Nanoparticle mediated in vivo cell-type specific drug delivery for pain relief

描述(由申请人提供)：现有数据支持神经激肽1受体(NK1受体)在脊髓背侧表达神经元在介导疼痛处理中的关键作用。利用新开发的纳米颗粒的优势，我们打算在这一探索性方案中研究纳米颗粒与P物质(一种疼痛诱导肽和NK1受体的特异性配体)的偶联是否能够通过配体诱导的内吞作用实现小干扰RNA(SiRNA)到NK1受体表达细胞的细胞型特异性递送，如果是的话，这种方法是否可以在动物模型中导致有效的基因沉默和止痛。我们将首先研究纳米粒子在体内分布的最佳剂量和时间点。其次，我们将研究纳米颗粒在不同细胞类型中的分布。第三，我们将检验这种方法是否可以用于体内NK1受体基因沉默和阻断动物模型的疼痛处理。从这个项目中获得的有希望的数据将被用于一个更大规模的NIH R01项目的应用，该项目与siRNA/纳米颗粒在靶向基因沉默和止痛方面的应用有关。 公共卫生相关性：慢性疼痛是一种常见的临床综合征，缺乏特异、有效和安全的治疗药物。利用新开发的纳米颗粒的优势，我们计划研究将疼痛中介受体的特异性配体偶联到纳米颗粒上是否可以改善小干扰RNA(SiRNA)的细胞型特异性递送，从而在体内有效地基因沉默和止痛。这项研究的完成将使我们能够深入了解纳米颗粒作为体内细胞型特异性药物输送载体的潜在用途。

DESCRIPTION (provided by applicant): Existing data support a critical role of neurokinin 1 receptor (NK1 receptor) expressing neurons in the dorsal spinal cord in mediating pain processing. Taking the advantage of newly developed nanoparticles, we propose to study in this exploratory proposal whether conjugation of nanoparticles with Substance P, a pain- inducing peptide and specific ligand to NK1 receptors, can achieve cell-type specific delivery of small interference RNA (siRNA) into NK1 receptor expressing cells upon ligand-induced endocytosis, and if so, whether this approach can lead to effective gene silencing and pain relief in animal models. We will first study the optimal dose and time point for nanoparticle distributio in vivo. Second, we will examine nanoparticle distribution in different cell types. Third, we wil examine if this approach can be used for in vivo NK1 receptor gene silencing and blocking pain processing in animal models. Promising data derived from this project will be used for the application of a larger scale NIH R01 project related to application of siRNA/nanoparticles in targeted gene silencing and pain relief. PUBLIC HEALTH RELEVANCE: Chronic pain is a common clinical syndrome lacking specific, effective and safe therapeutic agents. Taking the advantage of newly developed nanoparticles, we plan to study whether conjugation of a ligand specific to pain-mediating receptors to nanoparticles can improve cell-type specific delivery of small interference RNA (siRNA) for effective gene silencing and pain relief in vivo. Completion of this study will allow us to gain insights into the potential use of nanoparticles as a carrier for cell-type specific drug delivery n vivo.