Shen Ai-jun, Xia Deng-ning, Gan Yong, Li Juan
Yao Xue Xue Bao. 2016 Jul;51(7):1136-43.
Polyelectrolyte layer-by-layer assembled lipid nanoparticles (NPs) were prepared to improve their stability against lipolysis in gastrointestinal tract, and efficiency of oral absorption of doxorubicin (DOX). The lipid NPs were prepared by hot melt-probe sonication method. The polyelectrolyte layer-by-layer assembled lipid NPs (DOX-NPs/CS/γ-PGA) was prepared by layer-by-layer self-assembling polyelectrolytes cationic chitosan (CS) and anionic poly (γ-glutamic acid) (γ-PGA) on the surface of lipid NPs based on electrostatic interaction. The particle size, polydispersity index (PDI) and zeta potential of lipid NPs and DOX-NPs/CS/γ-PGA were determined by dynamic light scattering (DLS). The in vitro drug release was determined in p H 1.2 HCl solution and p H 6.8 phosphate buffer solution (PBS). The stability of lipid NPs against lipolysis was evaluated in simulated gastrointestinal medium containing lipase. The cellular uptake of lipid NPs and DOX-NPs/CS/γ-PGA was evaluated in Caco-2 cell model. The pharmacokinetic of DOX after oral absorption was studied in SD rats. Results showed that the average particle size and zeta potential of DOX-NPs/CS/γ-PGA were 180.6 ± 5.4 nm and-38.53 ± 0.29 m V, respectively. The DOX-NPs/CS/γ-PGA effectively slowed down the release of DOX from nanoparticles, and decreased the lipolysis of lipid NPs in simulated gastrointestinal medium. The cell study showed that DOX-loaded lipid NPs and DOX-NPs/CS/ γ-PGA remarkably enhanced the cell uptake in comparison with DOX solution. The DOX-NPs/CS/γ-PGA significantly improved oral absorption of DOX compared with DOX-loaded lipid NPs. The C(max), t(max) were 0.76 ± 0.25 μg·m L(-1) and 0.5 h, respectively; AUC(0-24 h) was 3.02 folds and the relative bioavailability was 302.46% with DOX solution as reference. The stability of lipid NPs against lipolysis and drug release were significantly improved by layer-by-layer assembling, leading to an improved oral absorption.
制备了聚电解质层层组装脂质纳米粒（NPs），以提高其在胃肠道中抗脂解的稳定性，以及阿霉素（DOX）的口服吸收效率。脂质纳米粒采用热熔探针超声法制备。基于静电相互作用，通过在脂质纳米粒表面层层自组装聚电解质阳离子壳聚糖（CS）和阴离子聚（γ-谷氨酸）（γ-PGA），制备了聚电解质层层组装脂质纳米粒（DOX-NPs/CS/γ-PGA）。通过动态光散射（DLS）测定脂质纳米粒和DOX-NPs/CS/γ-PGA的粒径、多分散指数（PDI）和zeta电位。在pH 1.2盐酸溶液和pH 6.8磷酸盐缓冲溶液（PBS）中测定体外药物释放。在含有脂肪酶的模拟胃肠道介质中评估脂质纳米粒抗脂解的稳定性。在Caco-2细胞模型中评估脂质纳米粒和DOX-NPs/CS/γ-PGA的细胞摄取。在SD大鼠中研究DOX口服吸收后的药代动力学。结果表明，DOX-NPs/CS/γ-PGA的平均粒径和zeta电位分别为180.6±5.4nm和-38.53±0.29mV。DOX-NPs/CS/γ-PGA有效减缓了DOX从纳米粒中的释放，并降低了模拟胃肠道介质中脂质纳米粒的脂解。细胞研究表明，与DOX溶液相比，载DOX脂质纳米粒和DOX-NPs/CS/γ-PGA显著增强了细胞摄取。与载DOX脂质纳米粒相比，DOX-NPs/CS/γ-PGA显著改善了DOX的口服吸收。C(max)、t(max)分别为0.76±0.25μg·mL(-1)和0.5h；以DOX溶液为参比，AUC(0-24h)为3.02倍，相对生物利用度为302.46%。通过层层组装显著提高了脂质纳米粒抗脂解和药物释放的稳定性，从而改善了口服吸收。
