<br>NHS-SS-NHS 交联壳聚糖纳米水凝胶的定制设计，通过 GSH 响应药物释放增强抗肿瘤功效,Biomedical Materials

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NHS-SS-NHS 交联壳聚糖纳米水凝胶的定制设计，通过 GSH 响应药物释放增强抗肿瘤功效
Biomedical Materials ( IF 3.9 ) Pub Date : 2024-05-30 , DOI: 10.1088/1748-605x/ad4e86
Cuiling Ouyang ₁ , Minxin Deng ₁ , Xiaowei Tan ₁ , Ziyi Liu ₁ , Tuo Huang ₁ , Siyu Yu ₁ , Zan Ge ₁ , Yafang Zhang ₁ , Yujun Ding ₁ , Hezhang Chen ₁ , Hui Chu ₁ , Jian Chen ₁

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传统化疗药物存在毒性高、非靶向、水溶性差等缺点，导致化疗效果不佳，限制了其临床应用。在这项工作中，通过壳聚糖（含有–NH ₂ ）和交联剂（含有NHS）之间的活性酯法成功制备了新型尺寸合适且谷胱甘肽（GSH）响应的纳米水凝胶。特别是，交联剂经过精心设计，具有二硫键（SS）以及两个末端NHS基团，即NHS-SS-NHS。这些功能赋予基于壳聚糖的交联支架具有药物装载和递送的能力，以及药物释放的 GSH 响应机制。所制备的纳米水凝胶表现出优异的性能、适用的形态、优异的载药效率（~22.5%）、合适的尺寸（~100 nm）和长期稳定性。所制备的纳米水凝胶在 10 mM GSH 中孵育后释放超过 80% 的阿霉素 (DOX)，而在正常生理缓冲液 (pH = 7.4) 中测试的最小 DOX 释放量低于 25%。卸载的纳米水凝胶对 A 549 细胞没有表现出任何明显的细胞毒性。相比之下，负载 DOX 的纳米水凝胶对 A 549 细胞表现出显着的抗肿瘤活性，尤其是在高 GSH 环境中。最后，通过荧光成像和流式细胞仪分析，异硫氰酸荧光素标记的纳米水凝胶与GSH高表达的A549细胞表现出明显的特异性结合，而与GSH低表达的A549细胞表现出明显的非特异性结合。因此，通过这种交联方法，我们目前的研究结果表明，交联壳聚糖纳米水凝胶药物载体可以提高A 549细胞的抗肿瘤效果，并可作为潜在的可注射递送载体。

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Tailored design of NHS–SS–NHS cross-linked chitosan nano-hydrogels for enhanced anti-tumor efficacy by GSH-responsive drug release

The traditional chemotherapeutic agents’ disadvantages such as high toxicity, untargeting and poor water solubility lead to disappointing chemotherapy effects, which restricts its clinical application. In this work, novel size-appropriate and glutathione (GSH)-responsive nano-hydrogels were successfully prepared via the active ester method between chitosan (containing –NH₂) and cross-linker (containing NHS). Especially, the cross-linker was elaborately designed to possess a disulfide linkage (SS) as well as two terminal NHS groups, namely NHS–SS–NHS. These functionalities endowed chitosan-based cross-linked scaffolds with capabilities for drug loading and delivery, as well as a GSH-responsive mechanism for drug release. The prepared nano-hydrogels demonstrated excellent performance applicable morphology, excellent drug loading efficiency (∼22.5%), suitable size (∼100 nm) and long-term stability. The prepared nano-hydrogels released over 80% doxorubicin (DOX) after incubation in 10 mM GSH while a minimal DOX release less than 25% was tested in normal physiological buffer (pH = 7.4). The unloaded nano-hydrogels did not show any apparent cytotoxicity to A 549 cells. In contrast, DOX-loaded nano-hydrogels exhibited marked anti-tumor activity against A 549 cells, especially in high GSH environment. Finally, through fluorescent imaging and flow cytometry analysis, fluorescein isothiocyanate-labeled nano-hydrogels show obvious specific binding to the GSH high-expressing A549 cells and nonspecific binding to the GSH low-expressing A549 cells. Therefore, with this cross-linking approach, our present finding suggests that cross-linked chitosan nano-hydrogel drug carrier improves the anti-tumor effect of the A 549 cells and may serve as a potential injectable delivery carrier.

更新日期：2024-05-30

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