红细胞膜伪装的吉非替尼纳米药物对肺癌荷瘤裸鼠的抑制效应研究  

Study on inhibitory effect of erythrocyte membrane camouflaged gefitinib nanoparticles on lung cancer-bearing nude mice

作　　者：范运秀 杨波 周丽 黄小平 FAN Yunxiu;YANG Bo;ZHOU Li;HUANG Xiaoping(Department of Oncology,Affiliated Three Gorges Hospital of Chongqing University,Chongqing 404100,China)

机构地区：[1]重庆大学附属三峡医院肿瘤中心,重庆404100

出　　处：《重庆医学》2024年第20期3041-3047,3054,共8页Chongqing Medical Journal

基　　金：重庆市自然科学基金面上项目(cstc2020jcyj-msxmX1037)。

摘　　要：目的制备红细胞膜伪装的吉非替尼(GEF)纳米药物,并应用肺癌荷瘤裸鼠模型观察药物体内半衰期和血药浓度,探讨其抑瘤作用和抑瘤机制。方法采用高效液相色谱(HPLC)建立GEF标准曲线。构建A549荷瘤裸鼠,分为GEF组、GEF纳米粒组(GEF-NPs组)、红细胞伪装GEF纳米粒组(RBC@GEF-NPs组)。使用HPLC检测不同时间点的血药浓度、流式细胞技术检测细胞周期、TUNEL法检测肿瘤细胞凋亡。结果RBC@GEF-NPs组肿瘤体积较GEF组和GEF-NPs组更小(P<0.05);RBC@GEF-NPs组体内GEF半衰期较GEF组和GEF-NPs组更长(18.90 h vs.2.44 h vs.10.50 h),差异有统计学意义(P<0.05)。RBC@GEF-NPs组肿瘤组织GEF药物浓度为48.5 ng/mg,约为GEF-NPs组(24.7 ng/mg)的2倍,约为GEF组(10.8 ng/mg)的5倍(P<0.05)。与GEF组比较,RBC@GEF-NPs组G_(0)/G_(1)期细胞比例从55.5%上升到71.35%,G_(2)/M期从10.05%下降到4.22%,S期从34.62%下降到24.43%(P<0.05)。RBC@GEF-NPs组细胞凋亡指数明显高于GEF组和GEF-NPs组[(23.42±2.47)%vs.(8.34±1.32)%vs.(14.32±2.59)%],差异有统计学意义(P<0.05)。结论RBC@GEF-NPs可提高A549肺癌荷瘤裸鼠中药物半衰期及血药浓度,并通过促进肿瘤细胞凋亡及G_(1)期阻滞抑制肺癌的生长。Objective To prepare the erythrocyte membrane camouflaged gefitinib(GEF)nanomedicine,and to observe its in vivo half-life and blood drug concentration by using the lung cancer bearing nude mouse model and explore its tumor suppression effect and tumor suppression mechanism.Methods The GEF standard curve was established by HPLC.A549 tumor bearing nude mice were constructed and divided into the GEF group,GEF nanoparticles group(GEF-NPs group),erythrocyte camouflaged GEF nanoparticles group(RBC@GEF-NPs group).The plasma drug concentration at different time points was detected by HPLC,the cell cycle was detected by flow cytometry and the tumor cellular apoptosis was detected by TUNEL.Results The tumor volume in the RBC@GEF-NPs group was significantly smaller than that in the GEF group and GEF-NPs group(P<0.05);the in vivo half-life period in the RBC@GEF-NPs group was significantly longer than the GEF group and GEF-NPS group(18.90 h vs.2.44 h vs.10.50 h,P<0.05),and the difference was statistically significant(P<0.05);the GEF drug concentration in the tumor tissues of the RBC@GEF-NPs group was 48.5 ng/mg,which was 5 times and 2 times of that in the GEF group(10.8 ng/mg)and GEF-NPs group(24.7 ng/mg)respectively(P<0.05).Compared with the GEF group,the proportion of G_(0)/G_(1) phase cells in the RBC@GEF-NPs group was increased from 55.5%to 71.35%(P<0.05)and which in the G_(2)/M stage was decreased from 10.05%to 4.22%(P<0.05),which in the S stage was decreased from 34.62%to 24.43%(P<0.05);the cellular apoptosis index in the RBC@GEF-NPs group was significantly higher than that in the GEF group and GEF-NPs group[(23.42±2.47)%vs.(8.34±1.32)%vs.(14.32±2.59)%,P<0.05],and the differences were statistically significant.Conclusion RBC@GEF-NPs could increase the half-life and blood concentration of A549 lung cancer bearing nude mice,block and inhibit the lung cancer growth by promoting tumor cell apoptosis and G 1 phase arrest.

关 键 词：红细胞膜伪装 吉非替尼 纳米药物 肺癌细胞 荷瘤裸鼠 

分 类 号：R965[医药卫生—药理学]