Modular Acid-Activatable Acetone-Based Ketal-Linked Nanomedicine by Dexamethasone Prodrugs for Enhanced Anti-Rheumatoid Arthritis with Low Side Effects,Nano Letters

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Modular Acid-Activatable Acetone-Based Ketal-Linked Nanomedicine by Dexamethasone Prodrugs for Enhanced Anti-Rheumatoid Arthritis with Low Side Effects
Nano Letters ( IF 9.6 ) Pub Date : 2020-03-13 , DOI: 10.1021/acs.nanolett.9b05340
Yang Xu ₁ , Jingqing Mu ₁ , Zunkai Xu ₁ , Haiping Zhong ₁ , Ziqi Chen ₁ , Qiankun Ni _{2,

3} , Xing-Jie Liang _{2,

3} , Shutao Guo ₁

Affiliation

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 acetone-based ketal-linked prodrugs of dexamethasone (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.

中文翻译：

地塞米松前药的模块化酸活化丙酮基缩酮连接纳米药物对低风湿性关节炎的增强作用

考虑到具有药物爆发释放和/或低药物装载的物理封装有效载荷，启动创新的前药策略以优化模块化纳米药物的设计至关重要。在这里，我们设计模块化pH敏感的一个基于cetone ķ等人联p的rodrugs DEX氨甲酮（AKP-dexs）并将其配制成纳米颗粒。我们全面研究了AKP-dex结构与性质之间的关系，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负载纳米颗粒进行体内研究。在胶原蛋白诱发的关节炎大鼠模型中，与游离地塞米松磷酸酯相比，这些负载AKP-dex的纳米颗粒在发炎关节中表现出更高的蓄积性和更好的治疗效果，且副作用较小。载有AKP-dex的纳米颗粒可用于治疗其他炎症疾病，因此具有巨大的翻译潜力。我们的发现代表了开发基于丙酮的缩酮连接前药的实际应用的重要一步，可用于模块化纳米药物的设计。

更新日期：2020-04-24

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