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。

基本信息

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
项目类别：
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

项目摘要

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在男性人群中诊断出的最常见的癌症类型，第六个原因每年死亡。尽管可以使用不同的治疗策略疾病（手术，放射治疗，化学疗法，荷尔蒙治疗）的研究正在转变为创新基于RNA干扰剂的递送，包括小干扰RNA（siRNA）。尽管它们在促进肿瘤抑制有效，但基于siRNA的策略受到负面影响 siRNA的递送不良，半衰期短的体内和免疫反应的改变，这阻碍了他们的转化为临床实践。由于它们自然参与蛋白质和核酸的细胞间转运。但是，外泌体遭受技术限制（靶向效率低，生物分布不良，内体捕获）。 exonanorna 提出了一种基于RNA纳米技术的新方法，以生成RNA纳米颗粒播放 siRNA在前列腺癌细胞中靶向递送的外泌体。 RNA纳米颗粒的使用与外泌体相关的允许优质细胞靶向和siRNA的有效递送。外泌体是设计以显示出良好的药代动力学特征和低免疫原性，并避免内体陷阱。该公司的初步验证了使用纳米颗粒方向控制RNA负载的使用在外泌体上的配体显示在概念证明的研究中，该研究支持RNA纳米颗粒的使用 - 载有外泌体以靶向前列腺癌。在这个SBIR阶段项目中，Exonanorna将产生铅具有高水平稳定性，生产效率，治疗功效和安全性的候选人适合临床测试。这个目标将通过两个目标实现。目标1）最合适的选择靶向配体以确保对前列腺细胞的最大特异性并识别最佳数字与电动汽车相关的RNA NPS的实现，以实现最有效的靶向效率。目标2）最好候选者将在人类前列腺腺癌（LNCAP+）细胞上进行体外测试，并在体内进行体内测试。异种移植物可研究疗效和安全性。拟议的活动将导致II期项目 exonanorna可以预见的是，经过验证的候选人的生产规模并执行指数在大小动物（大鼠，小猎犬）中进行研究。