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ROS scavenging nanoparticles for mitigating oxidative stress in osteoarthritis

ROS清除纳米颗粒可减轻骨关节炎的氧化应激

基本信息

批准号：
10584738
负责人：
Blanka Sharma
金额：
$ 40.27万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-23 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584738
关键词：
Address Affect Animal Model Anti-Inflammatory Agents Antiinflammatory Effect Antioxidants Arthralgia Artificial nanoparticles Behavioral Assay Benchmarking Biochemical Biological Biological Availability Cartilage Cells Characteristics Chondrocytes Clinical Degenerative polyarthritis Development Disadvantaged Disease Disease Progression Disease model Dose Engineering Enzymes Extracellular Matrix Face Histologic Human In Vitro Inflammation Inflammatory Intra-Articular Injections Joints Location Macrophage Manganese Mediating Modeling Monitor Morphology Motivation Natural regeneration Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Pain Pathogenesis Pathway Analysis Pathway interactions Phenotype Play Production Property Rattus Reactive Oxygen Species Regimen Reporting Research Rodent Role Signal Transduction Source Structure Symptoms Synovial Fluid Tactile Testing Therapeutic Tissues Translations Traumatic Arthropathy Work antioxidant enzyme arthropathies bone chondroprotection cost cytokine delivery vehicle design disability effective therapy efficacy evaluation efficacy testing extracellular gait examination human tissue immunogenicity improved in vivo joint destruction joint function joint injury longitudinal analysis nanomaterials nanoparticle nanoparticle delivery novel strategies particle preservation prevent protein degradation reduce symptoms small molecule success targeted agent therapeutic target therapy outcome transcriptome sequencing treatment response treatment strategy uptake

项目摘要

PROJECT SUMMARY Oxidative stress plays a key role in the pathogenesis of osteoarthritis (OA) and is an important therapeutic target. While antioxidants or agents that target the reactive oxygen species (ROS) have been investigated for treating OA, many have demonstrated common disadvantages such as poor bioavailability and stability, as well as rapid joint clearance or release profiles from delivery vehicles following intra-articular injections. Therefore, there exists a critical need to localize and retain therapeutic levels of antioxidants within joint tissues for protection against the deleterious effects of oxidative stress. This proposal explores the application of manganese dioxide nanoparticles (MnO2 NPs) with antioxidant enzyme-like activity to reduce oxidative stress in OA joints while addressing limitations of small molecule antioxidants and natural enzymes, such as cost and stability. In addition, the properties of these nanomaterials can be tailored for tissue retention and cell targeting, which is important for addressing critical barriers to therapeutic localization and uptake in joint tissues. Recently, we reported engineering MnO2 NPs for uptake into cartilage and prolonged joint retention in vivo, as well as reduction of inflammation-induced oxidative stress in cartilage in vitro. Given its limited capacity to regenerate, cartilage is particularly vulnerable to oxidative stress and represents a crucial yet challenging tissue target. As such, this proposal focuses on interrogating the mechanisms of MnO2 NP-mediated chondroprotection while testing the efficacy of MnO2 NPs in an in vivo disease model. The central hypothesis is that MnO2 NPs will alleviate oxidative stress after joint injury and prevent or delay the onset of OA. In Aim 1, we will examine how uptake mechanisms and intracellular localization of MnO2 NPs affect compartment-specific ROS scavenging and the ability to rescue specific antioxidant pathways in chondrocytes. Furthermore, the effects of intracellular targeting versus extracellular retention on redox signaling, chondroprotective, and anti-inflammatory effects will be determined. In Aim 2, we will evaluate the effects of MnO2 NP treatment on oxidative stress and OA progression in vivo in a rat model of post-traumatic OA (PTOA). We will comprehensively evaluate the efficacy of the particles in modulating ROS in vivo, mitigating OA-related histological and biochemical (synovial fluid) changes, and alleviating OA-related pain and disability via behavioral assays. The proposed work will advance a new ROS scavenging strategy for the treatment of PTOA that overcomes persistent challenges with the delivery of antioxidants. The proposed work will also reveal key mechanisms involved in intracellular delivery to chondrocytes and how location and timing of antioxidant delivery impacts disease mechanisms. The mechanistic and comprehensive approach we propose here to characterize the effects of ROS scavenging by MnO2 NPs may facilitate successful translation long-term of this and/or other antioxidant strategies for joint injuries and disease.

项目总结