目的 制備負(fù)載二氫楊梅素（ Dmy）的類沸石咪唑酯骨架材料-8（ ZIF-8）納米粒（ Dmy@ZIF-8），對其理化性質(zhì)進(jìn)行表征，并在體內(nèi)外評價(jià)其抗腫瘤活性。方法 浸漬法制備Dmy@ZIF-8納米粒。單因素考察Dmy@ZIF-8納米粒制備的主要影響因素，選擇ZIF-8與Dmy質(zhì)量比、Dmy質(zhì)量濃度和制備時(shí)間作為主要影響因素，使用Box-Behnken設(shè)計(jì)-效應(yīng)面法優(yōu)化Dmy@ZIF-8納米粒處方工藝。采用X-射線粉末衍射法（XRPD）、傅里葉紅外光譜法（FT-IR）、掃描電鏡（SEM）進(jìn)行表征，考察Dmy@ZIF-8納米粒在pH 5.5、6.5、7.4磷酸鹽緩沖液中釋藥情況。采用MTT法和Annexin V/PI雙染法考察Dmy@ZIF-8納米粒對Hep3B細(xì)胞的抑制及促凋亡作用。應(yīng)用Hep3B細(xì)胞建立肝癌小鼠模型，考察Dmy@ZIF-8納米粒體內(nèi)抗腫瘤效果。結(jié)果 Dmy@ZIF-8納米粒最佳處方為： ZIF-8與Dmy質(zhì)量比2.43∶ 1，Dmy質(zhì)量濃度1.51 mg·mL^-1，制備時(shí)間24.50 h。Dmy@ZIF-8納米粒的包封率、載藥量、平均粒徑和ζ電位分別為（ 85.96±1.17）%、（ 24.96±0.25）%、（ 53.49±4.17） nm、-（ 15.69±1.04） mV。Dmy@ZIF-8納米粒大小均勻，Dmy在Dmy@ZIF-8納米粒中轉(zhuǎn)變?yōu)闊o定形態(tài)，Dmy@ZIF-8納米粒在pH 5.0、5.5磷酸鹽緩沖液中釋藥行為符合Weibull模型，體外釋藥具有pH敏感性。MTT法結(jié)果顯示，Dmy和Dmy@ZIF-8納米粒對Hep3B細(xì)胞半數(shù)抑制濃度（ IC₅₀）分別為74.16、55.89 μg·mL^-1。體內(nèi)藥效學(xué)實(shí)驗(yàn)結(jié)果表明，與模型組相比較，Dmy@ZIF-8納米粒顯著抑制荷瘤裸鼠的腫瘤生長，Dmy@ZIF-8納米粒組（25 mg·kg^-1）抑瘤率達(dá)66.28%。結(jié)論 成功制備了具有良好理化性質(zhì)和pH敏感性的Dmy@ZIF-8納米粒，顯著提高Dmy體內(nèi)外抗腫瘤活性。

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.

R283.6

河南省教育廳高等學(xué)校重點(diǎn)科研項(xiàng)目（24B310010）；山西省中醫(yī)藥科技創(chuàng)新工程項(xiàng)目（2023kjzy009）