The clinical implementation of molecularly targeted imaging modalities has progressed considerably in recent years. Fluorophores in the near-IR range are of particular interest for in vivo optical imaging due to the significant tissue penetration of light in this range. Despite a central role in modern biology and medicine, the compounds employed in near-IR fluorescence techniques have changed little in recent decades. Using molecular design concepts borrowed from related fields (e.g. medicinal chemistry and modern organic synthesis), we seek to develop new agents with improved utility for cancer-related imaging and microscopy. The long-term goal is to identify readily synthesized, stable, and bright fluorophores with optimal properties for biomedical imaging. Our current efforts in this area are split in two aims.
Aim 1 - Synthetic methods to prepare heptamethine cyanine fluorophores. The heptamethine cyanine class of near-IR fluorophores are used for many applications, with extensive recent progress in the context of fluorescence-guided surgery. We have developed a new rearrangement reaction that enables the synthesis of previously inaccessible variants. Compared to existing agents, the compounds we have prepared exhibit improved optical properties and significantly greater chemical stability to biological nucleophiles. We have shown that these new agents can be conjugated to the antibodies and resulting conjugates display exhibit excellent fluorescence properties in microscopy experiments and in vivo animal studies. We have also shown that small changes in the polar functional groups appended to these fluorophores can have a dramatic impact on biodistrubution and tumor accumulation. We are currently pursuing approaches to improve other aspects of the optical properties of these molecules, especially their brightness and absorption profile.
Aim 2 - Synthesis and evaluation of novel far-red probes. We have developed a chemical strategy to assemble polycyclic pentamethine cyanines through a cross metathesis/polycylcization strategy. When compared to conventional pentamethine cyanines, the resulting compounds exhibit significantly higher fluorescence quantum yield (4X) and, additionally, recover from sodium borohydride reduction with improved efficiency. These features allow these compounds to be used for super resolution microscopy and enable excellent photon counts without recourse to complex deoxygenation buffers. In ongoing efforts, we are developing targetable small molecules with enhanced solubility.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011506-06
Application #
9779940
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Michie, Megan S; Götz, Ralph; Franke, Christian et al. (2017) Cyanine Conformational Restraint in the Far-Red Range. J Am Chem Soc 139:12406-12409
Chan, Susanna T S; Nani, Roger R; Schauer, Evan A et al. (2016) Characterization and Synthesis of Eudistidine C, a Bioactive Marine Alkaloid with an Intriguing Molecular Scaffold. J Org Chem 81:10631-10640
Patel, Nayan J; Chen, Yihui; Joshi, Penny et al. (2016) Effect of Metalation on Porphyrin-Based Bifunctional Agents in Tumor Imaging and Photodynamic Therapy. Bioconjug Chem 27:667-80
Sato, Kazuhide; Gorka, Alexander P; Nagaya, Tadanobu et al. (2016) Effect of charge localization on the in vivo optical imaging properties of near-infrared cyanine dye/monoclonal antibody conjugates. Mol Biosyst 12:3046-56
Gorka, Alexander P; Schnermann, Martin J (2016) Harnessing cyanine photooxidation: from slowing photobleaching to near-IR uncaging. Curr Opin Chem Biol 33:117-25
Sato, Kazuhide; Gorka, Alexander P; Nagaya, Tadanobu et al. (2016) Role of Fluorophore Charge on the In Vivo Optical Imaging Properties of Near-Infrared Cyanine Dye/Monoclonal Antibody Conjugates. Bioconjug Chem 27:404-13
Nani, Roger R; Shaum, James B; Gorka, Alexander P et al. (2015) Electrophile-integrating Smiles rearrangement provides previously inaccessible C4'-O-alkyl heptamethine cyanine fluorophores. Org Lett 17:302-5
Gorka, Alexander P; Nani, Roger R; Schnermann, Martin J (2015) Cyanine polyene reactivity: scope and biomedical applications. Org Biomol Chem 13:7584-98
Sato, Kazuhide; Nagaya, Tadanobu; Nakamura, Yuko et al. (2015) Impact of C4'-O-Alkyl Linker on in Vivo Pharmacokinetics of Near-Infrared Cyanine/Monoclonal Antibody Conjugates. Mol Pharm 12:3303-11
Schnermann, Martin J; Shenvi, Ryan A (2015) Syntheses and biological studies of marine terpenoids derived from inorganic cyanide. Nat Prod Rep 32:543-77

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