Glial tumor image-guided surgery and treatment

胶质瘤影像引导手术和治疗

• 批准号: 9185848
• 负责人: Eggehard Holler
• 金额: $ 54.49万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-13 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185848
• 关键词: Acids; Adjuvant; Antibodies; Biodistribution; Biology; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Canis familiaris; Cells; Cetuximab; Chemicals; Chlorotoxin; Clinical; Clinical Trials; Data; Databases; Deposition; Development; Devices; Disease; Drug Delivery Systems; Drug Kinetics; Drug vehicle; Ensure; Epidermal Growth Factor Receptor; Excision; Fluorescence; Fluorescent Dyes; Future; Gene Proteins; Glioblastoma; Glioma; Heterogeneity; Image; Image-Guided Surgery; Imagery; In Vitro; Indocyanine Green; Infiltration; Lead; Light; Magnetic Resonance Imaging; Malignant Neoplasms; Membrane; Methods; Microscopic; Monitor; Monoclonal Antibodies; Mus; Nanoconjugate; Nature; Near-infrared optical imaging; Operative Surgical Procedures; Paint; Patients; Penetration; Peptides; Pharmacodynamics; Phase I Clinical Trials; Preparation; Publications; Publishing; Reproducibility; Research; Residual Tumors; Residual state; Resolution; Signaling Molecule; Surgeon; System; Technology; Testing; The Cancer Genome Atlas; Therapeutic; Thermal Ablation Therapy; Time; Tissues; Toxic effect; Translations; Tumor Biology; Tumor Burden; United States National Institutes of Health; acoustic imaging; base; brain parenchyma; brain tissue; cancer cell; cancer imaging; casein kinase II; chemical property; contrast imaging; epidermal growth factor receptor VIII; fluorescence imaging; image guided; imaging agent; improved; in vivo; innovation; molecular marker; molecular subtypes; monitoring device; mutant; nanodrug; nanoimaging; nanoparticle; nanosystems; neoplastic cell; noninvasive diagnosis; novel; novel marker; protein expression; targeted imaging; theranostics; transcytosis; translational study; tumor

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.

抽象的 尽管临床上有巨大的努力以及大量有关肿瘤生物学的数据，但神经胶质瘤的生存并未显着 在过去的25年中发生了变化。切除程度仍然是最重要的生存确定的 所有等级的神经膜瘤。但是，由于性质的渗透性，实现总切除的能力受到限制 神经胶质瘤，使外科医生难以区分肿瘤和正常的脑组织。那是 在开发新成像和药物输送技术以在 手术切除术，同时提供用于局部治疗正常大脑中的残留肿瘤沉积物。 已经制定了几种策略来改善肿瘤切除程度，同时将损害损害 周围的大脑，包括术中MRI和荧光成像。但是，这些方法遭受了 一个或几个缺点，例如缺乏深层组织穿透的光，而不是主动越过血脑 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/或肿瘤描述的时间延迟成像。一种有希望的最近方法是基于氯毒素 - 吲哚烷绿色（ICG）缀合物（BLZ-100，“肿瘤油漆”，第1阶段临床试验中存在），以改进 靶向NIR荧光引导切除（TFGR）。但是，仅切除就不足 完全去除浸润性神经胶质瘤细胞而无需牺牲健康的脑组织。我们假设我们的 新型的胶质瘤靶向成像和处理纳米缀合物能够越过BBB进行指导手术。 我们还假设类似的纳米缀合物可以有效地发出术后残余神经胶质瘤细胞 以双管制的方式抑制主要的胶质母细胞瘤标志物，蛋白激酶CK2和表皮生长 因子受体（EGFR和EGFRVIII突变体）。 特定目的1。新型神经胶质瘤的合成和表征，可靶向附近感染（NIR）荧光 成像剂。纳米影像剂PMLA/CTX/ICG和PMLA/CTX/anti-TFRMAB/ICG将合成 并研究用于产生密集的NIR荧光，合适的物理化学特性，合成 可重复性和稳定性。肿瘤可视化使用临床内部NIR的优化装置 将进行荧光成像，以确定用于脑肿瘤成像的铅纳米偶联物。 具体目标2。纳米缀合物的合成和表征多形胶质母细胞瘤。 精确的神经胶质瘤治疗取决于肿瘤特异性的分子亚型/异质性。 分子标记物（CK2作为一种新型生物标志物引入，而在神经胶质瘤中高度表达的EGFR/EGFRVIII）。 特定目的3。纳米缀合物对脑肿瘤成像和治疗的毒性研究。确保翻译 在临床试验的结果中，体外和体内效率研究中选定的铅纳米果必须是 在准备IND批准的情况下进行了检查。