Target-Specific Imaging and Delivery of siRNA to Tumors

靶标特异性成像和 siRNA 向肿瘤的递送

基本信息

批准号：
7469587
负责人：
Zdravka O Medarova
金额：
$ 14.18万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/7469587
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

项目摘要

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干扰作为治疗策略的潜力的兴趣增加，迫切需要将siRNA传递到目标组织的新型策略。此外，为了更准确地评估递送方法的功效，必不可少的检测和跟踪的非侵入性方法至关重要。我们先前已经描述了通过高分辨率磁共振和近红外光学成像技术在靶组织组织中的体内转移肿瘤的体内转移和同时在目标组织中积累的双重纳米颗粒探针的发展。这些探针由磁性纳米颗粒组成，标记为近红外染料，并与特异性或治疗靶标的siRNA分子共价链接。此外，用膜易位肽修饰这些纳米颗粒以进行细胞内递送。我们证明了在两个单独的肿瘤模型中通过MRI和NIRF成像跟踪这些复合物的体内肿瘤吸收的可行性，还使用原理光学成像来证实沉默过程的效率。在此提案中，我们计划将这种方法提升到一个新的水平，并开发针对肿瘤的成像和递送模块，其最终目标是介导治疗效果。在奖励的指导阶段，我们计划建立探测器的综合和体外功能。在独立阶段，我们将研究靶向肿瘤的纳米颗粒探针的潜力，不仅是评估siRNA向肿瘤递送的成像工具，而且还作为能够抑制肿瘤生长的治疗剂。我们将单独探测并与标准化疗结合进行治疗研究，以实现最重要的抗肿瘤作用。这些研究代表了探索siRNA对肿瘤疗法的潜力的早期一步。此外，我们的计划研究将成像和治疗剂递送在单个纳米颗粒模块中结合在一起，这对于癌症治疗产物的发展和优化至关重要。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Novel membrane-permeable contrast agent for brain tumor detection by MRI.

DOI：
10.1002/mrm.22216
发表时间：
2010-03
期刊：
MAGNETIC RESONANCE IN MEDICINE
影响因子：
3.3
作者：
Kumar, Mohanraja;Medarova, Zdravka;Pantazopoulos, Pamela;Dai, Guangping;Moore, Anna
通讯作者：
Moore, Anna

Development and application of a dual-purpose nanoparticle platform for delivery and imaging of siRNA in tumors.

开发和应用双用途纳米颗粒平台，用于肿瘤中 siRNA 的递送和成像。