Glial tumor image-guided surgery and treatment

摘要 尽管在临床上做出了巨大的努力，并获得了丰富的肿瘤生物学数据，但胶质瘤的生存率并不显着 在过去的25年里发生了变化。切除范围仍然是生存的最重要的决定因素， 所有级别的神经胶质瘤。然而，由于肿瘤的浸润性， 神经胶质瘤，使外科医生难以区分肿瘤和正常脑组织。照经上所 重要的是开发新的成像和药物输送技术，以在治疗期间特异性地对癌细胞进行成像。 手术切除，同时提供局部治疗正常脑中间隔的残留肿瘤沉积物的手段。 已经开发了几种策略来提高肿瘤切除的范围，同时限制对肿瘤的损伤。 包括术中MRI和荧光成像。然而，这些方法存在以下问题： 一个或多个缺点，例如缺乏深层组织穿透的光线，不能积极穿过血脑 屏障（BBB）和肿瘤细胞膜，缺乏白色光和荧光图像的精确重叠， 和/或肿瘤描绘的时间延迟成像。最近一种很有前途的方法是基于氯毒素- 吲哚菁绿色（ICG）缀合物（BLZ-100，“肿瘤涂料”，目前处于1期临床试验中）用于改善肿瘤细胞的增殖。 靶向近红外荧光引导切除术（TFGR）。然而，仅仅切除是不够的， 在不牺牲健康脑组织的情况下完全去除浸润性胶质瘤细胞。我们假设我们的 新的神经胶质瘤靶向成像和治疗纳米缀合物能够穿过BBB用于引导手术。 我们还假设类似的纳米复合物可以有效地根除术后残留的胶质瘤细胞 以双管齐下的方式抑制主要的胶质母细胞瘤标志物、蛋白激酶CK 2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荧光染料的合成与表征 显像剂合成了纳米显像剂PMLA/CTX/ICG和PMLA/CTX/anti-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 重现性和稳定性。使用优化的设备进行肿瘤可视化，用于临床术中NIR 将进行荧光成像以确定用于脑肿瘤成像的铅纳米缀合物。 具体目标2。用于多形性胶质母细胞瘤治疗的纳米缀合物的合成和表征。 精确的胶质瘤治疗取决于肿瘤特异性分子亚型/异质性， 分子标志物（CK 2作为新的生物标志物引入，EGFR/EGFRvIII在胶质瘤中高度表达）。 具体目标3。用于脑肿瘤成像和治疗的纳米缀合物的毒性研究。为了确保翻译 在临床试验的结果中，从体外和体内功效研究中选择的先导纳米药物必须是 为FDA的IND批准做准备。

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.