Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
Dr. JT Macdonald Foundation Biomedical Nanotechnology Institute of the University of Miami, Miami, Florida 33136, United States.
Mol Pharm. 2022 Jul 4;19(7):2254-2267. doi: 10.1021/acs.molpharmaceut.2c00079. Epub 2022 May 4.
The United States is in the midst of an opioid epidemic that is linked to a number of serious health issues, including an increase in cerebrovascular events, namely, stroke. Chronic prescription opioid use exacerbates the risk and severity of ischemic stroke, contributing to stroke as the fifth overall cause of death in the United States and costing the US health care system over $30 billion annually. Pathologically, opioids challenge the integrity of the blood-brain barrier (BBB), resulting in a dysregulation of tight junction (TJ) proteins that are crucial in maintaining barrier homeostasis. Despite this, treatment options for ischemic stroke are limited, and there are no pharmacological options to attenuate TJ damage, including in incidents that are linked to opioid use. Herein, we have generated carrier-free, pure "nanodrugs" or nanoparticles of naloxone and naltrexone with enhanced therapeutic properties compared to the original (parent) drugs. The generated nanoformulations of both opioid antagonists exhibited successful attenuation of morphine- or oxycodone-induced alterations of TJ protein expression and reduced oxidative stress to a greater extent than the parent drugs (non-nano). As a proof of concept, we then proceeded to evaluate the therapeutic effectiveness of the generated nanodrugs in an ischemic stroke model of mice exposed to morphine or oxycodone. Our results demonstrate that the opioid antagonist nanoformulations reduced stroke severity in mice. Overall, this research implements advances in nanotechnology-based repurposing of FDA-approved therapeutics, and the obtained results also suggest underlying pharmacological mechanisms of opioid antagonists, further supporting these opioid antagonists and their respective nanoformulations as potential therapeutic agents for ischemic stroke.
美国正处于阿片类药物泛滥的困境之中，这与许多严重的健康问题有关，包括脑血管事件（即中风）的增加。慢性处方类阿片药物的使用加剧了缺血性中风的风险和严重程度，导致中风成为美国的第五大致死原因，并使美国医疗保健系统每年花费超过 300 亿美元。从病理上看，阿片类药物挑战了血脑屏障（BBB）的完整性，导致紧密连接（TJ）蛋白的失调，而 TJ 蛋白在维持屏障内环境稳定方面至关重要。尽管如此，缺血性中风的治疗选择仍然有限，而且没有药理学选择来减轻 TJ 损伤，包括与阿片类药物使用有关的损伤。在此，我们生成了无载体、纯“纳米药物”或纳洛酮和纳曲酮纳米颗粒，与原始（母体）药物相比，具有增强的治疗特性。这两种阿片类拮抗剂的纳米制剂都成功地减轻了吗啡或羟考酮诱导的 TJ 蛋白表达改变，并减轻了氧化应激，其程度超过了母体药物（非纳米）。作为概念验证，我们随后在暴露于吗啡或羟考酮的小鼠缺血性中风模型中评估了所生成的纳米药物的治疗效果。我们的结果表明，阿片类拮抗剂纳米制剂减轻了小鼠的中风严重程度。总的来说，这项研究实施了基于纳米技术的重新利用 FDA 批准的治疗方法的进展，并且获得的结果还表明了阿片类拮抗剂的潜在药理学机制，进一步支持这些阿片类拮抗剂及其各自的纳米制剂作为缺血性中风的潜在治疗剂。
