White matter tract-specific near-infrared fluorescence probes for in vivo fluorescence guided white matter tractography

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PROJECT SUMMARY Over 700,000 people live with a primary brain tumor in the United States. Maximally safe surgical resection is the single most important initial predictor of quality of life and overall survival. To this end, the surgeon maximizes the extent of tumor resection (EOR) while preserving function. Preserving the integrity of white matter tracts (WMT) during brain tumor surgery is a necessary requirement to preserve function. However, the absence of a clear boundary between functioning WMTs and tumor tissue poses a significant challenge for the neurosurgeon. Magnetic resonance imaging (MRI) tractography provides the surgeon with preoperative images of WMTs to help predict their location. Intraoperatively, the surgeon can use tractography images with image-guidance to maximize preservation of WMT integrity, which has been shown to enable faster and safer surgeries, improved functional outcomes, and increased EOR. However, MRI tractography has practical limitations as a surgical aid for preserving WMT integrity. First, WMT reconstruction can be inaccurate and imprecise due to algorithm variability, user determined thresholds, variable tractographer expertise, and quality of MRI data, which leads to false positives and false negatives. In brain tumors, this challenge is exacerbated by unpredictable patterns of WMT displacement, brain edema, and signal alteration directly related to the underlying tumor. Even with optimal WMT reconstruction, intraoperative MRI tractography does not provide an accurate location of WMTs because it is not a real-time view of the dynamic changes that occur in the surgical field. WMTs shift relative to the pre- operative imaging (i.e., brain shift), thus making the location of WMTs as predicted by tractography inaccurate (e.g., errors up to 3 cm). Fluorescence guided surgery (FGS) helps surgeons visualize brain tumor tissue, with results showing increased EOR. FGS provides the surgeon real-time visualization of tumor tissue during surgery, and thus is not limited by brain shift, because FGS provides direct, in vivo information. We recently discovered that a subset of our first-in class near infrared nerve-specific small molecule fluorophores can cross the intact blood brain barrier, where a handful have demonstrated affinity for WMT. We hypothesize that FGS using a WMT-specific fluorophore could provide an objective methodology to accurately identify in real-time WMTs during surgery. The long-term goal of this project is to dramatically improve surgical outcomes by creating the first real-time intraoperative WMT imaging methodology. This project’s immediate milestones will include quantification of WMT affinity followed by pharmacodynamic and pharmacokinetic studies in healthy rodents. Then, pre-clinical studies in normal rodents and two models of WMT injury will enable selection of the most promising agents to deliver proof-of-concept data of at least one agent suitable for future clinical translation.