An insufficient drug concentration at the target site and drug efflux resulting in poor efficacy is recognized as important obstacles in tumor treatment. Herein, novel lipid nanoparticles (LNPs) with redox‐responsive properties based on disulfide bond‐contained, quercetin (Qu)‐grafted glyceryl caprylate‐caprate (Gcc) are introduced (Qu‐SS‐Gcc LNPs). Qu‐SS‐Gcc LNPs show good entrapment of paclitaxel (PTX) due to π–π stacking between the aromatic rings of Qu and PTX. In vitro experiments indicate that Qu‐SS‐Gcc LNPs can selectively respond to high levels of reducing substances by breakdown of disulfide bonds, thus achieving rapid and efficient drug release, and only dissociate rapidly in tumor cells rather than in normal cells. Meanwhile, the Qu released concomitantly with the breakdown of disulfide bonds combines with P‐gp and inhibits the drug efflux triggered by P‐gp. Using an orthotopic 4T1 mouse mammary tumor model in BALB/c mice, PTX/Qu‐SS‐Gcc LNPs exhibit superior antitumor efficacy compared to Taxol, in addition better biosafety and inhibition of chemotherapy‐triggered P‐gp overexpression are achieved. Taken together, this work designs and implements redox‐responsive drug release and drug efflux inhibition in tumor cells via modified LNPs, which not only leads to efficient drug release but also solves the problem of drug efflux that exists in stimulus‐responsive systems.

中文翻译：

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具有高捕获紫杉醇的氧化还原反应性和P-gp抑制性脂质纳米颗粒的合理设计，用于肿瘤治疗

在靶部位的药物浓度不足和药物流出导致疗效差被认为是肿瘤治疗中的重要障碍。本文介绍了基于二硫键，槲皮素（Qu）接枝的癸酸甘油酯-癸酸酯（Gcc）的具有氧化还原响应特性的新型脂质纳米颗粒（LNP）（Qu-SS-Gcc LNP）。Qu-SS-Gcc LNP由于Qu和PTX的芳环之间存在π-π堆积，因此显示出良好的紫杉醇（PTX）包封性。体外实验表明，Qu-SS-Gcc LNP可以通过分解二硫键选择性地响应高水平的还原物质，从而实现快速有效的药物释放，并且仅在肿瘤细胞而非正常细胞中快速解离。同时，与二硫键断裂同时释放的Qu与P-gp结合并抑制P-gp触发的药物外排。在BALB / c小鼠中使用原位4T1小鼠乳腺肿瘤模型，PTX / Qu‐SS‐Gcc LNP与紫杉醇相比具有更好的抗肿瘤功效，此外还具有更好的生物安全性和对化学疗法触发的P‐gp过表达的抑制作用。两者合计，这项工作设计并通过修饰的LNPs在肿瘤细胞中实现氧化还原反应性药物释放和药物外排抑制，这不仅导致有效的药物释放，而且解决了刺激反应系统中存在的药物外排问题。此外，还可以实现更好的生物安全性和抑制化学疗法触发的P-gp过表达。两者合计，这项工作设计并通过修饰的LNPs在肿瘤细胞中实现氧化还原反应性药物释放和药物外排抑制，这不仅导致有效的药物释放，而且解决了刺激反应系统中存在的药物外排问题。此外，还实现了更好的生物安全性并抑制了化学触发的P-gp过表达。两者合计，这项工作设计并通过修饰的LNPs在肿瘤细胞中实现氧化还原反应性药物释放和药物外排抑制，这不仅导致有效的药物释放，而且解决了刺激反应系统中存在的药物外排问题。