Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia.
Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia; Australian Research Council Centre for Nanoscale Biophotonics, Macquarie University, Sydney, NSW 2109, Australia.
Eur J Pharm Sci. 2019 Oct 1;138:105038. doi: 10.1016/j.ejps.2019.105038. Epub 2019 Aug 6.
Antioxidants play a vital role in scavenging reactive oxygen species (ROS) produced by the reduction of molecular oxygen from various cellular mechanisms. Under oxidative stress, an increase in the levels of ROS overwhelms the antioxidant response, causing oxidative damage to biological molecules, and leading to the development of various diseases. Drug compounds with potent antioxidant properties are typically poorly water soluble and highly hydrophobic. An extreme case is Probucol (PB), a potent antioxidant with reported water solubility of 5 ng/ml, and oral bioavailiability of <10%. In this study, PB was loaded in mesoporous silica at various drug loadings to understand the changes to the physical properties of the loaded drug, and it's in vitro drug release. Further in vitro studies were conducted in endothelial and microglia cell models to compare the free radical scavening efficiency of ascorbic acid, PB, and PB release from mesoporous silica particles. Out of the three different mesostructured particles studied, the maximum loading of PB was achieved for large pore mesoporous particles (SBA-15) at 50 wt% drug loading, before complete pore filling was observed. For all materials, loadings above complete pore filling resulted in the recrystallization of PB on the external surface. In vitro drug release measurements showed a rapid dissolution rate at low drug loadings compared to a bimodal release profile of amorphous and crystalline drug at higher drug loadings. PB loaded in mesoporous particle was shown to enhance the antioxidant response to extracellular ROS in the endothelial cell line model, and to intracellular ROS in the microglia cell model. Our results indicate that the antioxidant properties of PB can be significantly improved by using mesoporous silica as a delivery vehicle.
抗氧化剂在清除各种细胞机制中从分子氧还原产生的活性氧（ROS）方面发挥着至关重要的作用。在氧化应激下，ROS 水平的增加超过了抗氧化反应，导致生物分子发生氧化损伤，并导致各种疾病的发生。具有强抗氧化特性的药物化合物通常水溶性差且高度疏水。一个极端的例子是 Probucol（PB），一种具有报道的水溶性为 5ng/ml 和口服生物利用度<10%的强抗氧化剂。在这项研究中，将 PB 以不同的药物载药量载入介孔硅中，以了解载药后物理性质的变化及其体外药物释放情况。进一步在血管内皮细胞和小胶质细胞模型中进行了体外研究，以比较抗坏血酸、PB 和 PB 从介孔硅颗粒中释放的自由基清除效率。在所研究的三种不同的介孔颗粒中，在观察到完全孔填充之前，最大载药量达到了大孔介孔颗粒（SBA-15）的 50wt%药物载药量。对于所有材料，载药量高于完全孔填充会导致 PB 在外部表面重新结晶。体外药物释放测量结果表明，与较高药物载药量时无定形和结晶药物的双峰释放曲线相比，低药物载药量时药物释放速度更快。负载在介孔颗粒中的 PB 被证明可以增强内皮细胞系模型中细胞外 ROS 的抗氧化反应，并增强小胶质细胞模型中细胞内 ROS 的抗氧化反应。我们的结果表明，使用介孔硅作为递送载体可以显著提高 PB 的抗氧化性能。
