基于Box-Behnken法优选红细胞膜包裹的紫杉醇仿生纳米混悬剂处方  

Optimization of formulation of paclitaxel nanosuspension encapsulated by erythrocyte membrane based on Box-Behnken method

作　　者：范月月 崔曰新 郝文艳 陈梦雨 杨阳 高春生[1,2] FAN Yue-yue;CUI Yue-xin;HAO Wen-yan;CHEN Meng-yu;YANG Yang;GAO Chun-sheng(School of Pharmacy,Henan University,Kaifeng 475000,China;Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Bejing 100850,China)

机构地区：[1]河南大学药学院,河南开封475000 [2]军事医学研究院毒物药物研究所,北京100850

出　　处：《中国中药杂志》2022年第9期2457-2464,共8页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(82073783)。

摘　　要：基于红细胞的长循环及天然免疫逃逸效应,该研究构建了一种新型的红细胞膜包裹的紫杉醇仿生纳米混悬液[RBC-(PTX)NS],对其理化性质及体外抗肿瘤效果进行考察。采用超声-沉淀法制备紫杉醇纳米混悬液[(PTX)NS]及超声包膜法制备RBC-(PTX)NS。以粒径、电位、稳定性为指标,通过Box-Behnken法对(PTX)NS进行处方优化。并进一步对(PTX)NS及RBC-(PTX)NS的形态、粒径、稳定性、体外溶出及体外抗肿瘤特性进行表征。结果表明,优化所得的(PTX)NS粒径为(129.38±0.92)nm,Zeta电位(-22.41±0.48)mV;包裹细胞膜后RBC-(PTX)NS粒径为(142.5±0.68)nm,Zeta电位(-29.85±0.53)mV;透射电镜下(PTX)NS呈球形,RBC-(PTX)NS具有明显的核-壳结构;RBC-(PTX)NS在4℃下5 d保持稳定;体外溶出实验显示(PTX)NS在20 min内累积溶出度达79%,显著优于原料药溶出度(25%)(P<0.05);MTT细胞实验结果表明RBC-(PTX)NS对HepG2细胞的增殖有高效抑制作用,且具有明显的剂量依赖性。该研究探索制备的细胞膜仿生纳米制剂方法简单、重复性好,改善了PTX的溶解度,红细胞膜包裹后,RBC-(PTX)NS的稳定性提高,细胞毒作用增强,有望为PTX的纳米化给药提供新思路。In view of the longevity and innate immune escape of red blood cells,this study designed the red blood cell membrane-coated paclitaxel nanosuspension[RBC-(PTX)NS]and investigated its physicochemical properties and antitumor effect in vitro.Paclitaxel nanosuspension[(PTX)NS]was prepared by ultrasonic precipitation and then RBC-(PTX)NS by ultrasonic coating.The formulation of(PTX)NS was optimized with Box-Behnken method and indexes of particle diameter,zeta potential,and stability.The morphology,particle diameter,stability,in vitro dissolution,and antitumor effect of(PTX)NS and RBC-(PTX)NS were characterized.The results showed that the particle diameter and zeta potential were(129.38±0.92)nm and(-22.41±0.48)mV,respectively,for the optimized(PTX)NS,while(142.5±0.68)nm and(-29.85±0.53)mV,respectively,for RBC-(PTX)NS.Under the transmission electron microscope,(PTX)NS was spherical and RBC-(PTX)NS had obvious core-shell structure.RBC-(PTX)NS remained stable for 5 days at 4℃.The in vitro dissolution test demonstrated that the cumulative release rate of RBC-(PTX)NS reached 79%within 20 min,which was significantly higher than that(25%)of(PTX)NS(P<0.05).As evidenced by MTT assay,RBC-(PTX)NS highly inhibited the proliferation of HepG2 cells in a dose-dependent manner.The cell membrane-coated nano-preparation preparation method is simple and reproducible.It improves the solubility of PTX and endows RBC-(PTX)NS with higher stability and stronger cytotoxicity.Thus,it is a new method for the delivery of PTX via nanocrystallization.

关 键 词：紫杉醇 纳米混悬液 超声-沉淀法 Box-Behnken法 红细胞膜 

分 类 号：R283.6[医药卫生—中药学]