Multifunctional nanoparticles to improve treatment of human glioblastoma

多功能纳米粒子改善人类胶质母细胞瘤的治疗

• 批准号: 9228411
• 负责人: Miqin Zhang
• 金额: $ 7.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-11 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228411
• 关键词: Address; Adult; Adverse effects; Amino Acids; Binding; Biocompatible; Biodistribution; Blood; Blood - brain barrier anatomy; Bone Marrow; Brain Neoplasms; Cancer Biology; Cell membrane; Cells; Chemical Agents; Chitosan; Chlorotoxin; Clinical; Clinical Trials; Cytosol; DNA; DNA Methyltransferase Inhibitor; DNA Repair; DNA Repair Gene; Detection; Diffuse; Disulfide Linkage; Dose-Limiting; Drug Delivery Systems; Drug Kinetics; Elements; Evaluation; Glioblastoma; Glioma; Glutathione; Half-Life; Health; Human; Infiltration; Ligands; MGMT gene; Magnetic Resonance Imaging; Mediating; Membrane Microdomains; Metastatic malignant neoplasm to brain; Modeling; Mus; Nanotechnology; Neuroepithelial Neoplasms; Outcome; Patients; Penetration; Peptides; Permeability; Pharmaceutical Preparations; Polyethylene Glycols; Postoperative Period; Primary Brain Neoplasms; Property; Proteins; Radiation; Radiosensitization; Research; Resistance; Scorpion Venoms; Serum; Small Interfering RNA; Specificity; Structure; System; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Toxic effect; Treatment Efficacy; Visual; Wild Type Mouse; Work; Xenograft Model; analog; biodegradable polymer; brain parenchyma; brain tissue; cancer imaging; chemotherapeutic agent; crosslink; cytotoxic; cytotoxicity; design; endonuclease; fluorophore; image guided; improved; in vivo; inhibitor/antagonist; iron oxide; multidisciplinary; nanoparticle; neoplastic cell; novel strategies; novel therapeutic intervention; novel therapeutics; outcome forecast; prevent; prototype; radiosensitizing; repaired; standard of care; systemic toxicity; targeted imaging; temozolomide; therapy resistant; tumor; tumor growth; tumor specificity; uptake

DESCRIPTION (provided by applicant): Multifunctional nanoparticles to improve treatment of human glioblastoma The long-term objective of this research is to develop novel therapeutic approaches to improve the clinical outcome of adult patients with glioblastoma multiforme (GBM), the most common and lethal human primary brain tumor. Recent clinical trials have demonstrated that administration of the methylating agent temozolomide (TMZ) during post-operative therapy significantly increases survival of GBM patients. Although TMZ in combination with radiation is now the contemporary standard of care for GBMs, the majority of GBMs are not responsive due to the resistance mediated by O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein that limits the radiosensitizing and cytotoxic effects of TMZ. Recent studies from our group and others suggest that the resistance of GBMs to TMZ can be overcome by ablating MGMT activity with DNA repair inhibitors. However, the clinical utility of DNA repair inhibitors have been hindered by their poor pharmacokinetics such as poor permeability of the blood-brain barrier (BBB), a short half-life, and bone marrow producing deleterious side-effects. We propose to develop a multifunctional nanoparticle (NP) that can deliver DNA inhibitors specifically to GBM cells to circumvent treatment-resistance and treatment-limiting systemic toxicity. Our multidisciplinary team has developed prototype NPs consisting of an iron oxide core surrounded by a shell of a biodegradable polymer of polyethylene glycol grafted chitosan (PEG-chitosan). The core-shell structure is conjugated with the near-infrared fluorophore Cy5.5 and the targeting ligand chlorotoxin (CTX). Each element of this NP system confers a property that makes it an excellent candidate as an image-guided drug delivery vehicle. In this study, inhibitors are covalently attached to the outer shell of the NP tht is crosslinked by disulfide linkage and can be rapidly degraded by glutathione-mediated reduction in cytosol of target cells to release the payload but not in blood. The project includes the following Specific Aims: (1) Fabrication and characterization of inhibitor derivatized NPs; (2) Assessment of therapeutic effects of NPs on human GBM cells, and in vivo toxicity and BBB permeation of NPs; (3) Study of therapeutic efficacy of NPs in an orthotopic GBM xenograft model of human GBM. Our NPs incorporate features that facilitate drug loading, protect drug during transport, penetrate the BBB, facilitate rapid intracellular release, and confer tumor specificity. Moreover, each component material of the NP is biocompatible and assumes multiple functions. This strategy combines the advances in forefront research of GBM cancer biology with advanced nanotechnology in tumor imaging and therapeutics to circumvent the resistance to treatment. Successful completion of the proposed work may produce a novel therapeutic agent that can be readily brought to clinical trial as our NP is expressly designed to improve the efficacy of the current standard of care for GBM. The expanded health relevance of this research is that the NPs with BBB penetration ability may also facilitate the delivery of therapeutic agents to brain metastases from a variety of tumors.

