NMR IMAGING OF IRON OXIDE NANOPARTICLES

氧化铁纳米粒子的核磁共振成像

• 批准号: 8363206
• 负责人: Gavin P. Robertson
• 金额: $ 0.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363206
• 关键词: Animal Model; Animals; Antibodies; Apoptosis; Cell Survival; Cells; Clinical; Cultured Cells; Cutaneous; Cutaneous Melanoma; Detection; Development; Diagnosis; Disease; Dyes; Epitopes; Excision; Funding; Gene Targeting; Genes; Grant; Image; Individual; Invaded; KAI1 gene; Lesion; Liposomes; Lymphatic; Lymphatic Spread; Lymphatic System; Magnetic Resonance Imaging; Melanoma Cell; Metastatic Melanoma; Microscopy; Nanotechnology; National Center for Research Resources; Neoplasm Metastasis; Oncogenes; PTEN gene; Plasmids; Positive Lymph Node; Primary Lesion; Principal Investigator; Process; Radioisotopes; Research; Research Infrastructure; Resources; Sentinel Lymph Node Biopsy; Site; Skin; Small Interfering RNA; Source; Staging; Staining method; Stains; Suppressor Genes; System; Testing; Time; Tumor Suppressor Genes; United States National Institutes of Health; Work; antibody conjugate; base; cancer cell; cell killing; clinical practice; cost; iron oxide; killings; lymph nodes; man; melanoma; mortality; nanoparticle; novel; outcome forecast; prevent; prognostic indicator; skin lesion

