CNS Gene Delivery and Imaging in brain Tumor Therapy

脑肿瘤治疗中的中枢神经系统基因传递和成像

基本信息

批准号：
7228602
负责人：
EDWARD A. NEUWELT
金额：
$ 56.4万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-08-15 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7228602
关键词：
Adenovirus Vector Adenoviruses Adult Angiography Animal Model Binding Blood Blood - brain barrier anatomy Blood Vessels Blood Volume Bolus Infusion Brain Brain Neoplasms Breast Bystander Effect Carcinoma Cells Central Nervous System Neoplasms Cerebrum Cervical lymph node group Childhood Class Clinical Protocols Clinical Trials Clinical Trials Design Convection Cranial Irradiation Diffusion Disruption Disseminated Malignant Neoplasm Drainage procedure Drug Formulations ERBB2 gene Effectiveness Electron Microscopy Epidermal Growth Factor Receptor Evaluation Excision External Beam Radiation Therapy Ferumoxtran-10 Funding Gadolinium Gene Delivery Gene Expression Gene Transduction Agent Glioblastoma Glioma Goals Growth Histology Human Image Implant Infection Inflammatory Infusion procedures Injection of therapeutic agent Intercellular Fluid Iron Lesion Lung Magnetic Resonance Magnetic Resonance Angiography Magnetic Resonance Imaging Malignant neoplasm of brain Malignant neoplasm of lung Metastatic Neoplasm to the Breast Metastatic malignant neoplasm to brain Modeling Molecular Weight Multiple Sclerosis Neoplasm Metastasis Neuraxis Neurologic Neurosurgical Procedures New Agents Numbers Oncogene Proteins Particle Size Pathway interactions Patients Penetration Permeability Process Protein Overexpression Proteins Radiation Radiation therapy Radioimmunotherapy Rattus Reaction Recombinants Research Personnel Residual Tumors Resolution Route Specificity Spectrum Analysis Staining method Stains Stroke Testing Therapeutic Agents Time Tissue Sample Transformed Cell Line Transgenes Ventricular Viral Viral Vector Virion Virus Virus Diseases cell type cytotoxicity gene therapy herstatin in vivo interstitial iron oxide irradiation lung small cell carcinoma lymph nodes nanoparticle neoplastic cell novel strategies olfactory bulb particle perineural programs size trafficking transgene expression tumor tumor growth uptake

项目摘要

DESCRIPTION (provided by applicant): The efficacy of gene therapy against brain tumors will depend upon delivery of viral vector throughout tumor and specific cytotoxicity toward both infected and non-infected tumor cells. Previously this project has focused on delivery, assessing interstitial infusion and transvascular delivery of particles by osmotic opening of the blood-brain barrier (BBB). While delivery remains our major focus, the current proposal will also move to a broader examination of virus and particle uptake and efflux. In addition to recombinant adenovirus vectors, as a model for virus particles we will use viral-sized iron oxide nanoparticles, Combidex and Code7228, because they allow direct comparison of magnetic resonance (MR) imaging with histology and ultrastructure. In Aim 1 we will assess influx and uptake of virus and iron particles into rat brain and intracerebral tumor, and investigate the effect of tumor size, permeability and prior irradiation. Since radiation may increase virus distribution and/or transgene expression, we will test a novel approach combining tumor-specific radioimmunotherapy with virus delivery. This aim will also evaluate iron particle influx in a rat stroke model, and characterize phagocytic and/or astrocytic reactive cells responsible for iron particle trapping. Aim 2 will evaluate virus and iron particle efflux from the brain, using mR and histology to delineate efflux pathways. In Aim 3, we will investigate the potential for gene therapy with Herstatin, a secreted protein which inhibits the epidermal growth factor receptor (EGFR). We will compare intratumor vs. transvascular delivery of protein and a Hestatin adenovirus construct, both in the LX-1 lung cancer metastasis model, as well as in glioma and breast metastasis models. We hypothesize that because Herstatin is secreted and has high activity against EGFR overexpressing cells, it will provide bystander efficacy even when a small proportion of tumor is infected. Finally, Aim 4 will be an expanded clinical protocol of rion particle imaging and localization, to assess BBB and blood-tumor barrier permeability and Combidex uptake in adult and pediatric brain tumors, and in CNS inflammatory lesions. We will also evaluate tumor vascularity using MR angiography with Code7228, a new formulation which allows bolus administration and dynamic MRA superior to Gd. Our hypothesis is that tumor imaging with the iron oxide particle agents requires both a leaky BBB and trapping by uptake into reactive cells. We anticipate that these studies will not only be useful in designing clinical trials of brain tumor gene therapy, but also in providing a new means to image CNS tumors, neurological lesions and even gene therapy approaches which evoke a cellular reaction.

