Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China.
J Control Release. 2017 Jan 28;246:133-141. doi: 10.1016/j.jconrel.2016.12.027. Epub 2016 Dec 28.
Effective treatment for rheumatoid arthritis is hindered by the lack of drugs that selectively target inflamed joints. Liposomes, nanoparticles and conventional micelles loaded with limited amounts of drugs may be unstable in the circulation and result in uncontrolled drug release kinetics. Here we developed a new drug delivery system of pH-sensitive polymeric micelles based on an acid-labile hydrazone bond. Amphiphilic conjugates of a PEG-based derivative and the hydrophobic drug prednisolone (PD) self-assembled into PD micelles with a drug loading of 19.29%. When the micelles reached the acidic environment of synovial fluid, the hydrazone bonds hydrolyzed, releasing free PD. Intravenous injection of PD micelles into mice with collagen-induced arthritis led to PD accumulation in affected joint tissues. PD concentrations in plasma and joints of arthritic mice were significantly higher after injection with PD micelles than after injection with free PD. The enhancement effect in joints was 4.63-fold based on the area under the concentration-time curve and 2.50-fold based on the maximum concentration (C). In vivo pharmacodynamics experiments showed PD micelles to have better anti-inflammatory and disease-modifying effects than free PD. Our results indicate the promise of PD micelles for targeted drug delivery in inflammatory disease.
类风湿性关节炎的有效治疗受到缺乏靶向炎症关节的药物的阻碍。载药有限的脂质体、纳米颗粒和常规胶束在循环中可能不稳定，导致药物释放动力学失控。在这里，我们开发了一种基于酸不稳定腙键的新型 pH 敏感聚合物胶束药物递送系统。基于聚乙二醇的衍生物和亲脂性药物泼尼松龙（PD）的两亲性缀合物自组装成 PD 胶束，载药量为 19.29%。当胶束到达滑液的酸性环境时，腙键水解，释放游离 PD。将 PD 胶束静脉注射到胶原诱导关节炎的小鼠中，导致 PD 在受累关节组织中积累。与注射游离 PD 相比，关节炎小鼠的血浆和关节中 PD 的浓度在注射 PD 胶束后显著升高。基于浓度-时间曲线下面积的增强效应为 4.63 倍，基于最大浓度（C）的增强效应为 2.50 倍。体内药效学实验表明，PD 胶束比游离 PD 具有更好的抗炎和疾病修饰作用。我们的结果表明 PD 胶束有望用于炎症性疾病的靶向药物递送。
