Therapeutic Evaluation of Magnetic Nanoprobes Specific for Malignant Tumor Marker

恶性肿瘤标志物特异性磁性纳米探针的治疗评价

• 批准号: 7738239
• 负责人: Rheal A Towner
• 金额: $ 18.42万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-17 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738239
• 关键词: Affinity; Albumins; Americas; Antibodies; Binding; Biological Markers; Biomedical Research; Blood; Blood Vessels; Brain Neoplasms; Cancer Patient; Characteristics; Contrast Media; Coupled; Detection; Development; Dextrans; Diagnostic; Disease; Early Diagnosis; Engineering; Event; Experimental Animal Model; Fever; Foundations; Frequencies; Future; Gadolinium; Glioblastoma; Glioma; Goals; Growth; Heating; Hepatocyte; Hepatocyte Growth Factor; Human; Image; Immune; Immunoglobulin G; Individual; Induced Hyperthermia; Laboratories; Magnetic Resonance Imaging; Magnetism; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of liver; Medical Research; Metabolic; Methodology; Modality; Modeling; Molecular; Molecular Probes; Molecular Target; Monitor; National Cancer Institute; Nature; Oklahoma; Patients; Peptides; Physiological; Primary Brain Neoplasms; Primary carcinoma of the liver cells; Procedures; Rattus; Receptor Protein-Tyrosine Kinases; Reporting; Research; Resolution; Rodent; Rodent Model; Screening for cancer; Specificity; Surface Antigens; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic heat application; Translating; Treatment Efficacy; Tumor Antigens; Tumor Cell Invasion; Tumor Markers; United States; Universities; Validation; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Water; albumin-(gadolinium-DTPA); angiogenesis; anti-cancer therapeutic; base; bevacizumab; cell growth; cell motility; clinical Diagnosis; crosslink; dextran; ferumoxtran; imaging modality; in vivo; innovation; iron oxide; magnetic field; magnetite ferrosoferric oxide; meetings; method development; molecular imaging; molecular marker; mortality; nanocrystal; nanoparticle; nanoprobe; novel; novel strategies; outcome forecast; prevent; public health relevance; radiofrequency; research and development; therapeutic evaluation; tool; tumor; tumor growth

DESCRIPTION (provided by applicant): The scope of this project is to establish whether magnetite or iron oxide (IO) nanoprobes, specific for tumor markers such as c-Met (tyrosine kinase receptor for the hepatocyte growth/scatter factor) or VEGF-R2 (vascular endothelial growth factor receptor), can be used therapeutically to inhibit or diminish glioma tumor growth in experimental rodent models. We plan to develop and synthesize IO nanoprobes, or characteristic tumor antigen-specific antibody tagged IO-based MRI contrast agents, for the in vivo detection of molecular events associated with tumor malignancy or angiogenesis in rat glioma models. We will assess the ability of these IO nanoprobes to detect malignant tumor markers such as c-MET, over-expressed in tumors that are invasive in nature, and VEGF-R2, which is associated with angiogenesis in malignant tumors, in an experimental C6 rat glioma model. It has also been recently established that IO nanoparticles can induce hyperthermia by being subjected to an alternating magnetic field (AMF), and that this may be used as a possible therapeutic modality against tumors. In a novel approach, we wanted to combine the therapeutic nature of the IO nanoparticles, and the specificity of tumor marker specific nanoprobes to direct hyperthermia therapy to malignant tumors targeted by anti-c-Met or anti-VEGF-R2 nanoprobes. Molecular magnetic resonance imaging (mMRI) will be used to assess the nanoprobe specificity for either c-Met or VEGF-R2, and morphological MRI will be used to assess the therapeutic efficacy of the nanoprobes on glioma growth in a rat glioma model. It is important that validation steps are initially studied in experimental animal models prior to the development of methods for clinical