Multichannel Fluorescence Guided Surgery Tools Enabling Simultaneous Cancer Margin and Nerve Visualization in Prostatectomy

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PROJECT SUMMARY Prostate cancer is the most prevalent cancer in men and the second leading cause of cancer death. Prostatec- tomy is one of the most common primary treatments for prostate cancer, where surgeons face two main goals: prostate cancer cure and nerve preservation. However, with little visual acuity for nerve plexus recognition and conclusive cancer delineation, ideal outcomes for patients continue to challenge even experienced surgeons. Positive surgical margins and nerve damage occur in up to 21 and 60% of patients, respectively, resulting in poor cancer control as well as incontinence and impotence severely affecting post-operative quality of life. No clinically approved methods exist to enhance direct cancer or nerve plexus visualization intraoperatively. Thus, technology to enable the direct visualization of cancer tissue and nerves simultaneously in real time would greatly reduce associated comorbidities and significantly improve prostatectomy outcomes. Fluorescence Guided Sur- gery (FGS) has successfully integrated into clinical medicine with only two FDA-approved fluorophores, providing surgeons real-time visualization. FGS systems operate mainly at near infrared (NIR, 700-900 nm) wavelengths, where tissue chromophore absorbance, autofluorescence and scatter fall to local minima, allowing high contrast imaging at up to centimeter depths. A number of targeted NIR contrast agents are under development, including nerve- and prostate-specific probes that together would provide an integrated FGS tool for prostatectomy. In the US, >80% of prostatectomies are performed using robotic-assistance, where the da Vinci surgical robot (Intuitive Surgical) is the most common and is equipped standard with a NIR fluorescence-imaging channel capable of real-time visualization. Herein, we will collaborate with Drs. Jonathan Sorger (Intuitive Surgical) and Scott Davis (Dartmouth) to develop a multicolor FGS solution for prostatectomy that highlights both cancer and nerve tissues to improve patient outcomes. Prostate specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancers making it a promising target for prostate cancer imaging. A handful of molecules have shown high affinity for PSMA following labeling, which have been extensively investigated, where 800 nm PSMA tar- geted IS-002 has successfully completed Phase I clinical trials sponsored by Intuitive Surgical. Herein, we will develop a NIR, spectrally-distinct, nerve-specific fluorophore for co-administration with PSMA-targeted IS-002 to bring this new FGS paradigm to prostate cancer patients. In exciting preliminary work, our team has synthesized NIR nerve-specific fluorophores that can be imaged with clinical FGS systems. Herein, 700 nm NIR nerve-spe- cific probes will be synthetically tuned for co-administration with PSMA-specific 800 nm IS-002 and validated for future translation to guided prostatectomy. These goals will be accomplished through the following specific aims: Aim 1: Synthesize 700 nm NIR nerve-specific FGS probes. Aim 2: Quantify preclinical pharmacology and toxi- cology of NIR nerve-specific probes co-administered with IS-002. Aim 3: Select a lead nerve-specific probe for co-administration with IS-002 through demonstration of nerve- and prostate cancer-specific contrast.