Evaluation of a cholecystokinin 2 receptor-targeted near-infrared dye for fluorescence-guided surgery of cancer.

Surgical resection of malignant disease remains one of the most effective tools for treating cancer. Tumor-targeted near-infrared dyes have the potential to improve contrast between normal and malignant tissues, thereby enabling surgeons to more quantitatively resect malignant disease. Because the cholecystokinin 2 receptor (CCK2R and its tumor-specific splice variant CCK2i4svR) is overexpressed in cancers of the lungs, colon, thyroid, pancreas, and stomach, but absent or inaccessible to parenterally administered drugs in most normal tissues, we have undertaken to design a targeting ligand that can deliver attached near-infrared dyes to CCK2R+ tumors. We report here the synthesis and biological characterization of a CCK2R-targeted conjugate of the near-infrared dye, LS-288 (CRL-LS288). We demonstrate that CRL-LS288 binds selectively to CCK2R+ cancer cells with low nanomolar affinity (Kd = 7 × 10(-9) M). We further show that CRL-LS288 localizes primarily to CCK2R-expressing HEK 293 murine tumor xenografts and that dye uptake in these xenografts is significantly reduced when CCK2R are blocked by preinjection of excess ligand (CRL) or when mice are implanted with CCK2R-negative tumors. Because CRL-LS288 is also found to reveal the locations of distant tumor metastases, we suggest that CRL-LS288 has the potential to facilitate intraoperative identification of malignant disease during a variety of cancer debulking surgeries.