目的 构建负载异鼠李素的类沸石咪唑酯骨架材料-8（ZIF-8）纳米粒（isorhamnetin loaded by ZIF-8 nanoparticles，ZIF-8@Iso），评价ZIF-8@Iso体内组织分布及对肺癌荷瘤小鼠的抗肿瘤作用。方法 采用自组装法制备ZIF-8纳米粒粉末，采用浸渍法制备ZIF-8@Iso。选择ZIF-8与异鼠李素质量比、异鼠李素质量浓度和制备时间作为ZIF-8@Iso主要影响因素，采用包封率、载药量和粒径的总评归一值（overall desirability，OD）为指标，使用Box-Behnken设计-效应面法（Box-Behnken design-response surface methodology，BBD-RSM）优化ZIF-8@Iso处方工艺。X射线粉末衍射（X-ray powder diffraction，XRPD）、透射电子显微镜（transmission electron microscope，TEM）及BET比表面积分析仪对ZIF-8@Iso进行表征。考察ZIF-8@Iso的丁达尔现象、pH值敏感性、血浆稳定性、溶血安全性及储存稳定性。采用Lewis肺癌细胞建立肿瘤模型，评价ZIF-8@Iso体内组织分布及抗肿瘤效果。采用HE染色法观察肿瘤组织病理学变化。结果 通过XRPD、TEM及傅里叶变换红外光谱（Fourier transform infrared spectroscopy，FT-IR）分析，表明ZIF-8纳米粒粉末制备成功。ZIF-8@Iso最佳处方工艺：ZIF-8与异鼠李素质量比为2.50∶1，异鼠李素质量浓度为2.05 mg/mL，制备时间为12.00 h。ZIF-8@Iso的平均包封率、载药量、粒径和ζ电位分别为（84.82±0.56）%、（24.05±0.16）%、（136.94±0.29）nm和（30.66±1.15）mV。异鼠李素在ZIF-8@Iso中可能以无定形态存在，ZIF-8@Iso粒径均一，ZIF-8@Iso比表面积、孔容和孔径均低于ZIF-8。ZIF-8@Iso混悬液具有丁达尔现象，体外释药具有pH敏感性。ZIF-8@Iso血浆稳定性、溶血安全性及储存稳定性均良好。ZIF-8@Iso在肿瘤组织中相对摄取率（relative uptake efficiency，RUE）达2.12，极大提高了其靶向性。体内抗肿瘤结果显示，ZIF-8@Iso（50 mg/kg）将异鼠李素抑瘤率由46.15%提高至62.64%。HE染色结果显示，ZIF-8@Iso组肿瘤细胞大面积坏死，坏死程度高于异鼠李素组。结论 成功构建了ZIF-8@Iso，包封率较高，具有良好的pH敏感性，增加了异鼠李素对肺癌荷瘤小鼠的抗肿瘤作用，值得进一步开发研究。

Objective Isorhamnetin loaded by zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (ZIF-8@Iso) were constructed, and their in vivo tissue distribution and antitumor effects on lung cancer-bearing mice in vivo was also evaluated. Methods ZIF-8 nanoparticles powder was prepared by self-assembly method, and ZIF-8@Iso was prepared by impregnation method. The mass ratio of ZIF-8 to isorhamnetin, concentration of isorhamnetin and preparation time were selected as the main influencing factors of ZIF-8@ Iso. Overall desirability (OD) of the encapsulation rate, drug loading and particle size was taken as the index, Box-Behnken design-response surface methodology (BBD-RSM) was used to optimize the prescription process of ZIF-8@Iso. X-ray powder diffraction (XRPD), transmission electron microscopy (TEM) and specific surface area analyzer (SSA) were employed to characterize ZIF-8@Iso. Tyndall phenomenon, pH-sensitivity, plasma stability, hemolysis safety and storage stability of ZIF-8@Iso were also studied. Lewis’s lung cancer cell was used to establish tumor model, and the in vivo tissue distribution and antitumor effect of ZIF-8@Iso were evaluated. The pathology changes of tumor tissue were observed by HE staining method. Results The successful preparation of ZIF-8 nanoparticles powder was proved by XRPD, TEM and Fourier transform infrared spectroscopy (FT-IR) analysis. Optimal prescription process of ZIF-8@Iso as follows: the mass ratio of ZIF-8 to isorhamnetin was 2.50:1, concentration of isorhamnetin was 2.05 mg/mL and preparation time was 12.00 h. Average encapsulation rate, drug loading, particle size and ζ potential were (84.82 ± 0.56)%, (24.05 ± 0.16)%, (136.94 ± 0.29) nm and (30.66 ± 1.15) mV, respectively. Isorhamnetin might exist as an amorphous form in ZIF-8@Iso, and the particle size of ZIF-8@Iso was uniform. Specific surface area, pore volume and pore size of ZIF-8@Iso were lower than those of ZIF-8. ZIF-8@Iso suspension showed obvious Tyndall phenomenon, and in vitro drug release was pH-sensitive. The plasma stability, hemolysis safety and storage stability of ZIF-8@Iso were all perfect. The relative uptake efficiency (RUE) of ZIF-8@Iso in tumor tissue reached 2.12, greatly improving the tumor targeting. In vivo antitumor results showed that ZIF-8@Iso (50 mg/kg) increased the inhibition rate of isorhamnetin from 46.15% to 62.64%. The results of HE staining showed that there was a large area of necrosis in the tumor cells of the ZIF-8@Iso group, the degree of necrosis was higher than that of isorhamnetin group. Conclusion ZIF-8@Iso was successfully constructed with high encapsulation rate and pH-sensitivity. ZIF-8@Iso increased the antitumor effects of isorhamnetin on lung cancer-bearing mice, which was worth further developing and studying.

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河南省2024年科技发展计划项目（242102310581）；河南省高等学校重点科研项目（23B310016）；河南省省级骨干教师（教职成[2024]38号-382）