CIQUP, Centro de Investigação em Química, Departmento de Química e Bioquímica, Faculdade de Ciências , Universidade do Porto , 4169-007 , Porto , Portugal.
CESPU , Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde , 4585-116 Gandra , Portugal.
Bioconjug Chem. 2018 May 16;29(5):1677-1689. doi: 10.1021/acs.bioconjchem.8b00151. Epub 2018 Apr 19.
The uptake and transport of dietary antioxidants remains the most important setback for their application in therapy. To overcome the limitations, a PEGylated-based platform was developed to improve the delivery properties of two dietary hydroxycinnamic (HCA) antioxidants-caffeic and ferulic acids. The antioxidant properties of the new polymer-antioxidant conjugates (PEGAntiOxs), prepared by linking poly(ethylene glycol) (PEG) to the cinnamic acids by a one-step Knovenagel condensation reaction, were evaluated. PEGAntiOxs present a higher lipophilicity than the parent compounds (caffeic and ferulic acids) and similar, or higher, antioxidant properties. PEGAntiOxs were not cytotoxic at the tested concentrations in SH-SY5Y, Caco-2, and hCMEC/D3 cells. By contrast, cytotoxic effects in hCMEC/D3 and SH-SY5Y cells were observed, at 50 and 100 μM, for caffeic and ferulic acids. PEGAntiOxs operate as antioxidants against several oxidative stress-cellular inducers in a neuronal cell-based model, and were able to inhibit glycoprotein-P in Caco-2 cells. PEGAntiOxs can cross hCMEC/D3 monolayer cells, a model of the blood-brain barrier (BBB) endothelial membrane. In summary, PEGAntiOxs are valid antioxidant prototypes that can uphold the antioxidant properties of HCAs, reduce their cytotoxicity, and improve their BBB permeability. PEGAntiOxs can be used in the near future as drug candidates to prevent or slow oxidative stress associated with neurodegenerative diseases.
膳食抗氧化剂的摄取和转运仍然是其在治疗中应用的最大障碍。为了克服这些限制，开发了一种基于聚乙二醇（PEG）的平台来改善两种膳食羟基肉桂酸（HCA）抗氧化剂-咖啡酸和阿魏酸的递送特性。通过一步克诺文纳格尔缩合反应将聚乙二醇（PEG）连接到肉桂酸上，制备了新的聚合物-抗氧化剂缀合物（PEGAntiOxs），评估了其抗氧化性能。与母体化合物（咖啡酸和阿魏酸）相比，PEGAntiOxs 具有更高的亲脂性，且具有相似或更高的抗氧化性能。在 SH-SY5Y、Caco-2 和 hCMEC/D3 细胞中，以测试浓度测试时，PEGAntiOxs 没有细胞毒性。相比之下，在 hCMEC/D3 和 SH-SY5Y 细胞中，在 50 和 100 μM 时观察到咖啡酸和阿魏酸的细胞毒性作用。PEGAntiOxs 作为抗氧化剂，可针对神经细胞模型中的几种氧化应激诱导剂发挥作用，并且能够抑制 Caco-2 细胞中的糖蛋白-P。PEGAntiOxs 可以穿过 hCMEC/D3 单层细胞，这是血脑屏障（BBB）内皮膜的模型。总之，PEGAntiOxs 是有效的抗氧化原型，可以保持 HCA 的抗氧化性能，降低其细胞毒性，并提高其 BBB 通透性。PEGAntiOxs 可在不久的将来用作预防或减缓与神经退行性疾病相关的氧化应激的候选药物。