diagnosis and/or treatment. The advantages of MRI as a molecular imaging modality are a higher spatial resolution (5m) and the ability to obtain morphological, physiological and metabolic information in a single imaging session. The specific aims that we will use to assess tumor marker specific nanoprobes as potential diagnostic and therapeutic agents are as follows: (1) Assess tumor marker specific magnetite nanoprobes in their ability to detect markers associated with tumor malignancy and angiogenesis, and (2) assess anti-tumor therapeutic effect of nanoprobes when used with an alternating magnetic field. For specific aim 1, we plan to covalently bind the IO nanoparticles to cross-linked IO (CLIO) in conjunction with anti-VEGF-R2 Ab or anti-c-Met Ab, so that they can be used as vascular nanoprobes. Dextran-based CLIO contrast agents have been previously used as 'blood pool' agents. The IO nanoprobes will be tested in a C6 rat glioma model extensively used in our laboratory. For a non-specific control, a normal non-immune rat IgG will be coupled to the CLIO moiety. For specific aim 2, the focus will be to combine the tumor marker specificity of the nanoprobes to target malignant tumors, and to utilize the IO component on these compounds as a means of generating hyperthermia via an alternating magnetic field (100 kHz to 500 kHz frequency range) as a possible anti-tumor therapeutic treatment. We plan to subject C6 glioma-bearing rats to alternating magnetic fields (AMF), following administration of IO nanoprobes targeting either c-Met or VEGF-R2, and monitor tumor growth via MRI. Controls will be treated with non-specific IO nanoparticles (containing normal non-immune rat IgG) and subjected to an AMF. The proposed research is highly innovative and involves the research and development of molecular targeting agents, magnetic nanoprobes, and therapeutic options associated with these nanoprobes, that can be used to inhibit the growth and possibly eradicate malignant gliomas. Our plan is to incorporate the potential hyperthermia therapeutic effect of the nanoparticles in combination with the specificity of targeting tumor markers on malignant tumors. This combination of concepts has never been attempted before by targeting c- MET or VEGF-R2 within a glioma model. The development of in vivo biomedical research tools to assess the detection of potential tumor biomarkers may have a significant impact on future diagnostic approaches to be used in the early detection of human gliomas. In addition, this project will also assess the chemo-preventative capabilities of potential agents in their ability to prevent malignant glioma formation. To accomplish the goals of the project we have compiled a multi-institutional team from the Oklahoma Medical Research Foundation (OMRF), Oklahoma State University (OSU), and the University of Central Oklahoma (UCO), with expertise in mMRI, nanoparticles, radiofrequency bio-engineering, and cancer therapeutics. PUBLIC HEALTH RELEVANCE: This project is focused on developing and assessing tumor marker specific magnetite or iron oxide (IO) nanoprobes in their ability to detect tumor markers in vivo, and in addition be used as anti-cancer therapeutic agents. IO nanoprobes, such as ultrasmall superparamagnetic iron oxides (USPIOs) have recently become popular as molecular reporting probes with the use of molecular magnetic resonance imaging (mMRI). We propose to develop and assess IO nanoprobes with the use of molecular magnetic resonance imaging (mMRI) in a rodent glioma model to follow molecular markers associated with tumor malignancy and angiogenesis, and to utilize the nanoprobes themselves as potential therapeutic agents. Studying a potentially effective anti- tumor therapeutic agent, as well as developing novel in vivo diagnostic and predictive procedures may significantly impact patient prognosis and survivability in the future.

