Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology and Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, P. R. China.
Laboratory of Controllable Nanopharmaceuticals, CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 First North Road, Zhongguancun, Beijing 100190, P. R. China.
Nano Lett. 2020 Apr 8;20(4):2558-2568. doi: 10.1021/acs.nanolett.9b05340. Epub 2020 Mar 13.
Given the physically encapsulated payloads with drug burst release and/or low drug loading, it is critical to initiate an innovative prodrug strategy to optimize the design of modular nanomedicines. Here, we designed modular pH-sensitive cetone-based etal-linked rodrugs of amethasone (AKP-dexs) and formulated them as nanoparticles. We comprehensively studied the relationships between AKP-dex structure and properties, and we selected two types of AKP-dex-loaded nanoparticles for in vivo studies on the basis of their size, drug loading, and colloidal stability. In a collagen-induced arthritis rat model, these AKP-dex-loaded nanoparticles showed higher accumulation in inflamed joints and better therapeutic efficacy than free dexamethasone phosphate with less-severe side effects. AKP-dex-loaded nanoparticles may be useful for treating other inflammatory diseases and thus have great translational potential. Our findings represent an important step toward the development of practical applications for acetone-based ketal-linked prodrugs and are useful in the design of modular nanomedicines.
鉴于具有药物爆发释放和/或低药物载量的物理包裹的有效载荷，启动创新前药策略以优化模块化纳米药物的设计至关重要。在这里，我们设计了基于酮的基于酮的阿美曲汀（AKP-dexs）的模块化 pH 敏感的 etal 连接的前药，并将其制成纳米颗粒。我们全面研究了 AKP-dex 结构与性能之间的关系，并根据其大小、载药量和胶体稳定性选择了两种类型的 AKP-dex 负载的纳米颗粒进行体内研究。在胶原诱导的关节炎大鼠模型中，与游离地塞米松磷酸酯相比，这些载有 AKP-dex 的纳米颗粒在炎症关节中的积累更高，治疗效果更好，副作用更轻。载有 AKP-dex 的纳米颗粒可能对治疗其他炎症性疾病有用，因此具有很大的转化潜力。我们的研究结果代表了在开发基于丙酮的缩酮连接前药的实际应用方面迈出的重要一步，并且对模块化纳米药物的设计很有用。
