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

RNA 纳米颗粒 - 展示外泌体以增强前列腺癌治疗的靶向 siRNA 递送。

• 批准号: 10483260
• 负责人: Shanqing Gu
• 金额: $ 29.45万
• 依托单位: EXONANORNA, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483260
• 关键词: Address; Animals; Apoptosis Inhibitor; Binding; Biodistribution; Biological Assay; Cancer Etiology; Canis familiaris; Carrier Proteins; Cause of Death; Cells; Cessation of life; Clinical Management; Custom; Diagnosis; Disease; Disease Management; Dose; Drug Kinetics; Economic Burden; Endosomes; Engineering; Ensure; Evaluation; Evaluation Studies; Exposure to; FOLH1 gene; Future; Gene Silencing; Generations; Genes; Goals; Half-Life; Health; Healthcare Systems; Human; Immune response; In Vitro; Innovative Therapy; Intervention; LNCaP; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Messenger RNA; Methods; Modification; Molecular; Mus; Nanotechnology; Newly Diagnosed; Nucleic Acids; Ohio; Oncogenes; Operative Surgical Procedures; Organ; Pharmacy (field); Pharmacy facility; Phase; Population; Preparation; Production; Prostate; Prostate Adenocarcinoma; Prostate Cancer therapy; RNA; RNA Interference; RNA delivery; Radiation therapy; Rattus; Reagent; Regimen; Research; Research Personnel; Resistance; Ribonucleases; Safety; Series; Small Business Innovation Research Grant; Small Interfering RNA; Small RNA; Specificity; Surface; Therapeutic; Therapeutic Studies; Toxic effect; Toxicology; Translating; Translations; Treatment Efficacy; Tumor Suppression; Universities; Validation; Xenograft procedure; aptamer; base; cancer cell; cancer diagnosis; cancer therapy; cancer type; chemotherapy; clinical application; clinical practice; college; cytotoxic; design; efficacy evaluation; engineered exosomes; exosome; fluorescence imaging; hormone therapy; immunogenicity; improved; in vitro testing; in vivo; innovation; knock-down; lead candidate; male; men; mid-career faculty; mouse model; nanoparticle; nanoparticle delivery; negative affect; novel; novel strategies; prostate cancer cell; prostate cancer model; research clinical testing; scaffold; scale up; survivin; targeted delivery; therapeutic RNA; therapeutically effective; tool; tumor

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).

项目摘要 前列腺癌是男性人群中最常见的癌症类型，也是第六大病因。 每年死亡。虽然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）研究正在转向创新 基于RNA干扰剂（包括小干扰RNA（siRNA））的递送的方法。 尽管它们在促进肿瘤抑制方面的功效，但基于siRNA的策略受到以下因素的负面影响： siRNA的递送差、体内半衰期短和免疫应答的改变，这阻碍了它们的表达。 转化为临床实践。外泌体已经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，外来体遭受 技术限制（靶向效率低、生物分布差、内体捕获）。ExonanoRNA 提出了一种基于RNA纳米技术的RNA纳米颗粒制备新方法--RNA纳米颗粒 用于在前列腺癌细胞中靶向递送siRNA的外来体。RNA纳米颗粒的应用 与外来体相关的siRNA允许siRNA的上级细胞靶向和有效递送。外来体是 工程化以显示有利的药代动力学特征和低免疫原性，并避免核内体 诱捕该公司已经初步验证了使用纳米颗粒定向来控制RNA加载 在一项支持使用RNA纳米颗粒的概念验证研究中， 装载外泌体以靶向前列腺癌。在这个SBIR第一阶段项目中，ExonanoRNA将产生铅 具有高水平的稳定性、生产效率、治疗功效和安全性的候选物， 临床试验这一目标将通过两个目标来实现。1、选择最合适的 靶向配体，以确保对前列腺细胞的最大特异性和鉴定最佳数量 的RNA纳米颗粒，以实现最有效的靶向效率。2）最好的 候选人将在体外对人前列腺腺癌（LNCaP+）细胞进行测试，并在体内对 异种移植小鼠以研究功效和安全性。拟议的活动将导致第二阶段项目 其中ExonanoRNA预见了经验证的候选物的生产规模的扩大，并进行IND- 能够在小型和大型动物（大鼠、比格犬）中进行研究。