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.
Accidental nerve damage or transection of vital nerve structures remains an unfortunate reality that is often associated with surgery. Despite the existence of nerve-sparing techniques, the success of such procedures is not only complicated by anatomical variance across patients but is also highly dependent on a surgeon’s first-hand experience that is acquired over numerous procedures through trial and error, often with highly variable success rates. Fluorescent small molecules, such as rhodamines and fluoresceins have proven incredibly useful for biological imaging in the life sciences, and they appeared to have potential in illuminating vital nerve structures during surgical procedures. In order to make use of the current clinically relevant imaging systems and to provide surgeons with fluorescent contrast largely free from the interference of hemoglobin and water, it was first necessary to spectrally tune known fluorescent scaffolds towards near infrared (NIR) wavelengths. To determine whether the well-documented Si-substitution strategy could be applied towards developing a NIR fluorophore that retained nerve-specific properties of candidate molecules, an in vivo comparison was made between two compounds previously shown to highlight nervous structures – TMR and Rhodamine B – and their Si-substituted derivatives.
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