title: Synthesis, biological evaluation, and in vivo imaging of the first camptothecin-fluorescein conjugate.
abstract: The first synthesis and photophysical properties of a fluorecently labeled camptothecin derivative, namely, camptothecin-FI (CPT-FI), an antitumoral agent that targets topoisomerase I, are reported. The preparation of this fluorescent conjugate is based on a highly convergent and flexible approach which enables the rapid chemical modification of the AB ring system of this fragile pentacyclic alkaloid, aimed at introducing an anchoring point to graft the fluorophore. The selection of a fluorescein analogue as the reporter group has enabled us to get the first green-emitting CPT conjugate exhibiting valuable spectral properties and retaining biological properties of native CPT. Indeed, in biological models, i.e., glioma cell lines U87 and/or T98, the kinetics of cell endocytosis, as well as the efficacy of CPT-FI were compared to those of CPT. CPT-FI fluorescence was measured in the cytosolic compartment of T98 glioma cells from 5 min treatment and remained detectable until 48 h. As CPT, CPT-FI drastically inhibited glioma growth and cell cycle but exhibited a reduced affinity as compared to the native CPT. In vivo and ex vivo imaging studies of CPT-FI intratumoraly injected into a model of NIH-3T3 murine tumor xenografts in nude mice, showed accumulation around the injected site area, which is very promising to target tumors and follow biodistribution in vivo.
authors.affiliation: Normandie University, COBRA, UMR 6014 and FR 3038, University of Rouen, INSA of Rouen, CNRS, 1 rue Tesnière 76821 Mont-Saint-Aignan, Cedex, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chevalier
authors.forename: Martine
authors.initials: M
authors.lastname: Dubois
authors.forename: Vadim
authors.initials: V
authors.lastname: Le Joncour
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dautrey
authors.forename: Céline
authors.initials: C
authors.lastname: Lecointre
authors.forename: Anthony
authors.initials: A
authors.lastname: Romieu
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Renard
authors.forename: Hélène
authors.initials: H
authors.lastname: Castel
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sabot
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry*; D002166:Camptothecin / Q000138:chemical synthesis / Q000737:chemistry*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D019793:Fluorescein / Q000138:chemical synthesis / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D041681:NIH 3T3 Cells; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019793:Fluorescein; D002166:Camptothecin