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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。对该分项目和该分项目首席调查员的主要支持可能是由其他来源提供的，包括国家卫生研究院的其他来源。列出的子项目总成本可能代表子项目使用的中心基础设施的估计数量，而不是NCRR拨款提供给子项目或子项目工作人员的直接资金。 目前对深度侵袭性皮肤黑色素瘤的诊断、预后和决定治疗方案的临床实践涉及一种称为前哨淋巴结活检的过程，该过程需要在原发灶部位注射染料和放射性同位素，并允许其引流到周围的淋巴管。迫切需要一种试剂来添加到用于成像的染料中，以阻止入侵，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，这可能会在黑色素瘤的最早阶段阻止扩散。因此，这项研究的中心假设是，利用抗体靶向氧化铁纳米颗粒可以想象黑色素瘤的淋巴侵袭。其基本原理是，在切除原发黑色素瘤皮肤病变时，没有靶向药物可以阻止皮肤扩散和淋巴结扩散，这可能有助于诊断和治疗。核心假设将通过创建与抗体GD2结合的纳米脂质体、识别侵袭性黑色素瘤细胞上优先存在的表位、表达肿瘤抑制基因(CD82和PTEN)和抑制癌基因(V600E)B-Raf来协同抑制黑色素瘤细胞的生存来检验。其次，将开发一种新的纳米技术，能够检测和杀死通过动物淋巴系统转移的黑色素瘤细胞。这将包括创建抗体9.2.27结合的氧化铁纳米颗粒，以使用MRI检测通过淋巴系统侵袭的黑色素瘤细胞，并将其与与抗体GD2结合的纳米脂质体结合，该纳米脂质体包含表达抑制基因CD82和PTEN的质粒，以及靶向关键黑色素瘤癌基因(V600E)B-Raf的siRNA。这些发现将具有非常重要的意义，为检测和治疗淋巴侵袭性黑色素瘤提供了一种新的药物，这种黑色素瘤具有显著降低死亡率的潜力。 具体目标 在切除原发黑色素瘤病变时，没有靶向药物可用于阻止侵袭性黑色素瘤在淋巴系统中的扩散。检测和协同靶向黑色素瘤细胞通过淋巴系统的药物可能具有非常重要的意义，使治疗能够在仍然侵入皮肤或淋巴系统的同时进行，这有可能降低转移扩散造成的死亡率。 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。一种重要的蓝色染料和放射性同位素被注射到原发病变的部位，通过淋巴盆地流入周围的淋巴结。然后将染色阳性的淋巴结取出，切片，并对转移细胞进行染色。淋巴结中黑色素瘤细胞的存在被用于分期，而淋巴结中癌细胞的存在是一个不良的预后指标。没有任何试剂可以添加到这种染料中，以协同作用阻止入侵并杀死黑色素瘤细胞。这种类型的制剂可以防止黑色素瘤的扩散，从而减少更具侵袭性的疾病的发展，这将具有重大的临床影响。因此，这项研究的中心假设是，可以利用抗体靶向氧化铁纳米颗粒来想象黑色素瘤的淋巴侵袭。此外，使用携带表达CD82和PTEN的质粒的抗体靶向纳米脂质体分别阻止侵袭和触发细胞凋亡，以及使用针对B-Raf的siRNA脂质体抑制黑色素瘤细胞的增殖潜能，可以杀死这些细胞。这一发现将具有非常重要的意义，为治疗淋巴侵袭性黑色素瘤提供了新的药物，这有可能降低死亡率。这种方法的基本原理是，在切除黑色素瘤皮肤病变时，没有靶向药物可用于延缓侵袭性黑色素瘤的扩散，这可能有助于诊断和治疗。