Glial tumor image-guided surgery and treatment

摘要 尽管有巨大的临床努力和大量的肿瘤生物学数据，但脑胶质瘤的存活率并不显著。 在过去的25年里发生了变化。手术切除范围仍然是影响患者生存的最重要因素。 所有级别的神经胶质瘤。然而，由于肿瘤的浸润性，实现全切除的能力是有限的。 胶质瘤，使外科医生很难区分肿瘤和正常脑组织。因此，它是 重要的是开发新的成像和药物输送技术，以在 手术切除，同时提供局部治疗在正常大脑中间隔分布的残留肿瘤沉积的方法。 已经开发了几种策略来提高肿瘤切除的程度，同时将损害限制在 包括术中MRI和荧光成像。然而，这些方法存在以下问题 一个或几个缺点，如缺乏光线，无法深入组织，不能积极地穿越血液和大脑 肿瘤细胞的屏障(BBB)和膜，缺乏白光和荧光图像的精确重叠， 和/或肿瘤轮廓的时间延迟成像。最近有一种很有希望的方法是基于氯毒素- 吲哚青绿(ICG)结合物(BLZ-100，“肿瘤涂料”，目前处于第一阶段临床试验)，用于改进 靶向近红外荧光引导切除(TFGR)。然而，仅靠切除是不够的。 在不牺牲健康脑组织的情况下完全切除浸润性胶质瘤细胞。我们假设我们的 新型胶质瘤靶向成像和治疗纳米结合物能够穿过血脑屏障进行引导手术。 我们还假设，类似的纳米结合物可以有效地根除手术后残留的胶质瘤细胞。 双管齐下抑制胶质母细胞瘤主要标志物蛋白激酶CK2和表皮生长 因子受体(EGFR和EGFRvIII突变体)。 具体目标1.新型胶质瘤靶向近红外(NIR)荧光材料的合成与表征 成像剂。将合成纳米成像剂PMLA/CTX/ICG和PMLA/CTX/抗TfRmAb/ICG 并研究了产生强烈的近红外荧光，合适的物理化学性质，合成 重复性和稳定性。临床术中近红外肿瘤可视化的优化装置 将进行荧光成像，以确定用于脑肿瘤成像的纳米铅结合物。 特定目的2.治疗多形性胶质母细胞瘤的纳米结合物的合成和表征。 精确的胶质瘤治疗取决于肿瘤特定的分子亚型/异质性由不同的 分子标志物(CK2是一种新的生物标志物，EGFR/EGFRvIII在胶质瘤中高表达)。 特定目的3.脑肿瘤成像和治疗用纳米结合物的毒性研究。确保翻译 在临床试验的结果中，从体外和体内疗效研究中选择的纳米铅必须是 在FDA批准IND的准备过程中进行了审查。

ABSTRACT In spite of huge clinical efforts, and a wealth of data on tumor biology, survival from glioma has not significantly changed in the last 25 years. Extent of resection remains the most important determinant of survival for gliomas of all grades. However, the ability to achieve total resection is limited due to the infiltrative nature of gliomas, making it difficult for surgeons to distinguish between tumor and normal brain tissue. Thus, it is important to develop new imaging and drug delivery technologies to specifically image cancer cells during surgical resection, while providing means to focally treat residual tumor deposits interspaced in normal brain. Several strategies have been developed to improve the extent of tumor resection while limiting damage to surrounding brain, including intraoperative MRI and fluorescence imaging. However, these methods suffer from one or several shortcomings, such as lack of light for deep tissue penetration, not actively crossing blood-brain barrier (BBB) and membranes of tumor cells, lack of precise overlap of white light and fluorescence images, and/or time delayed imaging of tumor delineations. A promising recent method is based on Chlorotoxin- Indocyanine Green (ICG) conjugate (BLZ-100, “tumor paint”, presently in phase 1 clinical trial) for improved Targeted NIR Fluorescence Guided Resection (TFGR). However, resection alone will not be sufficient for complete removal of infiltrating glioma cells without sacrificing healthy brain tissue. We hypothesize that our novel glioma targetable imaging and treatment nanoconjugates are able to cross the BBB for guided surgery. We also hypothesize that similar nanoconjugates can effectively eradicate postsurgical remnant glioma cells inhibiting in a dual-pronged fashion the major glioblastoma markers, protein kinase CK2 and epidermal growth factor receptor (EGFR and EGFRvIII mutant). Specific Aim 1. Synthesis and characterization of novel glioma targetable near infrared (NIR) fluorescent imaging agents. Nanoimaging agents PMLA/CTX/ICG and PMLA/CTX/anti-TfRmAb/ICG will be synthesized and studied for producing intensive NIR fluorescence, suitable physico-chemical properties, synthetic reproducibility and stability. Tumor visualization with an optimized device for clinical intra-operative NIR fluorescence imaging will be performed to determine lead nanoconjugate for brain tumor imaging. Specific Aim 2. Synthesis and characterization of nanoconjugates for glioblastoma multiforme treatment. Precise glioma treatment depends on tumor-specific molecular subtype/heterogeneity verified by different molecular markers (CK2 introduced as a novel biomarker, and EGFR/EGFRvIII highly expressed in glioma). Specific Aim 3. Toxicity study of nanoconjugates for brain tumor imaging and treatment. To ensure translation of the results to the clinical trial, the selected lead nanodrugs from in vitro and in vivo efficacy studies must be examined in preparation for IND approval by FDA.