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

• 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
• 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

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.

项目摘要 氧化应激在骨关节炎（OA）的发病机理中起关键作用，并且是重要的治疗靶点。 虽然已经研究了靶向活性氧（ROS）的抗氧化剂或药物以治疗 OA，许多人表现出常见的缺点，例如差的生物利用度和稳定性以及快速 关节内注射后的关节清除或释放档案。因此，存在 关节组织中局部定位和保留抗氧化剂的治疗水平的迫切需要 氧化应激的有害作用。该提案探讨了二氧化锰的应用 纳米颗粒（MNO2 NP）具有抗氧化酶样活性，以减少OA关节中的氧化应激 解决小分子抗氧化剂和天然酶的局限性，例如成本和稳定性。此外， 这些纳米材料的特性可以针对组织保留和细胞靶向定制，这很重要 解决关节组织中治疗定位和摄取的关键障碍。最近，我们报道 工程MNO2 NP，以吸收软骨和长时间的关节保留，并减少 炎症引起的体外软骨中的氧化应激。鉴于其再生能力有限，软骨是 特别容易受到氧化应激的影响，代表了至关重要但具有挑战性的组织靶标。因此，这个 提案的重点是询问MNO2 NP介导的软骨保护的机制，同时测试 MNO2 NP在体内疾病模型中的功效。中心假设是MNO2 NP会减轻氧化 关节损伤后的压力并防止或延迟OA的发作。在AIM 1中，我们将研究如何使用摄取机制 MNO2 NP的细胞内定位会影响室特异性ROS清除和营救能力 软骨细胞中的特定抗氧化途径。此外，细胞内靶向与 将确定氧化还原信号传导，软骨保护和抗炎作用的细胞外保留。 在AIM 2中，我们将评估MNO2 NP处理对A中氧化应激和OA进展的影响 创伤后OA（PTOA）的大鼠模型。我们将全面评估粒子在 调节ROS在体内，减轻与OA相关的组织学和生化（滑液）的变化，并且 通过行为分析缓解与OA相关的疼痛和残疾。拟议的工作将推动新的ROS 清除治疗PTOA的策略，通过交付来克服持续的挑战 抗氧化剂。拟议的工作还将揭示细胞内递送涉及的关键机制 软骨细胞以及抗氧化剂递送的位置和时间如何影响疾病机制。机械 我们在这里提出的全面方法是为了表征MNO2 NP的ROS清除的影响 可能会促进该和/或其他抗氧化剂的联合伤害策略的长期成功翻译 疾病。