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。子项目和子项目主要研究者的主要支持可能由其他来源提供，包括其他NIH来源。 为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数量，而不是NCRR赠款向子项目或子项目工作人员提供的直接资金。 目前用于诊断、预后和决定深度侵袭皮肤黑色素瘤的治疗方案的临床实践涉及称为前哨淋巴结活检的过程，其需要在原发病灶部位注射染料和放射性同位素，并使其引流到周围淋巴结。 迫切需要一种药物来添加到成像染料中，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，所提出的研究的中心假设是，可以使用抗体靶向氧化铁纳米颗粒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，不存在靶向药物来阻止皮肤扩散和淋巴结扩散，这有助于诊断和治疗。 将通过创建与抗体GD 2缀合的纳米脂质体、识别侵袭性黑素瘤细胞上优先存在的表位、表达肿瘤抑制基因（CD 82和PTEN）并抑制致癌基因（V600 E）B-Raf以协同抑制黑素瘤细胞存活来检验中心假设。 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。 这将涉及产生抗体9.2.27缀合的氧化铁纳米颗粒以使用MRI检测侵入淋巴系统的黑素瘤细胞，并将其与缀合至抗体GD 2的纳米脂质体组合，所述纳米脂质体含有用于表达抑制基因CD 82和PTEN的质粒以及用于靶向关键黑素瘤致癌基因（V600 E）B-Raf的siRNA。 这些发现将是非常重要的，提供了一种新的药物来检测和治疗恶性侵袭性黑色素瘤，这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，没有靶向药物可用于阻止淋巴系统中的侵袭性黑色素瘤传播。 检测和协同靶向移动通过淋巴系统的黑素瘤细胞的试剂可能是非常重要的，能够在仍然侵入皮肤或淋巴系统的同时进行治疗，这有可能降低由转移性传播引起的死亡率。 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。 在原发性病变部位注射一种活性蓝色染料和放射性同位素，这些染料通过淋巴池流向周围的淋巴结。 然后将染料阳性淋巴结取出，切片并染色以检测转移细胞。 淋巴结中黑色素瘤细胞的存在用于分期，淋巴结中癌细胞的存在是不良预后指标。 没有试剂可以添加到染料中，协同阻止入侵并杀死黑色素瘤细胞。 这种类型的药剂可以防止黑色素瘤扩散，从而减少更具侵袭性的疾病的发展，这将具有显著的临床影响。 因此，所提出的研究的中心假设是，可以使用抗体靶向氧化铁纳米颗粒来想象黑色素瘤淋巴结侵袭。 此外，这些细胞可以使用携带表达CD 82和PTEN的质粒的抗体靶向纳米脂质体来杀死，以分别停止侵袭和触发凋亡，并且使用递送靶向B-Raf的siRNA的脂质体来杀死黑色素瘤细胞的增殖潜力。 这一发现将是非常重要的，提供了新的药物来治疗恶性侵袭性黑色素瘤，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传播，这可能有助于诊断和治疗。