title: Targeting tumor hypoxia: a third generation 2-nitroimidazole-indocyanine dye-conjugate with improved fluorescent yield.
abstract: Tumor hypoxia is associated with the rapid proliferation and growth of malignant tumors, and the ability to detect tumor hypoxia is important for predicting tumor response to anti-cancer treatments. We have developed a class of dye-conjugates that are related to indocyanine green (ICG, ) to target tumor hypoxia, based on in vivo infrared fluorescence imaging using nitroimidazole moieties linked to indocyanine fluorescent dyes. We previously reported that linking 2-nitroimidazole to an indocyanine dicarboxylic acid dye derivative () using an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG, ), led to a dye-conjugate that gave promising results for targeting cancer hypoxia in vivo. Structural modification of the dye conjugate replaced the ethanolamine unit with a piperazineacetyl unit and led a second generation dye conjugate, piperzine-2-nitroimidazole-ICG (). This second generation dye-conjugate showed improved targeting of tumor hypoxia when compared with . Based on the hypothesis that molecules with more planar and rigid structures have a higher fluorescence yield, as they could release less absorbed energy through molecular vibration or collision, we have developed a new 2-nitroimidazole ICG conjugate, , with two carbon atoms less in the polyene linker. Dye-conjugate was prepared from our new dye (), and coupled to 2-nitroimidazole using a piperazine linker to produce this third-generation dye-conjugate. Spectral measurements showed that the absorption/emission wavelengths of 657/670 were shifted ∼100 nm from the second-generation hypoxia dye of 755/780 nm. Its fluorescence quantum yield was measured to be 0.467, which is about 5 times higher than that of (0.083). In vivo experiments were conducted with balb/c mice and showed more than twice the average in vivo fluorescence intensity in the tumor beyond two hours post retro-orbital injection as compared with . These initial results suggest that may significantly improve in vivo tumor hypoxia targeting.
authors.affiliation: Department of Biomedical Engineering and Electrical Engineering, University of Connecticut, Storrs, CT, USA. zhu@engr.uconn.edu.
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Biomedical Engineering and Electrical Engineering, University of Connecticut, Storrs, CT, USA. zhu@engr.uconn.edu.
authors.forename: Saeid
authors.initials: S
authors.lastname: Zanganeh
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs, CT, USA. michael.smith@uconn.edu.
authors.forename: Innus
authors.initials: I
authors.lastname: Mohammad
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs, CT, USA. michael.smith@uconn.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Dietz
authors.affiliation: Department of Biomedical Engineering and Electrical Engineering, University of Connecticut, Storrs, CT, USA. zhu@engr.uconn.edu.
authors.forename: Akram
authors.initials: A
authors.lastname: Abuteen
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs, CT, USA. michael.smith@uconn.edu.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Smith
authors.affiliation: Department of Biomedical Engineering and Electrical Engineering, University of Connecticut, Storrs, CT, USA. zhu@engr.uconn.edu.
authors.forename: Quing
authors.initials: Q
authors.lastname: Zhu
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes / Q000737:chemistry* / Q000493:pharmacokinetics; D000860:Hypoxia / Q000150:complications* / Q000175:diagnosis*; D007208:Indocyanine Green / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000150:complications* / Q000473:pathology; D009593:Nitroimidazoles / Q000737:chemistry / Q000493:pharmacokinetics; D061848:Optical Imaging
chemical_list: D005456:Fluorescent Dyes; D009593:Nitroimidazoles; D007208:Indocyanine Green; C006667:azomycin