Department of Surgery, Division of Vascular Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Oxid Med Cell Longev. 2018 Feb 14;2018:2468457. doi: 10.1155/2018/2468457. eCollection 2018.
Reactive oxygen and nitrogen species are indispensable in cellular physiology and signaling. Overproduction of these reactive species or failure to maintain their levels within the physiological range results in cellular redox dysfunction, often termed cellular oxidative stress. Redox dysfunction in turn is at the molecular basis of disease etiology and progression. Accordingly, antioxidant intervention to restore redox homeostasis has been pursued as a therapeutic strategy for cardiovascular disease, cancer, and neurodegenerative disorders among many others. Despite preliminary success in cellular and animal models, redox-based interventions have virtually been ineffective in clinical trials. We propose the fundamental reason for their failure is a flawed delivery approach. Namely, systemic delivery for a geographically local disease limits the effectiveness of the antioxidant. We take a critical look at the literature and evaluate successful and unsuccessful approaches to translation of redox intervention to the clinical arena, including dose, patient selection, and delivery approach. We argue that when interpreting a failed antioxidant-based clinical trial, it is crucial to take into account these variables and importantly, whether the drug had an effect on the redox status. Finally, we propose that local and targeted delivery hold promise to translate redox-based therapies from the bench to the bedside.
活性氧和氮物种在细胞生理学和信号转导中是不可或缺的。这些活性物质的过度产生或未能将其水平维持在生理范围内会导致细胞氧化还原功能障碍，通常称为细胞氧化应激。氧化还原功能障碍反过来又是疾病病因和进展的分子基础。因此，抗氧化干预以恢复氧化还原平衡已被作为心血管疾病、癌症和神经退行性疾病等多种疾病的治疗策略进行研究。尽管在细胞和动物模型中取得了初步成功，但基于氧化还原的干预措施在临床试验中实际上无效。我们提出它们失败的根本原因是输送方法有缺陷。也就是说，针对局部疾病的全身输送会限制抗氧化剂的有效性。我们仔细研究了文献，并评估了将氧化还原干预转化为临床领域的成功和不成功方法，包括剂量、患者选择和输送方法。我们认为，在解释抗氧化剂为基础的临床试验失败时，必须考虑到这些变量，重要的是，药物是否对氧化还原状态有影响。最后，我们提出局部和靶向输送有可能将基于氧化还原的治疗方法从实验室转化为临床。
