The surgical removal of solid tumor has been the foundation of treatment for most types of cancers. While combination of chemo- and radiotherapy cure less than 5% of all cancer patients, surgery cures 50% of patients with solid tumors in the US. However, out of over 700,000 patients undergoing cancer surgery in each year in the US, 40% of them have a recurrence of the disease within 5 years.  Therefore, there is an unmet medical demand to develop techniques to remove primary malignant mass with entirely negative margins and remove all lymph nodes having metastatic cancer cells. Motivated to achieve these goals, we recently have developed a novel FR-targeted near-infrared (NIR) fluorescence probe (OTL-0038) for use in image-guided tumor surgery. Herein we show that the lead optimization, structure activity relationships, scale-up synthesis, and chiral analysis of OTL-0038. Moreover, the binding and specificity of OTL-0038 for FR using (1) FR+ cancer cells in culture, (2) in vivo whole body imaging and ex vivo biodistribution in mice with FR+ or FR- tumor xenografts, (3) dose escalation studies in nude mice, and (4) safety studies will be demonstrated. OTL-0038 can be synthesized from milligram to multi gram scale in high purity and high yield. It is compatible with both organic and aqueous solvents, easy to purify and characterize, and stable during synthesis and storage. Finally, OTL-0038 demonstrates ~20 nM affinity for FR and accumulates exclusively in FR expressing tumors. In near future we anticipate the examination of OTL-0038 in human clinical trials with appropriate stability and toxicity data.

OTL-0038: A potent folate receptor (FR)-targeted NIR dye

246th National Meeting (2013)

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