Nerve-Specific Near-Infrared Fluorescent Contrast Agents for Image-Guided Surgery

DESCRIPTION (provided by applicant): The ability to spare nerves during surgical procedures has remained a vexing problem because surrounding tissue often obscures them. Indeed, for a majority of surgical procedures, nerve damage is the major morbidity. For example, sparing of the inferior hypogastric plexus and cavernous nerve is of paramount importance during radical prostatectomy. Male potency and urinary continence is dependent on proper functioning of these nerves. At the present time, nerve-sparing radical prostatectomies are based on the surgeon's knowledge of general prostate nerve anatomy, rather than nerve visualization in individual men. The ideal nerve-specific contrast agent should fulfill the following criteria: 1) have a LogD at pH 7.4 between 0.5 to 3 to maximize blood-nerve-barrier (BNB) penetration, 2) have a MW d 500 Da to maximize BNB penetration, 3) bind to a nerve-specific target and be retained in nerve for several hours, and 4) be a near-infrared (NIR) fluorophore having excitation and emission wavelengths in the NIR "window" between 700 nm and 900 nm. NIR fluorophores are particularly exciting agents for image-guided surgery since photon penetration is maximal, tissue autofluorescence is minimal, and the FLARE (Fluorescence-Assisted Resection and Exploration) imaging system, developed by the mentor's laboratory, is already available and is being used in three separate clinical trials. Although the FLARE system has a wavelength channel reserved for nerve visualization, no nerve-specific NIR fluorophore presently exists. In preliminary studies conducted by the applicant, two nerve-specific agents have been synthesized and found to highlight a multitude of nervous structures in mice, rats and pigs. Although a positive start, these agents are far from ideal in absorption wavelength, emission wavelength, quantum yield, and solubility properties for image-guided surgery. The goals of this K01 award will be 1) to systematically modify the existing agents to achieve NIR excitation and emission, 2) to develop a viable in vivo formulation to quantify the agent's biodistribution and clearance and 3) to perform animal validation studies in image-guided surgery. This K01 application is designed as a training vehicle for a candidate with a strong background in optical imaging technology from her Ph.D. work with Dr. Brian Pogue at Dartmouth, but limited experience in the development of optical contrast agents or clinical translation of optical technology. Through the K01 award application, the candidate requests intensive training in contrast agent chemistry and in vivo optical imaging. The Mentor's laboratory has expertise in the development of NIR fluorescent contrast agents and the clinical translation of optical technology. The Co-Mentor's laboratory has over 20 years of experience in fluorophore chemistry. Within this academic environment, the K01 application describes a career development plan and institutional commitment that will permit the transition of the candidate to independence over a period of five years, while she simultaneously contributes to an area of investigation with profound clinical significance. PUBLIC HEALTH RELEVANCE: Nerve damage is a serious complication of surgery. Presently, finding nerves during surgery is extremely difficult since they are embedded within normal tissue. This study is focused on developing new "contrast agents" that "light up" nerves using invisible near-infrared fluorescent light. When these contrast agents are used with a newly available camera that detects this special type of invisible light, the surgeon is able to see nerves before they are accidentally cut, and thus spare them from damage.