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.

项目概要 在本提案中，我们的目标是表征多酶和软骨保护功能 生物活性生物材料，二氧化锰（MnO2）纳米粒子（NPs），作为一种治疗策略 减轻骨关节炎（OA）中的氧化应激。这项工作的动机是解决以下问题的迫切需要 将骨关节炎视为迫在眉睫的公共卫生危机的局限性，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）生成与抗氧化之间的不平衡 功能，已知有助于 OA 进展，可能是一个重要的治疗靶点。那里 已经有大量研究评估抗氧化剂和小分子作为治疗剂的用途， 然而，这些疗法受到关节内生物利用度和稳定性差的限制。此举的目的 建议利用金属氧化物生物材料（MnO2）来克服保留和生物利用度的限制 并试图探索模拟酶的功能以减少氧化应激的影响。我们之前有过 研究表明，MnO2 可以设计成具有软骨靶向特性，例如尺寸和电荷，这可以 克服传统抗氧化疗法的局限性。利用这些特性，我们已经看到了改进 MnO2 NPs 在健康关节和 OA 关节中的保留。由于针对软骨的障碍，这一进步是 对于软骨保护疗法的开发至关重要。我们假设 MnO2 NPs 具有酶 模仿可减少关节氧化应激的特性，从而减轻疼痛和疾病 发病。 酶模拟功能的表征对于 MnO2 NP 在生物医学中的应用至关重要 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 MnO2 NPs 的过氧化氢清除特性，我们预计“纳米酶”分类将概述 MnO2 的过氧化氢酶样、超氧化物样和过氧化物酶样功能。在目标 1 中，我们将研究 MnO2 NPs 如何 影响隔室特异性 H2O2 的产生和氧化应激的下游影响。具体来说， 我们将描述 MnO2 NP 的抗氧化特性及其对氧化还原信号传导的影响， 软骨保护和炎症作用。在目标 2 中，我们将评估 MnO2 NPs 在以下疾病中的治疗效果： 使用创伤后 OA (PTOA) 啮齿动物模型通过体内 NP 保留的综合评估 关节、关节重塑和行为。关节外伤导致 PTOA 后立即治疗是一种有效的方法 通过利用仍然完整的软骨来转化软骨靶向治疗的关键机会 可能对减轻氧化应激有反应。拟议的工作具有重要意义和创新性，揭示了 减轻氧化应激和促进酶模拟疗法的使用的关键机制 可能有助于减缓关节疾病进展的策略的转化。