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 = 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 FLARETM (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 FLARETM 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 developed and found to highlight a multitude of nervous structures including the inferior hypogastric plexus. Although a positive start, these agents are far from ideal in absorption wavelength, emission wavelength, quantum yield, and solubility properties for use in vivo. 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 supervised by Dr. Brian Pogue at Dartmouth, but limited experience in the development of optical contrast agents or clinical translation of optical technology. Through this 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 clinical translation of optical devices and contrast agents. Within this academic environment, this 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.
(provided by applicant): Nerve damage is a serious complication of surgery, especially cancer 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 will is able to see nerves before they are accidentally cut, and thus spare them from damage.
|Hackman, Kayla M; Doddapaneni, Bhuvana Shyam; Barth, Connor W et al. (2015) Polymeric Micelles as Carriers for Nerve-Highlighting Fluorescent Probe Delivery. Mol Pharm 12:4386-94|
|Davis, Scott C; Gibbs, Summer L; Gunn, Jason R et al. (2013) Topical dual-stain difference imaging for rapid intra-operative tumor identification in fresh specimens. Opt Lett 38:5184-7|
|Gibbs, Summer L; Xie, Yang; Goodwill, Haley L et al. (2013) Structure-activity relationship of nerve-highlighting fluorophores. PLoS One 8:e73493|
|Gibbs-Strauss, Summer L; Nasr, Khaled A; Fish, Kenneth M et al. (2011) Nerve-highlighting fluorescent contrast agents for image-guided surgery. Mol Imaging 10:91-101|