描述(由申请人提供)：本项目的范围是确定针对肿瘤标记物的磁铁或氧化铁(IO)纳米探针，如c-Met(肝细胞生长/分散因子酪氨酸激酶受体)或VEGF-R2(血管内皮生长因子受体)，是否可以在治疗上用于抑制或减少实验性啮齿动物模型中胶质瘤的生长。我们计划开发和合成IO纳米探针，或标记IO的特异性肿瘤抗原特异性抗体的基于IO的MRI造影剂，用于在体内检测与大鼠脑胶质瘤模型的肿瘤恶性或血管生成相关的分子事件。我们将评估这些IO纳米探针在实验性C6大鼠胶质瘤模型中检测恶性肿瘤标记物的能力，如c-met，在侵袭性肿瘤中过度表达，以及与恶性肿瘤血管生成相关的VEGF-R2。最近还证实，IO纳米颗粒可以通过受到交变磁场(AMF)而导致体温升高，这可能是一种可能的抗肿瘤治疗方式。在一种新的方法中，我们想要结合IO纳米颗粒的治疗性质和肿瘤标志物特异性纳米探针的特异性来指导针对抗c-Met或抗VEGF-R2纳米探针靶向的恶性肿瘤的热疗。分子磁共振成像(MMRI)将用于评估c-Met或VEGF-R2的纳米探针的特异性，形态MRI将用于评估纳米探针对大鼠脑胶质瘤模型中胶质瘤生长的治疗效果。重要的是，在开发临床诊断和/或治疗方法之前，首先在实验动物模型中研究验证步骤。磁共振成像作为一种分子成像手段的优势在于较高的空间分辨率(5m)，以及在一次成像过程中获得形态、生理和代谢信息的能力。我们将用来评估肿瘤标记物特异性纳米探针作为潜在的诊断和治疗试剂的具体目的如下：(1)评估肿瘤标记物特异性磁性纳米探针检测与肿瘤恶性肿瘤和血管生成相关的标记物的能力；(2)评估纳米探针在使用交变磁场时的抗肿瘤治疗效果。针对具体目标1，我们计划将IO纳米粒子与抗血管内皮生长因子-R2抗体或抗c-Met抗体一起共价结合到交联IO(CLIO)上，这样它们就可以用作血管纳米探针。以葡聚糖为基础的CLIO造影剂以前曾被用作“血池”试剂。IO纳米探针将在我们实验室广泛使用的C6大鼠胶质瘤模型中进行测试。对于非特异性对照，正常的非免疫大鼠免疫球蛋白将偶联到CLIO部分。对于具体目标2，重点将是结合肿瘤标记物的特异性纳米探针靶向恶性肿瘤，并利用这些化合物的IO成分作为一种手段，通过交变磁场(100 kHz至500 khz频率范围)产生热疗，作为一种可能的抗肿瘤治疗方法。我们计划在给予针对c-Met或VEGF-R2的IO纳米探针后，将C6胶质瘤荷瘤大鼠置于交变磁场(AMF)中，并通过MRI监测肿瘤生长。对照组将接受非特异性IO纳米颗粒(包含正常非免疫性大鼠免疫球蛋白)治疗，并接受AMF。这项拟议的研究具有很高的创新性，涉及分子靶向试剂、磁性纳米探针以及与这些纳米探针相关的治疗选择的研究和开发，这些纳米探针可用于抑制胶质瘤的生长，并可能根除恶性胶质瘤。我们的计划是将纳米粒子潜在的热疗效果与针对恶性肿瘤的肿瘤标记物的特异性结合起来。通过在胶质瘤模型中靶向c-met或VEGF-R2，这一概念的组合以前从未被尝试过。体内生物医学研究工具的发展，以评估潜在的肿瘤生物标志物的检测可能会对未来用于早期检测人脑胶质瘤的诊断方法产生重大影响。此外，该项目还将评估潜在药物在预防恶性胶质瘤形成方面的化学预防能力。为了实现该项目的目标，我们组建了一个由俄克拉荷马医学研究基金会(OMRF)、俄克拉荷马州立大学(OSU)和中俄克拉荷马大学(UCO)组成的多机构团队，他们拥有mMRI、纳米颗粒、射频生物工程和癌症治疗方面的专业知识。与公众健康相关：该项目致力于开发和评估肿瘤标记物特异性磁性或氧化铁(IO)纳米探针在体内检测肿瘤标记物的能力，并将其用作抗癌治疗药物。IO纳米探针，如超小的超顺磁性氧化铁(USPIO)，最近随着分子磁共振成像(MMRI)的使用而成为流行的分子报告探针。我们建议在啮齿动物胶质瘤模型中利用分子磁共振成像(MMRI)来开发和评估IO纳米探针，以跟踪与肿瘤恶性和血管生成相关的分子标记，并将纳米探针本身用作潜在的治疗药物。研究一种潜在有效的抗肿瘤治疗药物，以及开发新的体内诊断和预测程序，可能会对未来患者的预后和存活率产生重大影响。