Target-Specific Imaging and Delivery of siRNA to Tumors

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siRNA递送至靶组织的新策略。此外，为了更准确地评估递送方法的功效，用于检测和跟踪siRNA生物利用度的非侵入性方法是必不可少的。我们先前已经描述了用于将合成siRNA体内转移至肿瘤的双重目的纳米颗粒探针的开发，以及通过高分辨率磁共振和近红外光学成像技术对其在靶组织中的积累的同时成像。这些探针由磁性纳米颗粒组成，用近红外染料标记，并共价连接到对模型或治疗靶点特异性的siRNA分子。此外，这些纳米颗粒被修饰有用于细胞内递送的膜易位肽。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摄取的可行性，并且还使用原理验证光学成像来证实沉默过程的效率。在这项提案中，我们计划将这种方法提升到一个新的水平，并开发一种肿瘤靶向成像和递送模块，其最终目标是介导治疗效果。在该奖项的指导阶段，我们计划建立我们的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递送到肿瘤的成像工具，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单独或与标准化疗联合进行治疗研究，以达到最显著的抗肿瘤效果。这些研究代表了探索siRNA用于肿瘤治疗的潜力的早期步骤。此外，我们计划的研究将联合收割机成像和治疗剂递送结合在单个纳米颗粒模块中，这对于癌症治疗产品的开发和优化至关重要。

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.