Mursaleen Leah, Noble Brendon, Somavarapu Satyanarayana, Zariwala Mohammed Gulrez
Centre for Nutraceuticals, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK.
Department of Pharmaceutics, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
Antioxidants (Basel). 2021 May 31;10(6):887. doi: 10.3390/antiox10060887.
Hydroxytyrosol (HT) is a natural phenolic antioxidant which has neuroprotective effects in models of Parkinson's disease (PD). Due to issues such as rapid metabolism, HT is unlikely to reach the brain at therapeutic concentrations required for a clinical effect. We have previously developed micellar nanocarriers from Pluronic F68 (P68) and dequalinium (DQA) which have suitable characteristics for brain delivery of antioxidants and iron chelators. The aim of this study was to utilise the P68 + DQA nanocarriers for HT alone, or in combination with the iron chelator deferoxamine (DFO), and assess their physical characteristics and ability to pass the blood-brain barrier and protect against rotenone in a cellular hCMEC/D3-SH-SY5Y co-culture system. Both HT and HT + DFO formulations were less than 170 nm in size and demonstrated high encapsulation efficiencies (up to 97%). P68 + DQA nanoformulation enhanced the mean blood-brain barrier (BBB) passage of HT by 50% ( < 0.0001, = 6). This resulted in increased protection against rotenone induced cytotoxicity and oxidative stress by up to 12% and 9%, respectively, compared to the corresponding free drug treatments ( < 0.01, = 6). This study demonstrates for the first time the incorporation of HT and HT + DFO into P68 + DQA nanocarriers and successful delivery of these nanocarriers across a BBB model to protect against PD-related oxidative stress. These nanocarriers warrant further investigation to evaluate whether this enhanced neuroprotection is exhibited in in vivo PD models.
羟基酪醇（HT）是一种天然酚类抗氧化剂，在帕金森病（PD）模型中具有神经保护作用。由于代谢迅速等问题，HT不太可能以临床疗效所需的治疗浓度到达大脑。我们之前已用普朗尼克F68（P68）和地喹氯铵（DQA）开发出胶束纳米载体，其具有适合抗氧化剂和铁螯合剂脑递送的特性。本研究的目的是将P68 + DQA纳米载体用于单独的HT或与铁螯合剂去铁胺（DFO）联合使用，并在细胞hCMEC/D3 - SH - SY5Y共培养系统中评估其物理特性、通过血脑屏障的能力以及对鱼藤酮的防护作用。HT和HT + DFO制剂的尺寸均小于170 nm，并显示出高包封效率（高达97%）。P68 + DQA纳米制剂使HT通过血脑屏障（BBB）的平均通过率提高了50%（<0.0001，n = 6）。与相应的游离药物治疗相比，这分别使对鱼藤酮诱导的细胞毒性和氧化应激的防护作用提高了12%和9%（<0.01，n = 6）。本研究首次证明将HT和HT + DFO掺入P68 + DQA纳米载体，并成功将这些纳米载体递送至BBB模型以抵御与PD相关的氧化应激。这些纳米载体值得进一步研究，以评估在体内PD模型中是否表现出这种增强的神经保护作用。
