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载多柔比星(DOX)脂质纳米粒经聚合物电解质层层组装后,增加脂质纳米粒在胃肠道内的酶稳定性,以提高DOX的口服吸收。采用热熔均质-超声法制备了载DOX脂质纳米粒;利用静电作用将带相反电荷的聚合物电解质γ-聚谷氨酸(γ-PGA)和壳聚糖(chitosan,CS)层层组装在脂质纳米粒表面,得到聚合物电解质层层组装的载DOX脂质纳米粒(DOX-NPs/CS/γ-PGA);采用动态光散射激光粒度仪测定了纳米粒的粒径、粒度分布及zeta电位;考察聚合物电解质层层组装后的脂质纳米粒的体外药物释放和在体外模拟消化道环境下的酶解稳定性;以人结肠癌细胞Caco-2为细胞模型,对纳米粒的摄取进行了研究;以SD大鼠为动物模型对口服吸收后的药物动力学进行了研究。结果表明,制备的DOX-NPs/CS/γ-PGA平均粒径为180.6±5.4 nm,粒度分布均一,多分散性指数(PDI)为0.220±0.02,zeta电位为-38.53±0.29 m V;体外药物释放研究表明,采用聚合物电解质在脂质纳米粒表面层层组装后延缓DOX的释放,同时降低脂质纳米粒被脂肪酶降解的速率;细胞摄取实验研究表明,该组制剂的细胞摄取明显高于DOX溶液组;动物实验研究表明,经聚合物电解质层层组装后的脂质纳米粒可明显提高DOX的口服吸收,DOX-NPs/CS/γ-PGA的Cmax和tmax分别为0.76±0.25μg·m L-1和0.5 h,AUC0-24 h是溶液参比制剂的3.02倍,与DOX溶液口服组相比,其相对生物利用度是302.46%。通过聚合物电解质在脂质纳米载体表面进行层层组装,延缓了药物释放,降低了消化道酶对载体的酶解,增加了其在消化道内的稳定性,提高了DOX的口服吸收。
Doxorubicin (DOX) -based liposomes can increase the enzyme stability of lipid nanoparticles in the gastrointestinal tract after being assembled by the polymer electrolyte layer to improve the oral absorption of DOX. The DOX-loaded nanoparticles were prepared by hot-melt homogenization-ultrasonication. The oppositely charged polymer electrolytes γ-polyglutamic acid (γ-PGA) and chitosan (CS) (DOX-NPs / CS / γ-PGA) loaded on the surface of the lipid nanoparticles were obtained. The particle size and particle size of the nanoparticles were measured by a dynamic light scattering laser particle size analyzer Distribution and zeta potential. The drug release of the lipid nanoparticles assembled in the polymer electrolyte layer and the enzymatic stability under simulated digestive tract environment were investigated. The human colon cancer cell Caco-2 was used as the cell model, The intake of granule was studied. The pharmacokinetics of orally taken SD rats were studied. The results showed that the average particle size of DOX-NPs / CS / γ-PGA was 180.6 ± 5.4 nm with uniform particle size distribution. The polydispersity index (PDI) was 0.220 ± 0.02 and the zeta potential was -38.53 ± 0.29 mV. Drug release studies have shown that the use of polymer electrolyte in the lipid nanoparticles surface layer delay after the release of DOX, while reducing lipid lipase degradation rate of lipid nanoparticles; cell uptake experiments show that the preparation of cells significantly uptake Higher than the DOX solution group; animal experiments show that the lipid nanoparticles assembled through the polymer electrolyte layer can significantly improve the oral absorption of DOX, Cmax and tmax of DOX-NPs / CS / γ-PGA were 0.76 ± 0.25 μg · m L-1 and 0.5 h, respectively. AUC0-24 h was 3.02-fold higher than that of the reference solution. Compared with the oral solution of DOX solution, the relative bioavailability was 302.46%. The polymer electrolyte layer-by-layer assembly on the surface of the lipid nanocarrier delayed release of the drug, reduced digestion of the enzyme enzyme carrier, increased its stability in the digestive tract, increased oral absorption of DOX.