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

项目总结 在美国，有超过70万人患有原发性脑瘤。最安全的手术切除是 生活质量和总体生存的唯一最重要的初始预测因素。为此，外科医生最大限度地 保留功能的肿瘤切除范围(EOR)。保护白质束的完整性 脑肿瘤手术中(WMT)是保留功能的必要条件。然而，由于没有一个 功能正常的WMT和肿瘤组织之间的清晰边界对神经外科医生来说是一个巨大的挑战。 磁共振成像(MRI)为外科医生提供了WMTs的术前图像 帮助预测他们的位置。在手术中，外科医生可以在图像引导下使用纤维束成像技术 最大限度地保持WMT的完整性，这已被证明能够实现更快和更安全的手术，改进 功能结果和提高的提高采收率。然而，作为外科辅助手段，mri纤维束造影术有实际的局限性。 以维护WMT的完整性。首先，由于算法的不同，WMT重建可能不准确和不精确 可变性、用户确定的阈值、可变的跟踪记录仪专业知识以及MRI数据的质量，这将导致 假阳性和假阴性。在脑瘤中，这一挑战因不可预测的模式而加剧 WMT移位、脑水肿和信号改变与潜在肿瘤直接相关。即使是最优的 WMT重建，术中MRI纤维束成像不能提供WMT的准确位置，因为 它不是外科领域发生的动态变化的实时视图。WMT相对于Pre-Mate的偏移 手术成像(即脑移位)，从而使纤维束造影术预测的WMT位置不准确 (例如，误差高达3厘米)。荧光引导手术(FGS)帮助外科医生可视化脑肿瘤组织， 结果显示提高了EOR。FGS为外科医生提供了手术期间肿瘤组织的实时可视化， 因此不受大脑变化的限制，因为FGS提供了直接的活体信息。我们最近发现 我们一流的近红外神经特异性小分子荧光团的一个子集可以穿过完整的 血脑屏障，少数人表现出对WMT的亲和力。我们假设FGS使用一个 WMT特异性荧光团可以提供一种客观的方法学来准确识别实时WMT 在手术期间。该项目的长期目标是通过创建 第一个术中实时WMT成像方法学。该项目近期的里程碑将包括 在健康啮齿动物体内进行药效学和药代动力学研究后，对WMT亲和力进行量化。 然后，在正常啮齿动物和两种WMT损伤模型上进行的临床前研究将使我们能够选择最 有希望的代理提供至少一个适合未来临床翻译的代理的概念验证数据。

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.