title: NIR-Cyanine Dye Linker: a Promising Candidate for Isochronic Fluorescence Imaging in Molecular Cancer Diagnostics and Therapy Monitoring.
abstract: Personalized anti-cancer medicine is boosted by the recent development of molecular diagnostics and molecularly targeted drugs requiring rapid and efficient ligation routes. Here, we present a novel approach to synthetize a conjugate able to act simultaneously as an imaging and as a chemotherapeutic agent by coupling functional peptides employing solid phase peptide synthesis technologies. Development and the first synthesis of a fluorescent dye with similarity in the polymethine part of the Cy7 molecule whose indolenine-N residues were substituted with a propylene linker are described. Methylating agent temozolomide is functionalized with a tetrazine as a diene component whereas Cy7-cell penetrating peptide conjugate acts as a dienophilic reaction partner for the inverse Diels-Alder click chemistry-mediated ligation route yielding a theranostic conjugate, 3-mercapto-propionic-cyclohexenyl-Cy7-bis-temozolomide-bromide-cell penetrating peptide. Synthesis route described here may facilitate targeted delivery of the therapeutic compound to achieve sufficient local concentrations at the target site or tissue. Its versatility allows a choice of adequate imaging tags applicable in e.g. PET, SPECT, CT, near-infrared imaging, and therapeutic substances including cytotoxic agents. Imaging tags and therapeutics may be simultaneously bound to the conjugate applying click chemistry. Theranostic compound presented here offers a solid basis for a further improvement of cancer management in a precise, patient-specific manner.
authors.affiliation: 1. German Cancer Research Center, Department of Medical Physics in Radiology, INF 280, 69120 Heidelberg, Germany.
authors.forename: Dorde
authors.initials: D
authors.lastname: Komljenovic
authors.affiliation: 1. German Cancer Research Center, Department of Medical Physics in Radiology, INF 280, 69120 Heidelberg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wiessler
authors.affiliation: 2. German Cancer Research Center, Division of Biophysics of Macromolecules, INF 580, 69120 Heidelberg, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Waldeck
authors.affiliation: 3. University of Heidelberg, Institute of Pathology, INF 224, 69120 Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.affiliation: 4. German Cancer Research Center, Department of Translational Immunology, INF 580, 69120 Heidelberg, Germany.
authors.forename: Ruediger
authors.initials: R
authors.lastname: Pipkorn
authors.affiliation: 1. German Cancer Research Center, Department of Medical Physics in Radiology, INF 280, 69120 Heidelberg, Germany.
authors.forename: Hans-Hermann
authors.initials: HH
authors.lastname: Schrenk
authors.affiliation: 5. University of Heidelberg, Department of Radiation Oncology, INF 400, 69120 Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: 1. German Cancer Research Center, Department of Medical Physics in Radiology, INF 280, 69120 Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Braun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000175:diagnosis*; D061848:Optical Imaging / Q000379:methods*; D057285:Precision Medicine / Q000379:methods; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes
keywords: Click chemistry; fluorescent dye; inverse Diels-Alder reaction; molecular diagnostics; multimodal imaging; near infrared imaging; solid phase peptide synthesis.