Design, Synthesis, and Biological Evaluation of Dexamethasone-Salvianolic Acid B Conjugates and Nanodrug Delivery against Cisplatin-Induced Hearing Loss
Design, Synthesis, and Biological Evaluation of Dexamethasone-Salvianolic Acid B Conjugates and Nanodrug Delivery against Cisplatin-Induced Hearing Loss
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地塞米松-丹酚酸 B 缀合物的设计、合成和生物学评价以及针对顺铂引起的听力损失的纳米药物递送
DOI：
10.1021/acs.jmedchem.0c01916
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Gang Chen
中科院分区：
文献类型：
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作者：
Ruiqin Ye;Lifang Sun;Jinghui Peng;Aixin Wu;Xiaozhu Chen;Lu Wen;Chuan Bai;Gang Chen
顺铂（CDDP）是一种广泛使用的化疗药物，但严重的耳毒性发生率高。虽然一些分子已经进入临床试验，但没有一个被美国食品和药物管理局批准用于预防或治疗CDDP诱导的听力损失。本研究通过酯键或酰胺键将地塞米松（DEX）和丹参酮酸B（SAL）共价连接，合成了两亲性药物-药物偶联物。该偶联物可自组装成载药量大、稳定性好的纳米粒。与相同浓度的DEX、SAL或它们的物理混合物相比，缀合物和纳米颗粒在体外和体内均显示出增强的耳保护作用。更重要的是，缀合物和NP几乎完全恢复了豚鼠模型中的听力，具有良好的生物相容性。免疫组织化学分析表明，结合物和纳米颗粒激活糖皮质激素受体，这可能是其保护作用的主要机制之一。
Cisplatin (CDDP) is an extensively used chemotherapeutic agent but has a high incidence of severe ototoxicity. Although a few molecules have entered clinical trials, none have been approved to prevent or treat CDDP-induced hearing loss by the Food and Drug Administration. In this study, an amphiphilic drug–drug conjugate was synthesized by covalently linking dexamethasone (DEX) and salvianolic acid B (SAL) through an ester or amide bond. The conjugates could self-assemble into nanoparticles (NPs) with ultrahigh drug loading capacity and favorable stability. Compared with DEX, SAL, or their physical mixture at the same concentrations, both conjugates and NPs showed enhanced otoprotection in vitro and in vivo. More importantly, the conjugates and NPs almost completely restored hearing in a guinea pig model with good biocompatibility. Immunohistochemical analyses suggested that conjugates and NPs activated the glucocorticoid receptor, which may work as one of the major mechanisms for their protective effects.