Peripheral nerve injuries are among the most frequent iatrogenic complications, resulting in persistent postsurgical numbness, chronic pain, and paralysis. Nerve-sparing can be a difficult task due to patient-patient variability and the difficulty of nerve visualization in the operating room. Fluorescence image-guided surgery (FGS) to aid in the precise visualization of vital nerve structures in real time during surgery could greatly improve patient outcomes. However, a clinically approved near infrared (NIR) nerve-specific contrast agent does not exist. Contrast agents that fall within the NIR window (650-900 nm) are particularly attractive for FGS, because absorbance, scattering, and autofluorescence are all at local minima, making tissue light penetration maximal in this range. Herein we report our efforts to synthesized a focused library of 80 systematically-modified far red to NIR fluorophores to define the factors that modulate a molecule’s nerve specificity. Nerve specificity screening was completed using murine models following both topical and systemic administration strategies. Several 700 nm and 800 nm nerve-specific lead compounds have been identified, and their nerve specificity and scalability have been confirmed in the swine models. Additionally, clinically relevant formulation strategies for both topical and systemic administration have been developed to facilitate clinical translation. Notably, the topical administration strategy allows clinical translation of these novel agents under the exploratory investigational new drug (eIND) application to the FDA, making these clinical applications more financial achievable and rapid. Given the interplay between novel nerve-specific contrast agent development and clinically relevant formulation strategies, translation to the clinic should be feasible within the next five years.

Toward clinical translation of near-infrared nerve-specific fluorophores for fluorescence image-guided nerve sparing surgical procedures

2019 Spring National Meeting

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