橙皮素负载ZIF-8的一锅法制备及肿瘤微酸响应释药行为

One-pot Preparation of Hesperetin-loaded ZIF-8 for Tumor Acidic Microenvironment-responsive Drug Release

摘要

采用一锅法将橙皮素（HES）引入沸石咪唑酯骨架-8（Zeolitic imidazolate framework-8，ZIF-8），构建了HES@ZIF-8纳米复合材料.利用扫描电子显微镜、透射电子显微镜、X射线衍射、傅里叶变换红外光谱、氮气吸附-脱附及热重分析等对其形貌、晶体结构、孔结构及热稳定性进行了系统表征，并测定了其载药率及不同pH值下的体外释放行为.结果表明，HES@ZIF-8被成功构建，负载后颗粒仍保持ZIF-8规则多面体形貌及特征晶体骨架，说明HES的引入未破坏主体框架结构；孔结构参数及热失重行为的变化进一步证实HES已有效整合进入ZIF-8体系，载药率达72.0%.体外释药研究显示，HES@ZIF-8具有显著的pH值依赖性释放特征，在pH值为7.4，6.5和5.5时的累积释放率分别为42.9%，72.6%和92.9%；酸性条件下颗粒骨架明显解离，表明其加速释放与ZIF-8的酸诱导结构破坏密切相关.体外细胞实验结果表明，HES@ZIF-8在0~40 μg/mL浓度范围内对正常成纤维细胞（L929）具有较好的生物相容性；同时，HES@ZIF-8可降低CAL-27和SACC细胞活力，抑制细胞迁移并促进其凋亡，其中对SACC细胞作用更为明显.上述体外实验结果表明，HES@ZIF-8兼具结构保持性负载与肿瘤微酸环境响应释放特征，提示其具有潜在的研究价值，可为天然小分子/金属有机框架复合智能递药材料的设计及机制研究提供实验依据.

Abstract

Hesperetin（HES）was incorporated into the zeolitic imidazolate framework-8（ZIF-8）via a one-pot method to construct HES@ZIF-8 nanocomposites. The morphology，crystal structure，pore structure，and thermal stability were systematically characterized using scanning electron microscopy，transmission electron microscopy，X-ray diffraction，Fourier transform infrared spectroscopy，nitrogen adsorption-desorption，and thermogravimetric analysis. Furthermore，the drug-loading capacity and in vitro release behavior under different pH values were evaluated. The results demonstrate the construction of HES@ZIF-8，which retained the regular polyhedral morphology and characteristic crystal framework of ZIF-8 after HES loading，indicating that the introduction of HES did not disrupt the host framework structure. Changes in pore structure parameters and thermal mass loss behavior further confirmed the effective integration of HES into the ZIF-8 system，achieving a drug-loading capacity of 72.0%.In vitro drug release studies revealed that HES@ZIF-8 exhibited a pronounced pH value-dependent release profile，with cumulative release rates of 42.9%，72.6%，and 92.9% at pH value of 7.4，6.5，and 5.5，respectively. The significant dissociation of the particle framework under acidic conditions indicates that the accelerated release is closely related to the acid-induced structural disruption of ZIF-8.In vitro cellular experiments showed that HES@ZIF-8 possessed good biocompatibility with normal fibroblasts（L929）within a working concentration range of 0—40 μg/mL. Concurrently，the material decreased the viability of oral squamous cell carcinoma（OSCC，CAL-27）and salivary adenoid cystic carcinoma（SACC），inhibited cell migration，and promoted apoptosis，with a more pronounced effect observed in SACC cells. These in vitro findings preliminarily suggest that HES@ZIF-8 features structure-retaining loading and tumor microacidic environment-responsive release，providing an experimental basis for further research on natural small molecule/metal-organic framework composite drug delivery systems.

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