Drug-induced hepatitis (DIH), which seriously interferes with disease treatment, is one of the most common reasons for termination of new drugs during preclinical studies or post-marketing surveillance. Although antioxidants and anti-inflammatory agents are promising, their nonspecific distribution and insolubility limit their application. Therefore, precise drug release at the disease site is an important way to alleviate DIH and avoid side effects./nMethods: A gripper-like hydrophilic cyclic phenylboronic acid (cPBA) was synthesized and a nanoprodrug (cPBA-BE) was established by coupling cPBA with hydrophobic baicalein (BE). The stimuli-responsive release properties and therapeutic effect of cPBA-BE on drug-injured hepatocyte were investigated. The biodistribution and therapeutic effect of cPBA-BE both in acetaminophen-induced acute hepatitis model and rifampicin-induced chronic hepatitis model were further evaluated./nResults: cPBA-BE conjugate could self-assemble into nanoprodrug with cPBA as the hydrophilic external layer and BE as the hydrophobic core. In HepaRG cells, cPBA-BE showed stronger cellular uptake. Due to the H₂O₂- and acid-sensitivity, cPBA-BE could achieve adequate BE release, significantly resist the depletion of GSH, mitochondrial dysfunction, downregulation of inflammation and cell apoptosis in the acetaminophen injured HepaRG cells. Biodistribution showed that cPBA-BE specifically increased the concentration of BE in the liver of DIH mice. cPBA-BE could alleviate acetaminophen-induced acute hepatitis or rifampicin-induced chronic hepatitis more effectively through relieving the oxidative stress, inflammation and block the neutrophil infiltration in liver./nConclusions: cPBA is expected to be a good platform for constructing injectable nanoprodrug with both H₂O₂ and pH-responsive properties by coupling a wide range of drugs containing o-diol. In this study, the nanoprodrug cPBA-BE was determined to be effective for alleviating the DIH.

中文翻译：

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基于Gripper样环状苯基硼酸的微环境激活纳米前药精准有效缓解药物性肝炎

药物性肝炎（DIH）严重干扰疾病治疗，是临床前研究或上市后监测期间终止新药的最常见原因之一。尽管抗氧化剂和抗炎剂很有前景，但它们的非特异性分布和不溶解性限制了它们的应用。因此，在疾病部位精准释放药物是缓解DIH、避免副作用的重要途径。/n方法：合成了一种类似抓手的亲水性环状苯基硼酸（cPBA），并通过将cPBA与疏水性黄芩素（BE）偶联建立了纳米前药（cPBA-BE）。研究了cPBA-BE对药物损伤肝细胞的刺激响应释放特性和治疗作用。进一步评价了cPBA - BE在对乙酰氨基酚诱导的急性肝炎模型和利福平诱导的慢性肝炎模型中的生物分布和治疗效果。BE 作为疏水核心。在 HepaRG 细胞中，cPBA-BE 表现出更强的细胞摄取。由于 H ₂ O ₂-和酸敏感性，cPBA-BE可以实现足够的BE释放，显着抵抗对乙酰氨基酚损伤的HepaRG细胞的GSH耗竭、线粒体功能障碍、炎症下调和细胞凋亡。生物分布表明，cPBA-BE 特异性增加了 DIH 小鼠肝脏中 BE 的浓度。cPBA-BE通过缓解肝内氧化应激、炎症反应和阻断中性粒细胞浸润，更有效地缓解对乙酰氨基酚引起的急性肝炎或利福平引起的慢性肝炎。/n结论： cPBA有望成为构建注射用纳米前药的良好平台。通过偶联多种含有o的药物，同时具有 H ₂ O _{2和 pH 响应特性}-二醇。在这项研究中，纳米前药 cPBA-BE 被确定可有效缓解 DIH。