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Current clinical practice for diagnosis, prognosis and deciding on treatment options for deeply invading cutaneous melanomas involves a process called sentinel lymph node biopsy, which entails injecting a dye and radioistope at the site of the primary lesion and allowing it to drain to the surrounding lymphatics. An agent is urgently needed to add to the dye for imaging, to halt invasion and to kill melanoma cells by targeting key genes regulating these processes, which has potential to halt spread at its very earliest stages. Therefore, the central hypothesis for the proposed research is that melanoma lymphatic invasion can be imagined using antibody targeted iron oxide nanoparticles. The rationale is that no targeted agents exist to halt cutaneous spread and lymph node dissemination at the time of excision of a primary melanoma skin lesion, which could aid in diagnosis and treatment. The central hypothesis will be tested by creating nanoliposomes conjugated to antibody GD2, recognizing epitopes preferentially present on invasive melanoma cells, expressing tumor suppressor genes (CD82 and PTEN) and inhibiting oncogene (V600E)B-Raf to synergistically inhibit melanoma cell survival. Second, a novel nanotechnology capable of detecting and killing melanoma cells metastasizing through the lymphatic system of animals would be developed. This would involve creating antibody 9.2.27 conjugated iron oxide nanoparticles to detect melanoma cells invading through the lymphatic system using MRI and combining it with nanoliposomes conjugated to antibody GD2, containing plasmids for expressing suppressor genes CD82 and PTEN as well siRNA for targeting the key melanoma oncogene (V600E)B-Raf. These discoveries would be highly significant, providing a novel agent to detect and treat lymphatically invading melanoma, which has significant potential to decrease mortality rates. SPECIFIC AIMS No targeted agents are available to halt invasive melanoma dissemination in the lymphatic system at the time of excision of a primary melanoma lesion. Agents to detect and synergistically target melanoma cells moving through the lymphatic system could be highly significant, enabling treatment while still invading the skin or lymphatic system, which has potential to decrease mortality rates resulting from metastatic dissemination. Currently, sentinel lymph node biopsy is used to determine disease staging, prognosis and treatment options for primary melanomas. A vital blue dye and radioactive isotope is injected at the site of the primary lesion, which drains through the lymphatic basin to the surrounding lymph nodes. Dye positive lymph nodes are then removed, sectioned and stained for metastatic cells. Presence of melanoma cells in lymph nodes is used for staging with presence of cancer cells in lymph nodes being a poor prognostic indicator. No agents are available that could be added to the dye that would synergistically halt invasion and kill melanoma cells. An agent of this type could prevent melanoma spread thereby reducing development of more aggressive disease, which would have significant clinical impact. Therefore, the central hypothesis for the proposed research is that melanoma lymph node invasion can be imagined using antibody targeted iron oxide nanoparticles. Furthermore, that these cells could be killed using antibody-targeted nanoliposomes carrying plasmids expressing CD82 and PTEN to halt invasion and trigger apoptosis respectively and liposomes delivering siRNA targeting B-Raf to halt melanoma cells' proliferative potential. This discovery would be highly significant, providing novel agents to treat lymphatically invading melanoma, which has potential to decrease mortality rates. The rationale for this approach is that no targeted agents are available to retard dissemination of invasive melanoma at the time of excision of a melanoma skin lesion, which could aid diagnosis and treatment.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。对该子项目的主要支持和子弹的主要研究者可能由其他来源（包括其他NIH来源）提供。 该子项目列出的总成本可能代表了子项目使用的估计中心基础设施的估计数量，而不是NCRR赠款向子项目或副标理人员提供的直接资金。 目前的诊断，预后和确定深度入侵皮肤黑色素瘤的治疗方案的临床实践涉及一个称为Sentinel淋巴结活检的过程，该过程需要在原发性病变的部位注入染料和放射性，并允许其排出周围的淋巴结。 迫切需要一种药物来添加到染料中进行成像，停止侵袭并通过靶向调节这些过程的关键基因来杀死黑色素瘤细胞，这可能会在其最早的阶段停止扩散。 因此，提出的研究的中心假设是，可以使用抗体靶向的氧化铁纳米颗粒来想象黑色素瘤淋巴侵袭。 理由是，在切除原发性黑色素瘤皮肤病变时，没有靶向药物可以停止皮肤扩散和淋巴结传播，这可以有助于诊断和治疗。 中心假设将通过创建与抗体GD2结合的纳米脂质体进行测试，并识别在浸润性黑色素瘤细胞上优先识别表位，表达肿瘤抑制基因（CD82和PTEN），并抑制癌基因（V600E）B-RAF，从而协同抑制了糖尿病细胞疾病。 其次，将开发一种能够检测和杀死通过动物淋巴系统转移黑色素瘤细胞转移的新型纳米技术。 This would involve creating antibody 9.2.27 conjugated iron oxide nanoparticles to detect melanoma cells invading through the lymphatic system using MRI and combining it with nanoliposomes conjugated to antibody GD2, containing plasmids for expressing suppressor genes CD82 and PTEN as well siRNA for targeting the key melanoma oncogene (V600E)B-Raf. 这些发现将是非常重要的，它为检测和治疗淋巴侵袭的黑色素瘤提供了新的药物，这具有降低死亡率的巨大潜力。 具体目标 在原发性黑色素瘤病变切除时，没有靶向剂可以在淋巴系统中停止侵入性黑色素瘤。 试剂检测和协同靶向通过淋巴系统运动的黑色素瘤细胞可能非常重要，可以使治疗能够侵入皮肤或淋巴系统，这有可能降低因转移性传播而导致的死亡率。 目前，哨兵淋巴结活检用于确定原发性黑色素瘤的疾病分期，预后和治疗选择。 将重要的蓝色染料和放射性同位素注射在原发性病变的部位，该病变的部位通过淋巴盆地排入周围的淋巴结。 然后去除染料阳性淋巴结，切片并染色转移细胞。 淋巴结中的黑色素瘤细胞的存在用于分期分期，淋巴结中存在癌细胞是预后指标差。 没有任何可用的药物可以添加到染料中，可以协同停止侵袭并杀死黑色素瘤细胞。 这种类型的药物可以防止黑色素瘤扩散，从而减少更具侵略性疾病的发展，这将产生重大的临床影响。 因此，提出的研究的中心假设是，可以使用抗体靶向的氧化铁纳米颗粒来想象黑色素瘤淋巴结侵袭。 此外，这些细胞可以使用表达CD82和PTEN的质粒的抗体靶向纳米脂质体杀死，分别停止侵袭和触发凋亡，以及脂质体和脂质体，将靶向B-RAF的siRNA靶向B-RAF来阻止黑色素黑色素瘤细胞的增殖潜力。 这一发现将非常重要，为治疗淋巴侵入性黑色素瘤的新型药物提供了降低死亡率的潜力。 这种方法的理由是，在切除黑色素瘤皮肤病变时，没有任何靶向剂可以阻止浸润性黑色素瘤的传播，这可以有助于诊断和治疗。