描述（由申请人提供）：针对脑肿瘤的基因治疗的功效将取决于病毒载体在整个肿瘤中的递送以及对感染和未感染的肿瘤细胞的特异性细胞毒性。此前，该项目重点关注输送、评估通过血脑屏障 (BBB) 渗透打开的颗粒间质输注和跨血管输送。虽然递送仍然是我们的主要关注点，但当前的提案也将转向对病毒和颗粒的吸收和流出进行更广泛的检查。除了重组腺病毒载体之外，我们还将使用病毒大小的氧化铁纳米粒子、Combidex 和 Code7228 作为病毒颗粒的模型，因为它们可以直接比较磁共振 (MR) 成像与组织学和超微结构。在目标 1 中，我们将评估病毒和铁颗粒进入大鼠大脑和脑内肿瘤的流入和摄取，并研究肿瘤大小、渗透性和先前照射的影响。由于辐射可能会增加病毒分布和/或转基因表达，因此我们将测试一种将肿瘤特异性放射免疫疗法与病毒递送相结合的新方法。该目标还将评估大鼠中风模型中铁颗粒的流入，并表征负责铁颗粒捕获的吞噬细胞和/或星形细胞反应细胞。目标 2 将评估病毒和铁粒子从大脑的流出，使用 mR 和组织学来描绘流出途径。在目标 3 中，我们将研究 Herstatin 基因治疗的潜力，Herstatin 是一种抑制表皮生长因子受体 (EGFR) 的分泌蛋白。我们将在 LX-1 肺癌转移模型以及神经胶质瘤和乳腺转移模型中比较蛋白质和 Hestatin 腺病毒构建体的肿瘤内与经血管递送。我们假设，由于 Herstatin 是分泌型的，并且对 EGFR 过表达细胞具有高活性，因此即使一小部分肿瘤被感染，它也会提供旁观者疗效。最后，Aim 4 将是 rion 粒子成像和定位的扩展临床方案，以评估成人和儿童脑肿瘤以及 CNS 炎症病变中的 BBB 和血液肿瘤屏障通透性以及 Combidex 摄取。我们还将使用 Code7228 的 MR 血管造影来评估肿瘤血管分布，Code7228 是一种新配方，可实现优于 Gd 的推注给药和动态 MRA。我们的假设是，使用氧化铁颗粒试剂进行肿瘤成像需要渗漏的血脑屏障和通过摄取进入反应细胞的捕获。我们预计这些研究不仅有助于设计脑肿瘤基因治疗的临床试验，而且还将提供一种对中枢神经系统肿瘤、神经病变甚至引起细胞反应的基因治疗方法进行成像的新方法。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience.

针对新诊断的原发性中枢神经系统淋巴瘤的血脑屏障破坏和基于动脉内甲氨蝶呤的治疗：多机构经验。

DOI：
10.1200/jco.2008.19.3789
发表时间：
2009-07-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
0
作者：
L. Angelov;N. Doolittle;D. Kraemer;T. Siegal;G. Barnett;D. Peereboom;G. Stevens;J. McGregor;K. Jahnke;C. Lacy;N. Hedrick;E. Shalom;S. Ference;S. Bell;L. Sorenson;R. M. Tyson;M. Haluska;E. Neuwelt
通讯作者：
E. Neuwelt

Pseudo-extravasation rate constant of dynamic susceptibility contrast-MRI determined from pharmacokinetic first principles.

根据药代动力学第一原理确定的动态磁敏对比 MRI 的伪外渗率常数。

DOI：
发表时间：
2017-11
期刊：
影响因子：
2.9
作者：
Li, Xin;Varallyay, Csanad G;Gahramanov, Seymur;Fu, Rongwei;Rooney, William D;Neuwelt, Edward A
通讯作者：
Neuwelt, Edward A

Intra-arterial chemotherapy with osmotic blood-brain barrier disruption for aggressive oligodendroglial tumors: results of a phase I study.

动脉内化疗结合渗透性血脑屏障破坏治疗侵袭性少突胶质细胞瘤：I 期研究的结果。

DOI：
10.1227/01.neu.0000363152.37594.f7
发表时间：
2024-09-14
期刊：
Neurosurgery
影响因子：
4.8
作者：
Daniel J. Guillaume;N. Doolittle;S. Gahramanov;N. Hedrick;J. Delashaw;E. Neuwelt
通讯作者：
E. Neuwelt

An exploratory study of ferumoxtran-10 nanoparticles as a blood-brain barrier imaging agent targeting phagocytic cells in CNS inflammatory lesions.

Ferumoxtran-10 纳米颗粒作为血脑屏障显像剂靶向中枢神经系统炎症病变吞噬细胞的探索性研究。