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Significance: Head and neck squamous cell carcinoma (HNSCC) has the sixth highest incidence worldwide, with > 650,000 cases annually. Surgery is the primary treatment option for HNSCC, during which surgeons balance two main goals: (1) complete cancer resection and (2) preservation of normal tissues to ensure post-surgical quality of life. Unfortunately, these goals are not synergistic, where complete cancer resection is often limited by efforts to preserve normal tissues, particularly nerves, and reduce life-altering comorbidities., Aim: Currently, no clinically validated technology exists to enhance intraoperative cancer and nerve recognition. Fluorescence-guided surgery (FGS) has successfully integrated into clinical medicine, providing surgeons with real-time visualization of important tissues and complex anatomy, where FGS imaging systems operate almost exclusively in the near-infrared (NIR, 650 to 900 nm). Notably, this spectral range permits the detection of two NIR imaging channels for spectrally distinct detection., Approach: Herein, we evaluated the utility of spectrally distinct NIR nerve- and tumor-specific fluorophores for two-color FGS to guide HNSCC surgery. Using a human HNSCC xenograft murine model, we demonstrated that facial nerves and tumors could be readily differentiated using these nerve- and tumor-specific NIR fluorophores., Results: The selected nerve-specific fluorophore showed no significant difference in nerve specificity and off-target tissue fluorescence in the presence of xenograft head and neck tumors. Co-administration of two NIR fluorophores demonstrated successful tissue-specific labeling of nerves and tumors in spectrally distinct NIR imaging channels., Conclusions: We demonstrate a comprehensive FGS tool for cancer resection and nerve sparing during HNSCC procedures for future clinical translation., (© 2024 The Authors.)

Patients undergoing gynecological procedures suffer from lasting side effects due to intraoperative nerve damage. Small, delicate nerves with complex and nonuniform branching patterns in the female pelvic neuroanatomy make nerve-sparing efforts during standard gynecological procedures such as hysterectomy, cystectomy, and colorectal cancer resection difficult, and thus many patients are left with incontinence and sexual dysfunction. Herein, a near-infrared (NIR) fluorescent nerve-specific contrast agent, LGW08-35, that is spectrally compatible with clinical fluorescence guided surgery (FGS) systems is formulated and characterized for rapid implementation for nerve-sparing gynecologic surgeries. The toxicology, pharmacokinetics (PK), and pharmacodynamics (PD) of micelle formulated LGW08-35 are examined, enabling the determination of the optimal imaging doses and time points, blood and tissue uptake parameters, and maximum tolerated dose (MTD). Application of the formulated fluorophore to imaging of female rat and swine pelvic neuroanatomy validates the continued clinical translation and use for real-time identification of important nerves such as the femoral, sciatic, lumbar, iliac, and hypogastric nerves. Further development of LGW08-35 for clinical use will unlock a valuable tool for surgeons in direct visualization of important nerves and contribute to the ongoing characterization of the female pelvic neuroanatomy to eliminate the debilitating side effects of nerve damage during gynecological procedures., (© 2023 Wiley‐VCH GmbH.)

Iatrogenic nerve injury significantly affects surgical outcomes. Although intraoperative neuromonitoring is utilized, nerve identification remains challenging and the success of nerve sparing is strongly correlated with surgeon experience levels. Fluorescence guided surgery (FGS) offers a potential solution for improved nerve sparing by providing direct visualization of nerve tissue intraoperatively. However, novel probes for FGS face a long regulatory pathway to achieve clinical translation. Herein, we report on the development of a clinically-viable, gel-based formulation that enables direct administration of nerve-specific probes for nerve sparing FGS applications, facilitating clinical translation via the exploratory investigational new drug (eIND) guidance. The developed formulation possesses unique gelling characteristics, allowing it to be easily spread as a liquid followed by rapid gelling for subsequent tissue hold. Optimization of the direct administration protocol with our gel-based formulation enabled a total staining time of 1-2 min for compatibility with surgical procedures and successful clinical translation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)