描述（由申请人提供）：用于改善人类胶质母细胞瘤治疗的多功能纳米颗粒本研究的长期目标是开发新的治疗方法，以改善多形性胶质母细胞瘤（GBM）成年患者的临床结果，GBM是最常见和致命的人类原发性脑肿瘤。最近的临床试验表明，在术后治疗期间使用甲基化剂替莫唑胺（TMZ）可显着提高 GBM 患者的生存率。虽然 TMZ 与放疗结合现在是 GBM 的当代治疗标准，但由于 O6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 介导的耐药性，大多数 GBM 没有反应，MGMT 是一种 DNA 修复蛋白，限制 TMZ 的放射增敏和细胞毒性作用。我们小组和其他人的最新研究表明，GBM 对 TMZ 的耐药性可以通过用 DNA 修复抑制剂消除 MGMT 活性来克服。然而，DNA修复抑制剂的临床应用因其较差的药代动力学而受到阻碍，例如血脑屏障（BBB）通透性差、半衰期短以及对骨髓产生有害副作用。我们建议开发一种多功能纳米颗粒（NP），可以将 DNA 抑制剂特异性递送至 GBM 细胞，以避免治疗耐药性和限制治疗的全身毒性。我们的多学科团队开发了原型纳米颗粒，其由氧化铁核心组成，周围包裹着聚乙二醇接枝壳聚糖（PEG-壳聚糖）可生物降解聚合物的外壳。核壳结构与近红外荧光团 Cy5.5 和靶向配体氯毒素 (CTX) 缀合。该 NP 系统的每个元素都具有一种特性，使其成为图像引导药物输送载体的优秀候选者。在这项研究中，抑制剂共价附着在 NP 的外壳上，通过二硫键交联，并且可以通过谷胱甘肽介导的靶细胞胞质溶胶还原而快速降解，以释放有效负载，但不会在血液中释放。该项目包括以下具体目标：（1）抑制剂衍生纳米颗粒的制备和表征； (2) 评估纳米粒子对人GBM细胞的治疗效果，以及纳米粒子的体内毒性和血脑屏障渗透性； (3) NPs在人GBM原位GBM异种移植模型中的治疗效果研究。我们的纳米颗粒具有促进药物装载、在运输过程中保护药物、穿透血脑屏障、促进细胞内快速释放以及赋予肿瘤特异性的功能。此外，NP的每种组成材料都具有生物相容性并具有多种功能。该策略将 GBM 癌症生物学的前沿研究进展与肿瘤成像和治疗领域的先进纳米技术相结合，以规避治疗耐药性。成功完成拟议的工作可能会产生一种新型治疗剂，可以很容易地进行临床试验，因为我们的 NP 专门设计用于提高 GBM 当前护理标准的功效。这项研究扩大了与健康的相关性，即具有血脑屏障渗透能力的纳米粒子也可能有助于将治疗药物递送至多种肿瘤的脑转移瘤。