title: The use of one-bead one-compound combinatorial library technology to discover high-affinity αvβ3 integrin and cancer targeting arginine-glycine-aspartic acid ligands with a built-in handle.
abstract: The αvβ3 integrin, expressed on the surface of various normal and cancer cells, is involved in numerous physiologic processes such as angiogenesis, apoptosis, and bone resorption. Because this integrin plays a key role in angiogenesis and metastasis of human tumors, αvβ3 integrin ligands are of great interest to advances in targeted therapy and cancer imaging. In this report, one-bead one-compound (OBOC) combinatorial libraries containing the arginine-glycine-aspartic acid (RGD) motif were designed and screened against K562 myeloid leukemia cells that had been transfected with the human αvβ3 integrin gene. Cyclic peptide LXW7 was identified as a leading ligand with a built-in handle that binds specifically to αvβ3 and showed comparable binding affinity (IC(50) = 0.68 ± 0.08 μmol/L) to some of the well-known RGD "head-to-tail" cyclic pentapeptide ligands reported in the literature. The biotinylated form of LXW7 ligand showed similar binding strength as LXW7 against αvβ3 integrin, whereas biotinylated RGD cyclopentapeptide ligands revealed a 2- to 8-fold weaker binding affinity than their free forms. LXW7 was able to bind to both U-87MG glioblastoma and A375M melanoma cell lines, both of which express high levels of αvβ3 integrin. In vivo and ex vivo optical imaging studies with the biotinylated ligand/streptavidin-Cy5.5 complex in nude mice bearing U-87MG or A375M xenografts revealed preferential uptake of biotinylated LXW7 in tumor. When compared with biotinylated RGD cyclopentapeptide ligands, biotinylated LXW7 showed higher tumor uptake but lower liver uptake.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California 95817, USA.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Xiao
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Edmond Y
authors.initials: EY
authors.lastname: Lau
authors.forename: Juntao
authors.initials: J
authors.lastname: Luo
authors.forename: Nianhuan
authors.initials: N
authors.lastname: Yao
authors.forename: Changying
authors.initials: C
authors.lastname: Shi
authors.forename: Leah
authors.initials: L
authors.lastname: Meza
authors.forename: Harry
authors.initials: H
authors.lastname: Tseng
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Maeda
authors.forename: Pappanaicken
authors.initials: P
authors.lastname: Kumaresan
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Liu
authors.forename: Felice C
authors.initials: FC
authors.lastname: Lightstone
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000818:Animals; D020650:Combinatorial Chemistry Techniques; D005434:Flow Cytometry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020014:K562 Cells; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D039302:Integrin alphaVbeta3; D008024:Ligands; D009842:Oligopeptides