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

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

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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.

项目摘要在过去的几年中，RNA纳米技术的发展迅速。这种纳米技术包括将多个功能模块整合到一个纳米颗粒中，其中脚手架，配体，治疗剂和调节剂可以主要或仅由RNA组成。我们已经构建了RNA 具有较高化学和热力学稳定性的不同尺寸，形状和化学计量的纳米颗粒并证明了他们藏有不同官能团的能力，例如siRNA，miRNA，核酶，药物，和针对RNA适体的癌症。所有功能模块都保留其真实的折叠和独立特定细胞结合，基因沉默和靶向体内癌症的功能。全身注射肿瘤轴承小鼠，RNA纳米颗粒与异种移植物结合，并与转移性肿瘤特别强，强烈地与管理后3-4小时，在健康的重要器官和组织中几乎没有积累。 RNA 纳米颗粒是无毒的，显示出有利的生物分布和药代动力学特征。我们的长期目标是将RNA纳米颗粒作为一种新一代药物来治疗诊所的癌症。该项目的短期目标是表征RNA纳米颗粒的行为体外和体内，旨在提高特定细胞靶向，内在化和细胞内的效率贩运，有利的生物分布，没有肝脏中的无夹具，内体逃生和肿瘤退化。这些研究基于三个中心假设：（1）细胞内贩运途径和内体逃生对于有效的癌症治疗至关重要；（2）RNA的生物分布和药理概况纳米颗粒是形状和尺寸依赖性的；（3）RNA纳米颗粒引起的免疫反应是高度取决于RNA序列，化学修饰，大小，形状和化学计量法。解决我们的目标，我们将（1）系统地剖析RNA纳米颗粒采取的细胞内途径并增强他们的内体逃生能力；（2）检查药代动力学（PK）；药效学（PD）；和 RNA纳米颗粒的生物分布，目的是增强癌症靶向，而在最小健康器官；（3）评估RNA纳米颗粒的免疫反应以最大程度地减少非特异性侧效果以及开发通过纳入免疫刺激的方法来刺激免疫系统用于RNA纳米颗粒的模块进行癌症免疫疗法。这些临床前研究完成后，我们将鉴定出具有优化形状，尺寸和化学计量的几个RNA纳米颗粒显示符合FDA调查新药物指南的有利安全性和高治疗功效用于启动临床试验。