title: Fluorescent cancer-selective alkylphosphocholine analogs for intraoperative glioma detection.
abstract: BACKGROUND
  5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence aids brain tumor resections but is not approved for routine use in the United States. We developed and describe testing of 2 novel fluorescent, cancer-selective alkylphosphocholine analogs, CLR1501 (green) and CLR1502 (near infrared), in a proof-of-principle study for fluorescence-guided glioma surgery.
  
  
  OBJECTIVE
  To demonstrate that CLR1501 and CLR1502 are cancer cell-selective fluorescence agents in glioblastoma models and to compare tumor-to-normal brain (T:N) fluorescence ratios with 5-ALA.
  
  
  METHODS
  CLR1501, CLR1502, and 5-ALA were administered to mice with magnetic resonance imaging-verified orthotopic U251 glioblastoma multiforme- and glioblastoma stem cell-derived xenografts. Harvested brains were imaged with confocal microscopy (CLR1501), the IVIS Spectrum imaging system (CLR1501, CLR1502, and 5-ALA), or the Fluobeam near-infrared fluorescence imaging system (CLR1502). Imaging and quantitative analysis of T:N fluorescence ratios were performed.
  
  
  RESULTS
  Excitation/emission peaks are 500/517 nm for CLR1501 and 760/778 nm for CLR1502. The observed T:N ratio for CLR1502 (9.28±1.08) was significantly higher (P<.01) than for CLR1501 (3.51±0.44 on confocal imaging; 7.23±1.63 on IVIS imaging) and 5-ALA (4.81±0.92). Near-infrared Fluobeam CLR1502 imaging in a mouse xenograft model demonstrated high- contrast tumor visualization compatible with surgical applications.
  
  
  CONCLUSIONS
  CLR1501 (green) and CLR1502 (near infrared) are novel tumor-selective fluorescent agents for discriminating tumor from normal brain. CLR1501 exhibits a tumor-to-brain fluorescence ratio similar to that of 5-ALA, whereas CLR1502 has a superior tumor-to-brain fluorescence ratio. This study demonstrates the potential use of CLR1501 and CLR1502 in fluorescence-guided tumor surgery.
authors.affiliation: *Department of Neurological Surgery, ‡Cellular and Molecular Biology Training Program, ¶Department of Radiology, ‖Department Medical Physics, and #Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; §Cellectar Biosciences, Inc, Madison, Wisconsin; **Department of Surgery, National University of Singapore, Singapore.
authors.forename: Kyle I
authors.initials: KI
authors.lastname: Swanson
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clark
authors.forename: Ray R
authors.initials: RR
authors.lastname: Zhang
authors.forename: Irawati K
authors.initials: IK
authors.lastname: Kandela
authors.forename: Mohammed
authors.initials: M
authors.lastname: Farhoud
authors.forename: Jamey P
authors.initials: JP
authors.lastname: Weichert
authors.forename: John S
authors.initials: JS
authors.lastname: Kuo
mesh_terms: D000622:Aminolevulinic Acid; D000818:Animals; D001932:Brain Neoplasms / Q000601:surgery*; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D005910:Glioma / Q000601:surgery*; D064593:Heterografts; D006801:Humans; D007211:Indoles; D008279:Magnetic Resonance Imaging; D051379:Mice; D018613:Microscopy, Confocal; D010767:Phosphorylcholine / Q000031:analogs & derivatives; D019265:Spectroscopy, Near-Infrared
chemical_list: C000602293:CLR1502; D005456:Fluorescent Dyes; D007211:Indoles; D010767:Phosphorylcholine; D000622:Aminolevulinic Acid