Manganese dioxide as a nanozyme to mitigate oxidative stress in osteoarthritis

二氧化锰作为纳米酶可减轻骨关节炎的氧化应激

• 批准号: 10751638
• 负责人: Jessica L Aldrich
• 金额: $ 4.24万
• 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: 2023-08-16 至 2025-08-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751638
• 关键词: Address; Advanced Development; Affect; Antioxidants; Arthralgia; Behavior; Binding Sites; Biocompatible Materials; Biological Availability; Biological Factors; Cartilage; Characteristics; Charge; Chondrocytes; Chronic; Classification; Clinic; Contralateral; Degenerative polyarthritis; Development; Disease; Disease Progression; Drug Delivery Systems; Engineering; Enzymes; Etiology; Evaluation; Feedback; Generations; Histologic; Homeostasis; Hydrogen Peroxide; In Vitro; Inflammation; Inflammatory; Injury; Interruption; Joints; Knee Injuries; Laboratory Research; Learning; Limb structure; Location; Manganese; Masks; Measures; Mitochondria; Modeling; Motivation; Orthopedics; Oxidation-Reduction; Oxidative Stress; Oxygen; Pain; Pathogenesis; Pathology; Peroxidases; Persons; Play; Production; Property; Public Health; Reactive Oxygen Species; Research; Rodent; Rodent Model; Role; Signal Transduction; Structure; Superoxides; Tactile; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Training; Translating; Traumatic Arthropathy; Treatment Efficacy; United States; Water; Work; aging population; antioxidant therapy; arthropathies; cartilage degradation; catalase; chondroprotection; conventional therapy; cost; disability; effective therapy; gait examination; improved; in vivo; inflammatory marker; injured; innovation; insight; joint destruction; joint function; joint injury; metal oxide; mitochondrial dysfunction; nanomaterials; nanoparticle; nanoparticle delivery; novel; preservation; prevent; sensor; small molecule; targeted treatment; therapeutic target; training opportunity; translational approach; translational medicine; translational potential; uptake

PROJECT SUMMARY In this proposal, we aim to characterize the multi-enzymatic and chondroprotective functions of a bioactive biomaterial, manganese dioxide (MnO2) nanoparticles (NPs), as a therapeutic strategy to mitigate oxidative stress in osteoarthritis (OA). The motivation for this work is the critical need to address limitations for treating OA as a looming public health crisis, projected to affect 130 million people worldwide by 2050 due to an aging population. Oxidative stress, the imbalance between reactive oxygen species (ROS) generation and antioxidant function, is known to contribute to OA progression and may represent an important therapeutic target. There have been numerous studies to evaluate the use of antioxidants and small molecules as therapeutic agents, however these therapies are limited by poor bioavailability and stability within the joint. The objective of this proposal is to utilize a metal-oxide biomaterial (MnO2) to overcome limitations of retention and bioavailability and seeks to explore enzyme-mimicking functions to reduce the effects of oxidative stress. We have previously shown that MnO2 can be engineered with cartilage-targeting properties, such as size and charge, that can overcome limitations of traditional antioxidant therapies. Leveraging these properties we have seen improved retention of MnO2 NPs in healthy and OA joints. Due to the barriers for targeting cartilage, this advancement is critical in the development of a chondroprotective therapy. We hypothesize that MnO2 NPs possess enzyme mimicking properties that will reduce oxidative stress in the joint thereby alleviating pain and disease pathogenesis. Characterization of enzyme mimicking functions is critical in the use of MnO2 NPs for biomedical applications and may further classify the biomaterial as a ‘nanozyme.’ Our lab has already characterized the hydrogen peroxide scavenging properties of MnO2 NPs and we anticipate ‘nanozyme’ classification will outline catalase-like, superoxide-like, and peroxidase-like functions of MnO2. In Aim 1, we will examine how MnO2 NPs influence compartment specific H2O2 production and the downstream effects of oxidative stress. Specifically, we will characterize the antioxidant-like properties of MnO2 NPs and their impact on redox signaling, chondroprotection, and inflammatory effects. In Aim 2 we will evaluate the therapeutic efficacy of MnO2 NPs in vivo using a rodent model of post traumatic OA (PTOA) through comprehensive evaluation of NP retention in the joint, joint remodeling, and behavior. Immediate treatment following joint trauma, which leads to PTOA, is a critical opportunity for translation of a cartilage targeting therapy by leveraging cartilage that is still intact and may be responsive to mitigating oxidative stress. The proposed work is significant and innovative by revealing key mechanisms for mitigating oxidative stress and advancing the use of an enzyme-mimicking therapy that may facilitate translation of strategies to slow the progression of joint disease.

项目摘要 在此提案中，我们旨在表征A的多酶和软骨保护功能 生物活性生物材料，锰二氧化碳（MNO2）纳米颗粒（NPS），作为一种治疗策略 减轻骨关节炎（OA）中的氧化应激。这项工作的动力是解决 将OA视为迫在眉睫的公共卫生危机的限制，预计将影响全球1.3亿人 2050年由于人口老龄化。 氧化应激，活性氧（ROS）产生与抗氧化剂之间的失衡 已知功能有助于OA进展，可能代表一个重要的治疗靶点。那里 已经进行了许多研究来评估抗氧化剂和小分子作为治疗剂的使用， 但是，这些疗法受到关节内的生物利用度和稳定性的限制。这个目的 建议是利用金属氧化物生物材料（MNO2）来克服保留率和生物利用度的限制 并试图探索模仿酶的功能，以减少氧化应激的影响。我们以前有 表明MNO2可以用软骨靶向特性（例如大小和电荷）进行设计，可以 克服传统抗氧化剂疗法的局限性。利用这些属性，我们已经改善了 在健康和OA关节中保留MNO2 NP。由于靶向软骨的障碍，这种进步是 对于软骨保护疗法的发展至关重要。我们假设MNO2 NP具有酶 模仿将减少关节中氧化应激的特性，从而减轻疼痛和疾病 发病。 模仿酶的表征对于使用MNO2 NP进行生物医学至关重要 应用，并可能进一步将生物材料分类为“纳米酶”。我们的实验室已经表征了该生物材料 MNO2 NPS的过氧化氢清除特性，我们预计“纳米酶”分类将概述 MNO2的类似过氧化氢酶样，超氧化物样和过氧化物酶样功能。在AIM 1中，我们将研究MNO2 NP 影响区室特异性H2O2的产生和氧化应激的下游效应。具体来说， 我们将表征MNO2 NP的类似抗氧化剂的特性及其对氧化还原信号的影响， 软骨保护和炎症作用。在AIM 2中，我们将评估MNO2 NP的治疗效率 通过对NP保留的全面评估，使用后创伤后OA（PTOA）的啮齿动物模型 关节，关节重塑和行为。联合创伤后立即治疗，导致PTOA，是一个 通过利用仍然完好无损的软骨来翻译软骨靶向治疗的关键机会 可能会响应缓解氧化应激。拟议的工作是重要的，并且通过揭示 减轻氧化应激的关键机制，并推进模仿酶的疗法的使用 可能有助于转化降低关节疾病进展的策略。