RNA Nanoparticles-Displaying Exosomes to enhance targeted siRNA delivery for Prostate Cancer treatment.

项目总结 前列腺癌是男性人群中诊断出的最常见的癌症类型，是第六大病因 每年的死亡人数。虽然有不同的治疗策略可用于临床管理 疾病(手术、放射治疗、化疗、激素治疗)的研究正在转向创新 基于递送RNA干扰剂的方法，包括小干扰RNA(SiRNA)。 尽管它们在促进肿瘤抑制方面有效，但基于siRNA的策略受到以下负面影响 SiRNA传递不良，体内半衰期短，以及免疫反应改变，这阻碍了他们的 转化为临床实践。外切体已被提议作为递送纳米颗粒，这要归功于它们的 天然参与蛋白质和核酸的细胞间运输。然而，外显色体会受到 技术限制(靶向效率低、生物分布差、内体捕获)。外向型RNA 提出了一种基于RNA纳米技术制备RNA纳米颗粒的新方法--展示 前列腺癌细胞中靶向递送siRNA的外切体。核糖核酸纳米颗粒的使用 与外切体相关允许更好的细胞靶向和有效的siRNA递送。外切体是 设计成具有良好的药代动力学特征和低免疫原性，并避免内吞 诱捕。该公司已经初步验证了使用纳米颗粒定向来控制RNA负载 以及在一项支持使用RNA纳米颗粒的概念验证研究中显示在外体上的配体- 以前列腺癌为靶标的外切体。在这个SBIR第一阶段项目中，ExonanoRNA将产生铅 具有较高的稳定性、生产效率、治疗效果和安全性的候选人 临床测试。这一目标将通过两个目标实现。目标1)选择最合适的 靶向配基以确保对前列腺细胞的最大特异性并确定最佳数量 与电动汽车相关的RNA NPs，以实现最有效的靶向效率。目标2)最好的 候选将在体外对人前列腺癌(LNCaP)细胞进行测试，并在体内进行 观察异种移植小鼠的疗效、安全性。拟议的活动将导致第二阶段项目。 其中ExonanoRNA预测经过验证的候选者的生产规模并执行IND- 能够在小动物和大动物(大鼠、比格犬)上进行研究。

PROJECT SUMMARY Prostate Cancer is the most common type of cancer diagnosed in the male population and the sixth cause of death every year. While different therapeutic strategies are available for the clinical management of the disease (surgery, radiation therapy, chemotherapy, hormonal therapy) research is shifting to innovative approaches based on the delivery of RNA interfering agents, including small interfering RNA (siRNA). Despite their efficacy in promoting tumor suppression, siRNA-based strategies are negatively affected by poor delivery of siRNA, short half-life in vivo, and alteration of the immune response, which hinder their translation into clinical practice. Exosomes have been proposed as delivery nanoparticles thanks to their natural involvement in intercellular transport of protein and nucleic acids. However, exosomes suffer from technical limitations (low targeting efficiency, poor biodistribution, endosome trapping). ExonanoRNA proposes a novel approach based on RNA Nanotechnology to generate RNA Nanoparticles-Displaying Exosomes for the targeted delivery of siRNA in prostate cancer cells. The use of RNA nanoparticles associated with exosomes allows superior cell targeting and efficient delivery of siRNA. Exosomes are engineered to display a favorable pharmacokinetic profile and low immunogenicity and to avoid endosome trapping. The company has preliminary validated the use of nanoparticle orientation to control RNA loading and ligand display on exosomes in a proof-of-concept study that supports the use of RNA nanoparticles- loaded Exosomes to target prostate cancer. In this SBIR Phase I project, ExonanoRNA will generate lead candidates with high level of stability, production efficiency, therapeutic efficacy, and safety suitable for clinical testing. This goal will be achieved through two aims. Aim 1) selection of the most appropriate targeting ligand to ensure the maximum specificity to prostate cells and identification of the optimal number of RNA NPs associated to the EVs to achieve the most efficient targeting efficiency. Aim 2) The best candidate will be tested in vitro on human prostate adenocarcinoma (LNCaP+) cells, and in vivo on xenografts mice to investigate efficacy, and safety. The proposed activities will lead to a Phase II project where ExonanoRNA foresees the scale up of production of the validated candidate and perform IND- enabling studies in small and large animals (rat, beagle dog).