Optimizing RNA nanoparticles size and shape for enhancing cancer targeting and treatment

优化 RNA 纳米粒子的大小和形状以增强癌症靶向和治疗

基本信息

批准号：
9166825
负责人：
WILLIAM E. CARSON
金额：
$ 55.31万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-26 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9166825
关键词：
Address Adverse effects Animals Antibodies Antineoplastic Agents Attributes of Chemicals B-Lymphocytes Behavior Binding Biodistribution Biological Sciences Biotechnology Catalytic RNA Caveolins Cells Chemicals Clathrin Clinic Clinical Clinical Trials Data Dendritic Cells Drug Kinetics Endocytosis Endosomes Excretory function Exhibits Gene Silencing Generations Goals Guidelines Hour Immune Immune response Immune system Immunotherapy In Vitro Injection of therapeutic agent Interferons Investigational Drugs Investigational New Drug Application Lead Ligands Liver Liver neoplasms Malignant Neoplasms Mediating Membrane Microdomains Metabolism Methods MicroRNAs Modification Molecular Mus Nanotechnology Nature Neoplasm Metastasis Nucleic Acids Organ Pathway interactions Phagocytosis Pharmacodynamics Pharmacotherapy Pinocytosis Process RNA RNA Sequences Reaction Reporting Research Safety Shapes Small Interfering RNA T-Lymphocyte Therapeutic Thermodynamics Tissues Toxic effect Translations Treatment Efficacy Tumor Escape Validation Xenograft procedure absorption aptamer base cancer immunotherapy cancer therapy clinically relevant cytokine functional group improved in vivo large scale production macrophage meetings mouse model nano nanoparticle pre-clinical preclinical study scaffold self assembly stoichiometry subcutaneous trafficking tumor uptake

项目摘要

PROJECT SUMMARY RNA nanotechnology has progressed rapidly during the past several years. This nanotechnology includes the integration of multiple functional modules into one nanoparticle, of which the scaffolds, ligands, therapeutics, and regulators can be composed mainly or exclusively of RNA. We have constructed RNA nanoparticles of diverse size, shape, and stoichiometry displaying high chemical and thermodynamic stability and demonstrated their ability to harbor different functional groups, such as siRNA, miRNA, ribozyme, drug, and cancer targeting RNA aptamer. All functional modules retain their authentic folding and independent functionalities for specific cell binding, gene silencing, and cancer targeting in vivo. Upon systemic injection in tumor bearing mice, RNA nanoparticles bind to xenograft and metastatic tumors specifically and strongly with little to no accumulation in healthy vital organs and tissues 3-4 hours post-administration. The RNA nanoparticles are non-toxic and display favorable biodistribution and pharmacokinetic profiles. Our long-term goal is to promote RNA nanoparticles as a new generation of drug for the treatment of cancers in the clinic. The short-term goal of this project is to characterize the behavior of RNA nanoparticles in vitro and in vivo, with an aim to improve the efficiency for specific cell targeting, internalization and intracellular trafficking, favorable biodistribution without entrapment in liver, endosome escape, and tumor regression. These studies are based on three central hypotheses: (1) intracellular trafficking pathways and endosome escape are critical for effective cancer therapy; (2) biodistribution and pharmacological profiles of RNA nanoparticles are shape and size dependent; and, (3) immune responses elicited by RNA nanoparticles are highly dependent on RNA sequence, chemical modifications, size, shape, and stoichiometry. To address our goals, we will (1) systemically dissect the intracellular pathways taken by RNA nanoparticles and enhance their endosome escape capabilities; (2) inspect the pharmacokinetics (PK); pharmacodynamics (PD); and biodistribution of RNA nanoparticles with the goal of enhancing cancer targeting with minimal accumulation in healthy organs; and, (3) evaluate the immune responses of RNA nanoparticles to minimize non-specific side effects, as well as develop methods to stimulate the immune system by incorporating immuno-stimulatory modules to RNA nanoparticles for cancer immunotherapy. Upon completion of these pre-clinical studies, we will have identified several RNA nanoparticles with optimized shape, size, and stoichiometry displaying favorable safety profiles and high therapeutic efficacy to comply with FDA Investigational New Drug guidelines for initiating clinical trials.

项目概要 RNA纳米技术在过去几年中发展迅速。该纳米技术包括将多个功能模块整合到一个纳米粒子中，其中支架、配体、治疗剂和调节剂可以主要或完全由RNA组成。我们构建了RNA 不同尺寸、形状和化学计量的纳米颗粒表现出高化学和热力学稳定性并证明了它们具有不同功能组的能力，例如 siRNA、miRNA、核酶、药物、和癌症靶向RNA适体。所有功能模块都保留了原汁原味的折叠性和独立性特定细胞结合、基因沉默和体内癌症靶向的功能。全身注射后荷瘤小鼠中，RNA 纳米粒子与异种移植物和转移性肿瘤特异性且强烈地结合给药后3-4小时，健康重要器官和组织中几乎没有蓄积。核糖核酸纳米颗粒无毒，并显示出良好的生物分布和药代动力学特征。我们的长期目标是推广RNA纳米颗粒作为新一代治疗药物诊所里的癌症。该项目的短期目标是表征 RNA 纳米粒子在体外和体内，旨在提高特定细胞靶向、内化和细胞内的效率运输、有利的生物分布而不被肝脏截留、内体逃逸和肿瘤消退。这些研究基于三个中心假设：（1）细胞内运输途径和内体逃避对于有效的癌症治疗至关重要； (2) RNA的生物分布和药理特征纳米粒子取决于形状和尺寸； (3) RNA 纳米颗粒引发的免疫反应是高度依赖于 RNA 序列、化学修饰、大小、形状和化学计量。为了解决我们的为了实现这一目标，我们将 (1) 系统地剖析 RNA 纳米粒子所采取的细胞内途径，并增强他们的内体逃逸能力； (2)检查药代动力学(PK)；药效学（PD）；和 RNA纳米粒子的生物分布，目的是增强癌症靶向性，并以最小的积累健康的器官； (3) 评估 RNA 纳米粒子的免疫反应，以尽量减少非特异性副作用效果，以及开发通过结合免疫刺激剂来刺激免疫系统的方法用于癌症免疫治疗的 RNA 纳米颗粒模块。完成这些临床前研究后，我们将鉴定出几种具有优化形状、尺寸和化学计量显示的 RNA 纳米颗粒良好的安全性和高治疗功效，符合 FDA 新药研究指南用于启动临床试验。