Department of Bionanotechnology and Bioconvergence Engineering, Jeonbuk National University, Jeonju, Jeonbuk, 54896, Republic of Korea.
Department of Bionanotechnology and Bioconvergence Engineering, Jeonbuk National University, Jeonju, Jeonbuk, 54896, Republic of Korea; Department of Polymer Nano Science and Technology, Jeonbuk National University, Jeonju, Jeonbuk, 54896, Republic of Korea.
Biomaterials. 2022 May;284:121515. doi: 10.1016/j.biomaterials.2022.121515. Epub 2022 Apr 8.
Self-assembling prodrugs are able to form stable nanoparticles without additional excipients and therefore have gained increasing interest in the field of drug delivery. As a natural derivative of vitamin A, all-trans retinoic acid (atRA) exerts antioxidant, anti-inflammatory, and immunostimulatory effects. However, the clinical translation of atRA has been hampered by its insufficient therapeutic efficacy. In this work, to fully maximize the therapeutic potential of atRA, we developed delicately designed self-assembling RABA (atRA-based hybrid prodrug) as a hybrid prodrug of atRA and hydroxybenzyl alcohol (HBA). RABA could form nanoassemblies and decompose to release atRA and HBA simultaneously in response to hydrogen peroxide (HO). In a mouse model of hepatic ischemia/reperfusion (IR) injury, RABA nanoassemblies accumulated in liver preferentially and exerted highly potent antioxidant, anti-inflammatory, and antiapoptotic effects, leading to effective protection of liver from IR injury. RABA nanoassemblies exhibited significantly higher therapeutic efficacy than the combination of equivalent atRA and HBA. Given its HO-responsiveness, self-assembling and self-immolating behaviors, and cooperative therapeutic actions, RABA nanoassemblies have great potential as a pure nanodrug for hepatic IR injury. This study also provides a new valuable addition in the development of prodrug self-assemblies that will emerge as next generation of drugs.
自组装前药能够在没有额外辅料的情况下形成稳定的纳米颗粒，因此在药物传递领域引起了越来越多的关注。全反式视黄酸（atRA）作为维生素 A 的天然衍生物，具有抗氧化、抗炎和免疫刺激作用。然而，atRA 的临床转化受到其治疗效果不足的限制。在这项工作中，为了充分发挥 atRA 的治疗潜力，我们设计了精巧的自组装 RABA（基于视黄酸的杂合前药）作为 atRA 和羟基苯甲醇（HBA）的杂合前药。RABA 可以在过氧化氢（HO）的响应下形成纳米组装体并同时分解释放出 atRA 和 HBA。在肝缺血/再灌注（IR）损伤的小鼠模型中，RABA 纳米组装体优先积聚在肝脏中，发挥出强大的抗氧化、抗炎和抗凋亡作用，有效保护肝脏免受 IR 损伤。RABA 纳米组装体的治疗效果明显优于等效的 atRA 和 HBA 的组合。鉴于其对 HO 的响应性、自组装和自燃烧行为以及协同治疗作用，RABA 纳米组装体具有作为肝 IR 损伤的纯纳米药物的巨大潜力。这项研究还为前药自组装的发展提供了新的有价值的补充，它将成为下一代药物。
