Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People's Republic of China.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People's Republic of China.
Int J Nanomedicine. 2018 Apr 10;13:2129-2141. doi: 10.2147/IJN.S158585. eCollection 2018.
Morin, one of the most widely distributed flavonoids in plants, has been identified as a potent antihyperuricemic agent. Its poor water solubility and fast in vivo clearance, however, have limited its application in the treatment of hyperuricemia. In this study, a novel amphiphilic polymer (hydroxyethyl starch-deoxycholic acid [HES-DOCA]) was synthesized to overcome these limitations.
HES-DOCA conjugates with various substitution degrees were prepared by chemical grafting DOCA to HES through ester formation. The structures of the conjugates were confirmed by infrared spectroscopy and H-NMR. Physicochemical characterizations of HES-DOCA nanoparticles-loaded Morin (Morin/HES-DOCA-NPs) were studied using dynamic light scattering and transmission electron microscopy (TEM). In vitro release studies were performed to evaluate the release properties of Morin from the NPs. Subsequently, in vivo pharmacokinetic parameters of Morin/HES-DOCA-NPs were investigated in Wistar rats through intravenous administration (2 mg/kg, equivalent to Morin). Antihyperuricemic efficacy of the NPs was evaluated in a rat hyperuricemic model.
The optimized HES-based amphiphilic polymer contained approximately 10 DOCA groups per 100 anhydroglucose units of HES, which can spontaneously self-assemble to form spherical NPs as demonstrated by TEM images. Morin/HES-DOCA-NPs were monodispersed (polydispersity index = 0.05) with a mean diameter of 197 nm and exhibited a zeta potential of -14 mV. The use of DOCA as the polymer's hydrophobic segment enabled high drug loading efficiency (15.6%). After systemic administration, Morin/HES-DOCA-NPs exhibited significantly longer half-life and higher systemic exposure (elimination half-life and area under the plasma concentration-time curve) compared with free drug Morin. In a rat hyperuricemic model, treatment with Morin/HES-DOCA-NPs demonstrated superior therapeutic efficacy over Morin in decreasing serum uric acid level, increasing the uricosuric action, as well as attenuating hyperuricemia-associated inflammation in kidney of rats.
Collectively, these findings suggest that the novel HES-based NP formulation of Morin may have great potential for clinical treatment of hyperuricemia.
植物中分布最广泛的黄酮类化合物之一的杨梅素已被确定为一种有效的抗高尿酸血症药物。然而，其较差的水溶性和体内快速清除率限制了其在高尿酸血症治疗中的应用。在本研究中，合成了一种新型两亲聚合物（羟乙基淀粉-去氧胆酸[HES-DOCA]）来克服这些限制。
通过酯键形成将 DOCA 通过化学接枝到 HES 上来制备具有不同取代度的 HES-DOCA 缀合物。通过红外光谱和 H-NMR 确认了缀合物的结构。通过动态光散射和透射电子显微镜（TEM）研究了负载杨梅素的 HES-DOCA 纳米粒子（Morin/HES-DOCA-NPs）的物理化学特性。进行体外释放研究以评估 NPs 中杨梅素的释放特性。随后，通过静脉注射（2mg/kg，相当于杨梅素）在 Wistar 大鼠中研究了 Morin/HES-DOCA-NPs 的体内药代动力学参数。在大鼠高尿酸血症模型中评价了 NPs 的抗高尿酸血症功效。
优化的基于 HES 的两亲聚合物每 100 个 HES 的无水葡萄糖单元中含有约 10 个 DOCA 基团，可自发自组装形成 TEM 图像所示的球形 NPs。Morin/HES-DOCA-NPs 为单分散体系（多分散指数=0.05），平均粒径为 197nm，表现出-14mV 的 ζ 电位。使用 DOCA 作为聚合物的疏水段可以实现高药物载药量（15.6%）。与游离药物 Morin 相比，全身给药后，Morin/HES-DOCA-NPs 表现出明显更长的半衰期和更高的系统暴露（消除半衰期和血浆浓度-时间曲线下面积）。在大鼠高尿酸血症模型中，Morin/HES-DOCA-NPs 在降低血清尿酸水平、增加尿酸排泄作用以及减轻大鼠肾脏高尿酸血症相关炎症方面显示出优于 Morin 的治疗效果。
总的来说，这些发现表明，新型基于 HES 的 Morin 纳米粒子制剂可能具有治疗高尿酸血症的临床潜力。
