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

用于体内荧光引导白质束成像的白质束特异性近红外荧光探针

• 批准号: 10708128
• 负责人: Pablo Andres Valdes Quevedo
• 金额: $ 20.06万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-29 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708128
• 关键词: 3-Dimensional; Address; Affinity; Algorithms; Blood - brain barrier anatomy; Brain; Brain Edema; Brain Neoplasms; Brain imaging; Characteristics; Clinical; Color; Contrast Media; Data; Development; Diagnostic; Excision; Fluorescence; Fluorescent Probes; Future; Glioma; Goals; Histology; Histopathology; Image; Imaging technology; Immunohistochemistry; Injury; Intervention; Libraries; Light; Location; Magnetic Resonance Imaging; Methodology; Modeling; Nerve; Neurosurgeon; Operative Surgical Procedures; Outcome; Patients; Pattern; Performance; Persons; Pre-Clinical Model; Primary Brain Neoplasms; Quality of life; Reporting; Resolution; Rodent; Rodent Model; Series; Signal Transduction; Specificity; Surgeon; Technology; Time; Tumor Tissue; United States; Validation; Visualization; brain tissue; clinical translation; comparative; contrast imaging; fluorescence imaging; fluorescence-guided surgery; fluorophore; functional improvement; functional outcomes; histological stains; image guided; imaging study; improved; in vivo; in vivo fluorescence; lead candidate; novel; pharmacokinetics and pharmacodynamics; preclinical study; preservation; reconstruction; small molecule; stroke model; surgery outcome; tool; tractography; tumor; white matter

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.

项目摘要 在美国，超过70万人患有原发性脑肿瘤。最安全的手术切除是 生活质量和总生存率的最重要的初始预测因素。为此，外科医生最大限度地 肿瘤切除范围（EOR），同时保留功能。保持白色物质束的完整性 (WMT)在脑肿瘤手术期间是保留功能的必要要求。然而，缺乏一个 功能性WMT和肿瘤组织之间的清晰边界对神经外科医生提出了重大挑战。 磁共振成像（MRI）纤维束成像为外科医生提供术前WMT图像， 帮助预测他们的位置术中，外科医生可以使用具有图像引导的纤维束成像图像， 最大限度地保持WMT的完整性，这已被证明可以实现更快，更安全的手术， 功能结果和提高EOR。然而，磁共振纤维束成像作为一种手术辅助手段有其实际局限性 保持WMT的完整性首先，由于算法的原因，WMT重建可能不准确和不精确 可变性、用户确定的阈值、可变的追踪仪专业知识和MRI数据的质量，这导致 假阳性和假阴性在脑肿瘤中，这种挑战因不可预测的肿瘤模式而加剧。 WMT移位、脑水肿和信号改变与潜在肿瘤直接相关。即使是最佳的 WMT重建，术中MRI纤维束成像不能提供WMT的准确位置，因为 它不是手术区域中发生的动态变化的实时视图。WMT相对于前 手术成像（即，脑移位），从而使得纤维束描记术预测的WMT位置不准确 (e.g.,误差不超过3 cm）。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EOR增加。FGS为外科医生提供手术期间肿瘤组织的实时可视化， 因此不受脑移位的限制，因为FGS提供直接的体内信息。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，其中少数人已经证明了对WMT的亲和力。我们假设FGS使用 WMT特异性荧光团可以提供一种客观的方法来实时准确地识别WMT 在手术中。该项目的长期目标是通过创建 第一个实时术中WMT成像方法。该项目的近期里程碑将包括 在健康啮齿动物中进行WMT亲和力定量，然后进行药效学和药代动力学研究。 然后，在正常啮齿动物和两种WMT损伤模型中的临床前研究将能够选择最多的 有希望的代理递送至少一种代理的概念验证数据，适合于未来的临床翻译。