Clinically translatable formulation strategies for systemic administration of nerve-specific probes.

Nerves are extremely difficult to identify and are often accidently damaged during surgery, leaving patients with lasting pain and numbness. Herein, a novel near-infrared (NIR) nerve-specific fluorophore, LGW01-08, was utilized for enhanced nerve identification using fluorescence guided surgery (FGS), formulated using clinical translatable strategies. Formulated LGW01-08 was examined for toxicology, pharmacokinetics (PK), and pharmacodynamics (PD) parameters in preparation for future clinical translation. Optimal LGW01-08 imaging doses were identified in each formulation resulting in a 10x difference between the toxicity to imaging dose window. Laparoscopic swine surgery completed using the da Vinci surgical robot (Intuitive Surgical) demonstrated the efficacy of formulated LGW01-08 for enhanced nerve identification. NIR fluorescence imaging enabled clear identification of nerves buried beneath ~3 mm of tissue that were unidentifiable by white light imaging. These studies provide a strong basis for future clinical translation of NIR nerve-specific fluorophores for utility during FGS to improve patient outcomes.
Competing Interests: COMPETING INTERESTS Alexander Antaris, Alwin Klaassen and Jonathan Sorger are employees of Intuitive Surgical. Lei Wang, Connor Barth and Summer Gibbs are inventors on patent application PCT/US19/43739 held by Oregon Health and Science University that cover the composition and methods of use of the nerve-specific oxazine compound (LGW01–08) discussed in this manuscript. Lei Wang, Connor Barth, Vidhi Shah, Adam Alani and Summer Gibbs are inventors on patent application PCT/US19/45347 held jointly by Oregon Health and Science University and Oregon State University that covers the compositions and methods of use of the formulation strategies developed herein. Lei Wang, Connor Barth and Summer Gibbs are co-founders of Inherent Targeting, LLC.