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 资助的中心拨款提供的资源的众多研究子项目之一。对子项目和子项目主要研究者的主要支持可能是由其他来源提供的，包括其他 NIH 来源。 子项目列出的总成本可能代表子项目使用的中心基础设施的估计金额，而不是 NCRR 拨款向子项目或子项目工作人员提供的直接资金。 目前针对深度侵袭性皮肤黑色素瘤的诊断、预后和治疗选择的临床实践涉及一种称为前哨淋巴结活检的过程，该过程需要在原发病变部位注射染料和放射性同位素，并使其排至周围的淋巴管。 迫切需要一种试剂添加到染料中进行成像，通过靶向调节这些过程的关键基因来阻止入侵和杀死黑色素瘤细胞，这有可能在最早阶段阻止扩散。 因此，本研究的中心假设是，可以使用靶向氧化铁纳米颗粒的抗体来想象黑色素瘤淋巴侵袭。 其基本原理是，在切除原发性黑色素瘤皮肤病变时，不存在可以阻止皮肤扩散和淋巴结播散的靶向药物，这可以帮助诊断和治疗。 我们将通过创建与抗体 GD2 缀合的纳米脂质体、识别优先存在于侵袭性黑色素瘤细胞上的表位、表达肿瘤抑制基因（CD82 和 PTEN）并抑制癌基因 (V600E)B-Raf 以协同抑制黑色素瘤细胞存活来测试中心假设。 其次，将开发一种能够检测和杀死通过动物淋巴系统转移的黑色素瘤细胞的新型纳米技术。 这将涉及创建抗体9.2.27缀合的氧化铁纳米粒子，以使用MRI检测侵入淋巴系统的黑色素瘤细胞，并将其与缀合抗体GD2的纳米脂质体相结合，其中包含用于表达抑制基因CD82和PTEN的质粒以及用于靶向关键黑色素瘤癌基因(V600E)B-Raf的siRNA。 这些发现非常重要，为检测和治疗淋巴侵袭性黑色素瘤提供了一种新药物，具有降低死亡率的巨大潜力。 具体目标 在切除原发性黑色素瘤病变时，没有靶向药物可以阻止淋巴系统中的侵袭性黑色素瘤播散。 检测并协同靶向穿过淋巴系统的黑色素瘤细胞的药物可能非常重要，可以在侵入皮肤或淋巴系统的同时进行治疗，这有可能降低转移性传播造成的死亡率。 目前，前哨淋巴结活检用于确定原发性黑色素瘤的疾病分期、预后和治疗方案。 在原发病变部位注射活性蓝色染料和放射性同位素，通过淋巴盆地排至周围淋巴结。 然后取出染色阳性淋巴结，切片并染色以寻找转移细胞。 淋巴结中存在黑色素瘤细胞用于分期，淋巴结中存在癌细胞是不良预后指标。 目前还没有任何药物可以添加到染料中来协同阻止入侵并杀死黑色素瘤细胞。 这种类型的药物可以预防黑色素瘤扩散，从而减少更具侵袭性的疾病的发展，这将产生重大的临床影响。 因此，本研究的中心假设是，可以使用靶向氧化铁纳米颗粒的抗体来想象黑色素瘤淋巴结的侵袭。 此外，可以使用携带表达 CD82 和 PTEN 的质粒的抗体靶向纳米脂质体杀死这些细胞，以分别阻止入侵并触发细胞凋亡，并使用递送靶向 B-Raf 的 siRNA 的脂质体来阻止黑色素瘤细胞的增殖潜力。 这一发现非常重要，它提供了治疗淋巴侵袭性黑色素瘤的新药物，有可能降低死亡率。 这种方法的基本原理是，在切除黑色素瘤皮肤病变时，没有靶向药物可以阻止侵袭性黑色素瘤的扩散，这可以帮助诊断和治疗。