analytic flow cytometry, the binding affinity (K(d)) of 1 to alpha3 integrin on MDA-MB-231 breast cancer cells was determined to be approximately 0.4 microM. 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 (IC(50) = 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.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, UC Davis Cancer Center, University of California, Davis, Sacramento, California 95817, USA.
authors.forename: Nianhuan
authors.initials: N
authors.lastname: Yao
authors.forename: Wenwu
authors.initials: W
authors.lastname: Xiao
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wang
authors.forename: Jan
authors.initials: J
authors.lastname: Marik
authors.forename: See Hyoung
authors.initials: SH
authors.lastname: Park
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D019921:Biotinylation; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D030562:Databases, Protein; D015195:Drug Design; D005260:Female; D006801:Humans; D039422:Integrin alpha3 / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D023041:Xenograft Model Antitumor Assays
chemical_list: D039422:Integrin alpha3; D008024:Ligands; D010455:Peptides