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 在这个建议中，我们的目标是表征多酶和软骨保护功能的一个 生物活性生物材料，二氧化锰（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。这项工作的动机是迫切需要解决 将OA作为迫在眉睫的公共卫生危机进行治疗的局限性，预计将影响全球1.3亿人， 2050年，由于人口老龄化。 氧化应激，即活性氧（ROS）生成和抗氧化剂之间的失衡 功能，已知有助于OA进展，并可能代表重要的治疗靶点。那里 已经有许多研究来评价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较差的生物利用度和稳定性的限制。的目的 建议利用金属氧化物生物材料（MnO 2）来克服保留和生物利用度的限制 并试图探索酶模拟功能以减少氧化应激的影响。我们先前已经 显示MnO2可以被设计成具有软骨靶向特性，例如尺寸和电荷， 克服了传统抗氧化疗法的局限性。利用这些特性，我们看到 MnO2 NPs在健康和OA关节中的保留。由于靶向软骨的障碍，这一进展是 在软骨保护疗法的发展中至关重要。我们假设MnO2纳米颗粒具有酶 模仿将减少关节中的氧化应激从而减轻疼痛和疾病的特性 发病机制 酶模拟功能的表征在MnO2 NPs用于生物医学用途中至关重要。 应用，并且可以进一步将生物材料分类为"纳米酶"。我们的实验室已经鉴定了 MnO2纳米颗粒的过氧化氢清除性能和我们预期的“纳米酶”分类将概述 MnO2的过氧化氢酶样、超氧化物酶样和过氧化物酶样功能。在目标1中，我们将研究MnO 2 NPs 影响隔室特异性H2O2产生和氧化应激的下游效应。具体地说， 我们将表征MnO2纳米颗粒的抗氧化剂样性质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在以下患者中的治疗效果： 体内使用创伤后OA（PTOA）的啮齿动物模型，通过综合评价NP保留， 关节、关节重塑和行为。关节创伤后立即治疗，导致PTOA，是一种 这是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。本文的工作具有重要意义和创新性， 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翻译。