Fluorescence-guided surgery (FGS) has the potential to significantly enhance patient outcomes by enabling precise real-time visualization of vital nerve structures during surgical procedures. However, a clinically approved nerve-specific contrast agent does not exist. To address this need, we adopted a medicinal chemistry approach to design and develop novel near-infrared (NIR) nerve-binding small molecule fluorophore libraries. Our first-in-class NIR nerve-binding small molecule fluorophores represent a significant advancement in the field. By enabling precise nerve visualization in real-time during surgery, these contrast agents have the potential to revolutionize nerve-sparing procedures and ultimately improve patient outcomes.
Iatrogenic nerve injuries are a major concern in various surgical fields, causing significant morbidity. These injuries lead to impaired sensory and motor functions, chronic pain, reduced limb control, and increased healthcare needs. Surgeons use techniques like white light visualization and intraoperative neuromonitoring (e.g., electromyography [EMG]) to identify nerve damage. However, the incidence rate remains high, necessitating better alternatives. Our team developed near-infrared (NIR) nerve-specific fluorophores to enhance nerve visualization, and one of our lead fluorophores exhibited reduced fluorescence intensity in injured nerve regions, providing contrast shortly after nerve injury. These results led us to hypothesize that the fluorophore could be used as an intraoperative neuromonitoring tool during fluorescence-guided surgery. Ultimately, this tool can be used intraoperatively to aid surgeons in timely detection and accurate assessment of nerve health, mitigating complications and improving patient outcomes. The culmination of our work will bring forth a novel methodology for localizing nerve injuries, benefiting both patients and surgical procedures.
Nerve damage ruins the lives of many patients post surgery, significantly affecting post-surgical quality of life. Intraoperative nerve detection is completed using anatomical knowledge and conventional white light visualization when possible. However, nerves can be difficult or impossible to identify by white light visualization and neuroanatomy is often varied between patients. We have developed nerve specific fluorescence guided surgery (FGS) contrast agents that provide real time direct visualization of nerves intraoperatively. These nerve-specific fluorophores represent the first of their kind and are capable of translation to clinical studies using existing clinical infrastructure of FGS systems. Work is underway to complete the preclinical pharmacology and toxicology testing required for a successful investigational new drug application to the FDA for first-in-human clinical trials and translation to surgical use should be feasible within the next five years.
Cranial and spinal nerve repair occurs at a very slow rate, and in most cases the iatrogenic injury can’t be fully repaired, leading to permanent motor or sensory disabilities as well as incurable neuropathies. The visualization and evaluation of tumor-involved nerves is extremely difficult during minimally invasive surgical procedures such as through at the skull base. Recently, our group developed a library of nerve-specific near infrared (NIR) oxazine scaffold dyes that have high specificity for cranial nerves, and the ability to permeate the Blood-Brain Barrier (BBB), which resulted in different degrees of the obtained cranial nerves SBR. These cranial nerve-specific fluorophores will significantly improve nerve visualization at depth, enhancing the ability to visualize and evaluate buried and tumor-involved cranial nerves. This could significantly decrease post-surgical morbidity rates and could solve the unmet clinical need for an intraoperative tool that enhances visualization.
Iatrogenic nerve injury is a major source of morbidity common to all surgical specialties. Prostate cancer, the second leading cause of cancer-related death among men in the U.S, is often treated surgically via prostatectomy. But visibility of the nerve plexus is extremely limited and nerve damage affects 60% of patients leading to post-surgical comorbidities.
We’ve developed a synthetic strategy to improve key properties of fluorophores with potential clinical translatability to generate an optimal 700 nm fluorophore to pair with a fluorescently labeled probe optimized for the 800 nm channel in FGS systems targeting PSMA via the EUK targeting sequence for use in two-color prostatectomy.
These new water-soluble, NIR, nerve-specific fluorophores show improved nerve specificity and in vivo brightness, require a lower dose to achieve contrast of superficial and buried nerve tissue and negate formulation development, improving safety profiles and lowering the cost of clinical translation.
This Conference Presentation, “Utilization of near infrared nerve-specific fluorescent contrast agents as an intraoperative assessment methodology for nerve damage,” was recorded for Photonics West BiOS 2022 On-Demand.
Iatrogenic nerve injury remains one of the most common surgical complications, often resulting in permanent disabilities that severely impact patient quality of life following surgery. Current means of intraoperative nerve identification are limited beyond white light visualization and neuroanatomical knowledge but include ultrasound and the gold standard electromyography (EMG). However, nerve identification in the surgical field of view often remains inadequate. Though fluorophores like rhodamine, cyanine, and others have found extensive and diverse uses in the life sciences, in the realm of fluorescence-guided surgery (FGS), fluorophores that absorb and emit in the NIR region (650-900 nm) have the highest potential for clinical translation. Combining the structural characteristics of a long wavelength emitting fluorophore cyanine like indocyanine green (ICG) with those of a topically nerve-specific fluorophore, like rhodamine B, could offer a strategy for generating NIR-emissive and nerve-specific fluorophores. This study investigated whether the topical nerve-affinity observed in rhodamines extends to systemic administration and whether the structural hybridization strategy used in the previously published Changsha dyes could prove useful in generating long-wavelength nerve-specific contrast agents for use in FGS.
Accidental damage of vital nerve structures remains a significant surgical morbidity. Patient-to-patient neuroanatomical variability requires considerable dependence on a surgeon’s first-hand experiences that primarily rely on proximal features for orientation, which can be further complicated in patients with nerve damage. As such, enhanced nerve visualization proves to be a vital avenue for advancing surgical precision and patient outcomes. Fluorescence guided surgery (FGS) has the potential to improve surgical guidance, but there are no current nerve-specific fluorophores approved for clinical use. Previous work has identified the oxazine scaffold as a promising avenue for nerve-specific contrast agent development, due to its sufficiently low molecular weight to cross the blood-nerve-barrier (BNB), tunable photophysical properties, and high nerve specificity. Herein we report our efforts to investigate the structure-function relationship of Oxazine-4 through fine-tuned terminal alkylamino modifications, both based on optical and physicochemical properties as well as their affected nerve specificities.
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