Target-Specific Imaging and Delivery of siRNA to Tumors

靶标特异性成像和 siRNA 向肿瘤的递送

• 批准号: 7301141
• 负责人: Zdravka O Medarova
• 金额: $ 14.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-13 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7301141
• 关键词: Animal Model; Area; Award; Biodistribution; Biological Availability; Cell Line; Clinical Trials; Complex; Confocal Microscopy; Contrast Media; Data; Detection; Development; Disease regression; Drug Kinetics; Dyes; Elements; Enzymes; Evaluation; Fluorescence Microscopy; Functional Imaging; Gene Silencing; Genes; Genetic; Goals; Green Fluorescent Proteins; Histology; Human; Image; Imaging Device; Imaging Techniques; In Situ Nick-End Labeling; In Vitro; Inflammatory; Interferon-alpha; Interleukin-6; Invasive; Label; Life; Link; Magnetic Resonance; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Measurement; Mediating; Membrane; Mentors; Mentorship; Methods; Microscopy; Mind; Modeling; Monitor; Mucin 1 protein; Optics; Outcome; Patients; Peptides; Phase; Pre-Clinical Model; Principal Investigator; Process; Protein Overexpression; Purpose; RNA Interference; Research; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Series; Small Interfering RNA; Solid Neoplasm; Specificity; Standards of Weights and Measures; TNF gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Studies; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; Tumor Antigens; Tumor Cell Line; Tumor Volume; Weight; Western Blotting; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; clinical application; cyanine dye 3; cytokine; design; imaging probe; in vivo; interest; iron oxide; molecular imaging; nanoparticle; neoplastic cell; novel; novel strategies; optical imaging; polyarginine; pre-clinical; programs; research study; response; survivin; therapeutic target; tumor; tumor growth; tumor progression; tumorigenesis; uptake

DESCRIPTION (provided by applicant): With the increased interest in the potential of RNA interference as a therapeutic strategy, novel strategies for siRNA delivery to target tissues are urgently needed. In addition, for a more accurate assessment of the efficacy of the delivery method, non-invasive approaches for detection and tracking of siRNA bioavailability are essential. We have previously described the development of dual-purpose nanoparticle probes for in vivo transfer of synthetic siRNA to tumors and the simultaneous imaging of its accumulation in target tissues by high resolution magnetic resonance and near-infrared optical imaging techniques. These probes consisted of magnetic nanoparticles, labeled with a near-infrared dye, and covalently linked to siRNA molecules specific for model or therapeutic targets. In addition, these nanoparticles were modified with a membrane translocation peptide for intracellular delivery. We demonstrated the feasibility of tracking the in vivo tumor uptake of these complexes by MRI and NIRF imaging in two separate tumor models and also used proof-of- principle optical imaging to corroborate the efficiency of the silencing process. In this proposal, we plan to take this approach to the next level and develop a tumor-targeted imaging and delivery module with the ultimate goal of mediating a therapeutic effect. In the mentored phase of the award, we plan to establish the synthesis and in vitro functionality of our probe. In the independent phase, we will investigate the potential of our tumor-targeted nanoparticle probe, not only as an imaging tool for the assessment of siRNA delivery to tumors, but also as a therapeutic agent capable of inhibiting tumor growth. We will perform therapeutic studies with our probe, alone and in combination with standard chemotherapy, in an attempt to achieve the most significant anti-tumor effects. These studies represent an early step towards exploring the potential of siRNA for tumor therapy. In addition, our planned studies combine imaging and therapeutic agent delivery in a single nanoparticle module, which is essential for cancer therapeutic-product development and optimization.

描述（由申请人提供）：随着对RNA干扰作为一种治疗策略的潜力的兴趣增加，迫切需要将siRNA递送到靶组织的新策略。此外，为了更准确地评估递送方法的有效性，检测和跟踪siRNA生物利用度的非侵入性方法是必不可少的。我们之前已经描述了双重用途纳米颗粒探针的发展，用于将合成的siRNA在体内转移到肿瘤中，并通过高分辨率磁共振和近红外光学成像技术同时成像其在靶组织中的积累。这些探针由磁性纳米颗粒组成，用近红外染料标记，并与模型或治疗靶点特异性的siRNA分子共价连接。此外，这些纳米颗粒被膜易位肽修饰，用于细胞内递送。我们在两种不同的肿瘤模型中通过MRI和NIRF成像证明了跟踪这些复合物在体内肿瘤摄取的可行性，并且还使用原理证明光学成像来证实沉默过程的效率。在本提案中，我们计划将这种方法提升到一个新的水平，开发一个肿瘤靶向成像和传递模块，最终目标是介导治疗效果。在该奖项的指导阶段，我们计划建立我们探针的合成和体外功能。在独立阶段，我们将研究我们的肿瘤靶向纳米颗粒探针的潜力，不仅作为评估siRNA向肿瘤传递的成像工具，而且作为能够抑制肿瘤生长的治疗剂。我们将使用我们的探针进行治疗研究，单独或与标准化疗相结合，试图达到最显著的抗肿瘤效果。这些研究为探索siRNA在肿瘤治疗中的潜力迈出了早期的一步。此外，我们计划的研究将成像和治疗剂输送结合在一个纳米颗粒模块中，这对癌症治疗产品的开发和优化至关重要。