Department of Bionanotechnology and Bioconvergence Engineering, Jeonbuk National University, Jeonju, Chonbuk 54896, Republic of Korea.
Department of Polymer Nano Science and Technology, Jeonbuk National University, Jeonju, Chonbuk 54896, Republic of Korea.
ACS Nano. 2023 Jul 11;17(13):12336-12346. doi: 10.1021/acsnano.3c01503. Epub 2023 Jun 29.
-retinoic acid (atRA) has potent anti-inflammatory and antiplatelet activity, but its clinical translation as an antithrombotic drug has been hampered by its low therapeutic efficacy. Here, we describe a facile and elegant strategy that converts atRA into systemically injectable antithrombotic nanoparticles. The strategy involves the dimerization of two atRA molecules using a self-immolative boronate linker that is cleaved specifically by hydrogen peroxide (HO) to release anti-inflammatory hydroxybenzyl alcohol (HBA), followed by dimerization-induced self-assembly to generate colloidally stable nanoparticles. The boronated atRA dimeric prodrug (BRDP) could form injectable nanoparticles in the presence of fucoidan that serves as an emulsifier and a targeting ligand to P-selectin overexpressed on the damaged endothelium. In response to HO, fucoidan-decorated BRDP (f-BRDP) nanoassemblies dissociate to release both atRA and HBA, while scavenging HO. In a mouse model of ferric chloride (FeCl)-induced carotid arterial thrombosis, f-BRDP nanoassemblies target the thrombosed vessel and significantly inhibit thrombus formation. The results demonstrate that dimerization of atRA molecules via a boronate linker enables the formation of stable nanoassemblies with several benefits: high drug loading, drug self-delivery, on-demand multiple antithrombotic actions, and simple fabrication of nanoparticles. Overall, this strategy provides a promising expedient and practical route for the development of translational self-deliverable antithrombotic nanomedicine.
视黄酸（atRA）具有很强的抗炎和抗血小板活性，但由于其治疗效果低，其作为抗血栓药物的临床转化受到阻碍。在这里，我们描述了一种简便而优雅的策略，将 atRA 转化为可系统注射的抗血栓纳米粒子。该策略涉及使用自耗竭硼酸酯键将两个 atRA 分子二聚化，该键可被过氧化氢（HO）特异性切割，释放抗炎的羟基苄醇（HBA），然后通过二聚诱导自组装生成胶体稳定的纳米粒子。硼酸酯化的 atRA 二聚体前药（BRDP）可在褐藻胶存在下形成可注射的纳米粒子，褐藻胶作为乳化剂和靶向配体与损伤内皮细胞上过度表达的 P 选择素结合。响应 HO，褐藻胶修饰的 BRDP（f-BRDP）纳米组装体解离，释放出 atRA 和 HBA，同时清除 HO。在氯化铁（FeCl）诱导的颈动脉血栓形成的小鼠模型中，f-BRDP 纳米组装体靶向血栓形成的血管，显著抑制血栓形成。结果表明，通过硼酸酯键将 atRA 分子二聚化能够形成稳定的纳米组装体，具有以下几个优点：高载药量、药物自递送、按需进行多种抗血栓作用，以及纳米粒子的简单制备。总体而言，该策略为开发可转化的自递送抗血栓纳米医学提供了一种有前途的简便实用途径。
