RNA Nanosystem for Posterior Eye Drug Delivery

用于眼后药物输送的 RNA 纳米系统

基本信息

批准号：
10322457
负责人：
Kevin S. Li
金额：
$ 39.57万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322457
关键词：
3D Print Adverse effects Affect Age related macular degeneration Angiogenesis Inhibitors Animal Model Animals Antibody Therapy Bacteriophages Biological Catalytic RNA Cell Culture Techniques Cells Characteristics Chemicals Chronic Disease Clinical Trials Confocal Microscopy Cornea Cytomegalovirus Retinitis DNA DNA Packaging Data Development Disease Dissociation Drug Delivery Systems Drug Kinetics Drug Stability Eye Eye diseases Fluorescence Microscopy Goals Growth Factor Implant In Vitro Injections Lead Ligands Membrane Methods MicroRNAs Modeling Monitor Monoclonal Antibodies Motor Mus Nanotechnology Nucleotides Oligonucleotides Oryctolagus cuniculus Particle Size Persons Pharmaceutical Preparations Pharmacodynamics Platelet-Derived Growth Factor Polymers Posterior eyeball segment structure Proteins RNA RNA Phages Reporter Research Resistance Retina Retinal Pigments Route Sclera Silicone Elastomers Small Interfering RNA Structure Structure of retinal pigment epithelium System Technology Therapeutic Therapeutic Agents Therapeutic Effect Thermodynamics Tissues Toxic effect Transfection United States aptamer base bevacizumab design drug discovery experimental study fluorescence imaging fomivirsen in vivo intravitreal injection macromolecule nanoparticle nanoparticle delivery nanosystems neovascular new technology novel oculomotor pegaptanib pharmacokinetics and pharmacodynamics scaffold small molecule systemic toxicity therapeutic RNA therapeutic target uptake

项目摘要

RNA nanotechnology provides molecules that have the simplicity in design with the characteristics of DNA and can be used in therapies. However, a major problem in RNA nanotechnology is that RNA molecules are relatively unstable such as their degradation in vivo and dissociation at ultra-low concentration after administration. Intravitreal injection is the most common method to deliver macromolecular therapeutic agents to the posterior segment of the eye for the treatments of diseases. Repeated intravitreal injection can cause severe adverse effects to the eye. For small drug molecules, systemic administration can be used but this route of administration is complicated by systemic toxicity. There is an unmet need of a more effective drug delivery method in the treatment of posterior eye diseases. We have recently studied RNA nanoparticles derived from the three-way junction (3WJ) of the packaging RNA (pRNA) of bacteriophage phi29 DNA packaging motor for ocular drug delivery. These nanoparticles are thermodynamically and chemically stable both in vitro and in vivo and can harbor multiple modules with different functionalities such as RNA aptamer, reporter moiety, and therapeutic siRNA, miRNA, or other chemical drugs or ligands as subunits all in the same nanoparticles. Our preliminary studies have shown that the pRNA nanoparticles (pRNA nano) were internalized in the cells in the cornea, retinal pigment epithelium, and retina in the eye after subconjunctival injection in mice in vivo. This suggests the potential of subconjunctival injection of pRNA nano as an efficient drug delivery system of RNA-based therapeutic agents to the cells in the posterior segment of the eye: pRNA nano can overcome both the RNA molecule stability and posterior eye delivery problems. The preliminary studies have also suggested that the delivery and retention of pRNA nano are particle size dependent and the existence of an optimal size range for their effective delivery to the cells in the eye. The objectives of the present project are to (a) determine the optimal pRNA nano for ocular drug delivery, (b) demonstrate the ability of pRNA nano to deliver therapeutic agents to treat posterior eye disease, and (c) develop an episcleral implant system for prolonged delivery of these nanoparticles. pRNA nano of different sizes and module subunits will be constructed and evaluated for effective intraocular delivery and therapeutic effects after subconjunctival injection in animal models. The episcleral implant is refillable and is placed on the sclera in the subconjunctival or sub-Tenon pocket to provide sustained delivery of the nanoparticles. The ultimate goal is to develop a platform of ocular drug delivery using the pRNA technology for nucleotide-based therapies via the periocular route (a less invasive approach than intravitreal injection). The present project will examine the feasibility of the combined pRNA nano and episcleral implant approach for the proof of concept of this new technology.

RNA纳米技术提供了设计简单、具有DNA特征的分子，可以用于治疗。然而，RNA纳米技术的一个主要问题是RNA分子相对不稳定，如体内降解和超低浓度解离行政。玻璃体内注射是递送大分子治疗药物的最常用方法到达眼睛的后段以治疗疾病。重复玻璃体内注射可导致对眼睛产生严重的不良影响。对于小分子药物，可以采用全身给药，但这由于全身毒性，给药途径变得复杂。对更有效药物的需求尚未得到满足治疗眼后部疾病的递送方法。我们最近研究了RNA纳米粒子源自噬菌体 phi29 DNA 包装 RNA (pRNA) 的三路连接 (3WJ) 用于眼部药物输送的包装电机。这些纳米颗粒具有热力学和化学稳定性在体外和体内，可以容纳具有不同功能的多个模块，例如RNA适体，报告基团和治疗性 siRNA、miRNA 或其他化学药物或配体作为亚基均位于同一区域纳米颗粒。我们的初步研究表明，pRNA 纳米颗粒（pRNA nano）结膜下植入后内化于眼角膜、视网膜色素上皮和视网膜的细胞中注射到小鼠体内。这表明结膜下注射 pRNA 纳米作为一种有效的方法具有潜力。基于 RNA 的治疗剂向眼后段细胞的药物输送系统：pRNA nano可以克服RNA分子稳定性和眼后部输送问题。初步的研究还表明，pRNA 纳米粒子的递送和保留取决于粒径，并且存在将它们有效递送至眼睛细胞的最佳尺寸范围。该计划的目标目前的项目是 (a) 确定用于眼部药物输送的最佳 pRNA 纳米，(b) 展示其能力 pRNA 纳米递送治疗剂来治疗眼后部疾病，以及 (c) 开发巩膜外层用于延长这些纳米颗粒递送时间的植入系统。不同尺寸和模块的pRNA纳米亚单位将被构建和评估有效的眼内递送和治疗效果动物模型中结膜下注射。巩膜外层植入物是可再填充的，并放置在巩膜上结膜下或眼球筋膜下袋以提供纳米颗粒的持续递送。最终目标是开发一个使用 pRNA 技术进行眼部药物输送的平台，用于基于核苷酸的治疗眼周途径（比玻璃体内注射侵入性较小的方法）。本项目将审查 pRNA 纳米和巩膜外层植入相结合的方法用于验证这一新概念的可行性技术。