DNA repair mechanisms have evolved to ensure the integrity of DNA and maintain cellular functions in the body.  However, these repair processes are the main causes of drug resistance to many chemotherapeutics designed to cause cell death through DNA damage.  Therefore, there is a need for the development of imaging tools that can indicate where and to what degree DNA repair occurs and possibly reduces the efficacy of cancer treatment.  In particular, new optical imaging probes could readily allow for evaluating new drug candidates in a preclinical setting and monitoring patient response to therapy.  To help address this need, we have developed a near infrared (NIR) fluorescent DNA repair-targeted compound for use in optical imaging.  This small molecule imaging probe, which we have designed, synthesized, and characterized, binds to abasic (or AP for apurinic/apyrimidinic) sites, key intermediates in the base excision repair (BER) pathway.  Taking advantage of the chemistry of BER, we have developed a fluorescent oligomer-based assay to evaluate the ability of this probe to bind to AP sites and stall further repair.  Through this assay, we have shown that the probe binds specifically and rapidly to AP sites in DNA.  In addition, using calf thymus DNA treated with heat and acid to induce AP sites, we have demonstrated that the probe is sensitive to the quantity of AP sites.  We are currently evaluating the potential of the probe to detect DNA damage and repair in vivo.

Development of a near infrared fluorescent probe for optical imaging of DNA base excision repair

248th National Meeting (2014)

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