title: Chemical re-engineering of chlorotoxin improves bioconjugation properties for tumor imaging and targeted therapy.
abstract: Bioconjugates composed of chlorotoxin and near-infrared fluorescent (NIRF) moieties are being advanced toward human clinical trials as intraoperative imaging agents that will enable surgeons to visualize small foci of cancer. In previous studies, the NIRF molecules were conjugated to chlorotoxin, which results in a mixture of mono-, di-, and trilabeled peptide. Here we report a new chemical entity that bound only a single NIRF molecule. The lysines at positions 15 and 23 were substituted with either alanine or arginine, which resulted in only monolabeled peptide that was functionally equivalent to native chlorotoxin/Cy5.5. We also analyzed the serum stability and serum half-life of cyclized chlorotoxin, which showed an 11 h serum half-life and resulted in a monolabeled product. Based on these data, we propose to advance a monolabeled chlorotoxin to human clinical trials.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Muharrem
authors.initials: M
authors.lastname: Akcan
authors.forename: Mark R
authors.initials: MR
authors.lastname: Stroud
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Hansen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Clark
authors.forename: Norelle L
authors.initials: NL
authors.lastname: Daly
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
mesh_terms: D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000737:chemistry; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000628:therapy; D002232:Carbocyanines / Q000737:chemistry*; D005456:Fluorescent Dyes / Q000737:chemistry*; D006207:Half-Life; D008239:Lysine / Q000737:chemistry; D008527:Medulloblastoma / Q000175:diagnosis* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000097:blood / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000097:blood / Q000737:chemistry; D012604:Scorpion Venoms / Q000097:blood / Q000737:chemistry*
chemical_list: C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D005456:Fluorescent Dyes; D010455:Peptides; D010456:Peptides, Cyclic; D012604:Scorpion Venoms; C091539:Chlorotoxin; D001120:Arginine; D008239:Lysine; D000409:Alanine