目的 制备负载二氢杨梅素（ Dmy）的类沸石咪唑酯骨架材料-8（ ZIF-8）纳米粒（ Dmy@ZIF-8），对其理化性质进行表征，并在体内外评价其抗肿瘤活性。方法 浸渍法制备Dmy@ZIF-8纳米粒。单因素考察Dmy@ZIF-8纳米粒制备的主要影响因素，选择ZIF-8与Dmy质量比、Dmy质量浓度和制备时间作为主要影响因素，使用Box-Behnken设计-效应面法优化Dmy@ZIF-8纳米粒处方工艺。采用X-射线粉末衍射法（XRPD）、傅里叶红外光谱法（FT-IR）、扫描电镜（SEM）进行表征，考察Dmy@ZIF-8纳米粒在pH 5.5、6.5、7.4磷酸盐缓冲液中释药情况。采用MTT法和Annexin V/PI双染法考察Dmy@ZIF-8纳米粒对Hep3B细胞的抑制及促凋亡作用。应用Hep3B细胞建立肝癌小鼠模型，考察Dmy@ZIF-8纳米粒体内抗肿瘤效果。结果 Dmy@ZIF-8纳米粒最佳处方为： ZIF-8与Dmy质量比2.43∶ 1，Dmy质量浓度1.51 mg·mL^-1，制备时间24.50 h。Dmy@ZIF-8纳米粒的包封率、载药量、平均粒径和ζ电位分别为（ 85.96±1.17）%、（ 24.96±0.25）%、（ 53.49±4.17） nm、-（ 15.69±1.04） mV。Dmy@ZIF-8纳米粒大小均匀，Dmy在Dmy@ZIF-8纳米粒中转变为无定形态，Dmy@ZIF-8纳米粒在pH 5.0、5.5磷酸盐缓冲液中释药行为符合Weibull模型，体外释药具有pH敏感性。MTT法结果显示，Dmy和Dmy@ZIF-8纳米粒对Hep3B细胞半数抑制浓度（ IC₅₀）分别为74.16、55.89 μg·mL^-1。体内药效学实验结果表明，与模型组相比较，Dmy@ZIF-8纳米粒显著抑制荷瘤裸鼠的肿瘤生长，Dmy@ZIF-8纳米粒组（25 mg·kg^-1）抑瘤率达66.28%。结论 成功制备了具有良好理化性质和pH敏感性的Dmy@ZIF-8纳米粒，显著提高Dmy体内外抗肿瘤活性。

Objective To prepare dihydromyricetin (Dmy) loaded by zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (Dmy@ZIF-8), characterize its physicochemical properties, evaluate its antitumor effects in vivo and in vitro. Methods Dmy@ZIF-8 nanoparticles were prepared by impregnation method. The main influencing factors of Dmy@ZIF-8 nanoparticles were investigated by single factor, and the mass ratio of ZIF-8 to Dmy, the mass concentration of Dmy and the preparation time were selected as the main influencing factors. Box-Behnken response surface design method was employed to optimize prescriptions of Dmy@ZIF-8 nanoparticles. X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM) were used for characterization. The drug release behavior of Dmy@ZIF-8 nanoparticles in phosphate buffer solution with pH 5.5, 6.5, 7.4 was investigated. MTT method and Annexin V/PI double staining method were used to investigate the inhibitory and proapoptotic effects of Dmy@Z-8 nanoparticles on Hep3B cells, respectively. Hep3B cell was used to establish the mouse model of hepatocellular carcinoma, and the in vivo antitumor effect of Dmy@IF-8 nanoparticles was investigated. Results Optimal formulation of Dmy@ZIF-8 nanoparticles as follows: mass ratio of ZIF-8 to Dmy was 2.43∶ 1, mass concentration of Dmy was 1.51 mg·mL^-1, and preparation time was 24.50 h. Envelopment efficiency, drug loading, average particle size and ζ potential were (85.96 ±1.17) %, (24.96 ±0.25) %, (53.49 ±4.17) nm and -(15.69 ±1.04) mV, respectively. Dmy@ZIF-8 nanoparticles were uniform in size. Dmy was transformed into amorphous state in Dmy@ZIF-8 nanoparticles. Drug release behavior of Dmy@ZIF-8 nanoparticles accorded with Weibull model in phosphate buffer solution with pH 5.5 and 6.5, and the in vitro drug release was pH sensitive. MTT method results shows that IC₅₀ of Dmy and Dmy@ZIF-8 nanoparticles on Hep3B cells were 74.6, 55.89 μg·mL^-1, respectively. In vivo pharmacodynamic experiment results shows that Dmy@ZIF-8 nanoparticles significantly inhibited tumor growth in nude mice comparing to model group, and tumor inhibition rate of Dmy@ZIF-8 nanoparticles group (25 mg·kg^-1) was 66.28%. Conclusion Dmy@ZIF-8 nanoparticles with excellent physicochemical properties and pH sensitivity were successfully prepared, significantly enhancing the in vitro and in vivo anti-tumor effects of Dmy.

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河南省教育厅高等学校重点科研项目（24B310010）；山西省中医药科技创新工程项目（2023kjzy009）