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

基本信息

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
项目类别：
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

项目摘要

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）：多功能纳米颗粒以改善人类胶质母细胞瘤的治疗，这项研究的长期目的是开发新的治疗方法，以改善成年人多形胶质瘤（GBM）（GBM）的临床结果，最常见和最致命的人类原发性脑肿瘤。最近的临床试验表明，术后治疗期间甲基化剂替莫唑胺（TMZ）的给药可显着提高GBM患者的存活率。尽管现在与辐射结合使用TMZ是GBMS的当代护理标准，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对DNA修复蛋白介导的耐药性无反应，这是一种限制TMZ的放射性和细胞毒性作用的DNA修复蛋白。我们小组和其他人的最新研究表明，通过用DNA修复抑制剂消除MGMT活性，可以克服GBMS对TMZ的耐药性。然而，DNA修复抑制剂的临床实用性受到了较差的药代动力学的阻碍，例如血脑屏障（BBB）的渗透性差，半寿命短，骨髓产生有害的副作用。我们建议开发一种多功能纳米颗粒（NP），该纳米颗粒可以将DNA抑制剂专门传递给GBM细胞，以避免治疗耐药性和治疗限制的全身毒性。我们的多学科团队开发了原型NP，该原型NP由氧化铁核心组成，该氧化铁芯被聚乙烯乙二醇接枝壳聚糖（PEG-Chitosan）的可生物降解聚合物的外壳包围。核壳结构与近红外荧光团Cy5.5和靶向配体氯毒素（CTX）结合。该NP系统的每个元素都赋予其作为图像引导的药物输送工具的出色候选物业。在这项研究中，抑制剂共价连接到NP THT的外壳上，通过二硫键交联，可以通过谷胱甘肽介导的靶细胞细胞溶胶降低靶细胞的减少来迅速降解，以释放有效载荷，但不能在血液中释放。该项目包括以下特定目的：（1）抑制剂衍生的NP的制造和表征；（2）评估NP对人GBM细胞的治疗作用，以及NP的体内毒性和BBB渗透；（3）研究NP在人GBM的原位GBM异种移植模型中的治疗功效。我们的NP具有促进药物载荷，在运输过程中保护药物，穿透BBB，促进细胞内释放并赋予肿瘤特异性的特征。此外，NP的每个组件材料都是生物相容性的，并具有多个功能。该策略结合了GBM癌症生物学最前沿研究的进步与肿瘤成像和疗法中的晚期纳米技术，以避免对治疗的抗药性。拟议工作的成功完成可能会产生一种新型的治疗剂，可以很容易地将其带入临床试验，因为我们的NP明确设计旨在提高当前GBM护理标准的功效。这项研究的健康相关性的扩大是，具有BBB渗透能力的NP还可以促进从多种肿瘤中递送治疗剂向脑转移剂。