title: Synthesis, characterization, and relaxation studies of Gd-DO3A conjugate of chlorambucil as a potential theranostic agent.
abstract: DO3A-based macrocycles serve as attractive templates from which clinically useful theranostic agents can be obtained after coupling with molecular targeted therapeutic drugs. In this study, we describe the chemical synthesis, relaxation, and cytotoxicity studies of a new DO3A conjugate of chlorambucil (CHL) as a magnetic resonance imaging (MRI) theranostic agent. A convenient route of synthesis is reported, which allowed conjugation of the macrocyclic ligand (DO3A) to the chemotherapeutic drug (CHL) via tyrosine for the preparation of an attractive chelate-drug ensemble (DO3A-TR-CHL). The structures of all intermediates and final compound have been determined by1H,13C NMR, and MS. The efficacy of DO3A-TR-CHL as a non-ionic magnetic contrast agent was tested by performing relaxometric studies on its gadolinium complex. The complex exhibited relaxivities (7.11 mm-1/s) higher than that of currently used MR contrast agents and showed enhanced contrast in T1-weighted images. MTT assays revealed that both DO3A-TR-CHL and Gd(III)-DO3A-TR-CHL conjugates exhibited dose-dependent toxicity and an enhanced antiproliferative activity against tumor (A549 and HeLa) cell lines compared to that of parent drug (CHL), thereby demonstrating their potential to be used as a magnetic resonance imaging theranostic for improved molecular imaging and therapy of human cancers.
authors.affiliation: Institute of Inorganic Chemistry, University of Cologne, Cologne, Germany.
authors.forename: Jasleen
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Department of Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Yoanna
authors.initials: Y
authors.lastname: Tsvetkova
authors.affiliation: Institute of Inorganic Chemistry, University of Cologne, Cologne, Germany.
authors.forename: Karim
authors.initials: K
authors.lastname: Arroub
authors.affiliation: Institute of Inorganic Chemistry, University of Cologne, Cologne, Germany.
authors.forename: Sabri
authors.initials: S
authors.lastname: Sahnoun
authors.affiliation: Department of Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.affiliation: Institute of Inorganic Chemistry, University of Cologne, Cologne, Germany.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mathur
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002699:Chlorambucil / Q000737:chemistry*; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry; D006367:HeLa Cells; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D008279:Magnetic Resonance Imaging; D009369:Neoplasms / Q000000981:diagnostic imaging; D009942:Organometallic Compounds / Q000737:chemistry*; D000068936:Theranostic Nanomedicine
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C062402:gadoteridol; D002699:Chlorambucil; D005682:Gadolinium
keywords: chlorambucil; gadolinium complex; macrocyclic ligand; magnetic resonance imaging; synthesis; tyrosine