Carbonic Anhydrase IX-Targeted Near-Infrared Dye for Fluorescence Imaging of Hypoxic Tumors
journal contributionposted on 06.09.2018 by Sakkarapalayam M. Mahalingam, Haiyan Chu, Xin Liu, Christopher P. Leamon, Philip S. Low
Any type of content formally published in an academic journal, usually following a peer-review process.
Use of tumor-targeted fluorescence dyes to help surgeons identify otherwise undetected tumor nodules, decrease the incidence of cancer-positive margins, and facilitate localization of malignant lymph nodes has demonstrated considerable promise for improving cancer debulking surgery. Unfortunately, the repertoire of available tumor-targeted fluorescent dyes does not permit identification of all cancer types, raising the need to develop additional tumor-specific fluorescent dyes to ensure localization of all malignant lesions during cancer surgeries. By comparing the mRNA levels of the hypoxia-induced plasma membrane protein carbonic anhydrase IX (CA IX) in 13 major human cancers with the same mRNA levels in corresponding normal tissues, we document that CA IX constitutes a nearly universal marker for the design of tumor-targeted fluorescent dyes. Motivated by this expression profile, we synthesize two new CA IX-targeted near-infrared (NIR) fluorescent imaging agents and characterize their physical and biological properties both in vitro and in vivo. We report that conjugation of either acetazolamide or 6-aminosaccharin (i.e., two CA-IX-specific ligands) to the NIR fluorescent dye, S0456, via an extended phenolic spacer creates a brightly fluorescent dye that binds CA IX with high affinity and allows rapid visualization of hypoxic regions of solid tumors at depths >1 cm beneath a tissue surface. Taken together, these data suggest that a CA IX-targeted NIR dye can constitute a useful addition to a cocktail of tumor-targeted NIR dyes designed to image all human cancers.