Oral mucus-penetrating PEGylated liposomes to improve drug absorption: Differences in the interaction mechanisms of a mucoadhesive liposome
Oral mucus-penetrating PEGylated liposomes to improve drug absorption: Differences in the interaction mechanisms of a mucoadhesive liposome
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DOI：
10.1016/j.ijpharm.2020.120148
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发表时间：
2021-01-25
影响因子：
5.8
通讯作者：
Tahara, Kohei
中科院分区：
文献类型：
--
作者：
Yamazoe, Eriko;Fang, Jia-You;Tahara, Kohei
我们研究了聚乙二醇(PEG2000)修饰的脂质体作为粘液穿透微粒(MPPs)口服给药系统吸收多肽的可行性。比较了乙二醇壳聚糖(GCS)修饰的MPPS和粘附性脂质体的口服吸收情况。在体外人工粘液模型中，聚乙二醇化脂质体表现出粘液通透性。在Caco-2和分泌粘液的Caco-2/HT29共培养中评价脂质体在细胞内的摄取。在共培养体系中，粘液对MPPS的细胞内摄取没有影响，而有粘液层的GCS脂质体的细胞摄取低于单独在Caco-2中的摄取。以荧光素异硫氰酸酯葡聚糖(FD)为模型多肽药物，考察脂质体在大鼠体内的吸收。聚乙二醇化密度高的脂质体的口服吸收比未修饰的脂质体高，且与聚乙二醇浓度有关，但过量的聚乙二醇化会降低FD的血液浓度。然后设计含有精胺(SPM)作为吸收促进剂的聚乙二醇化脂质体，在所有受试制剂中显示出最高的体内吸收。口服脂质体的药理作用是用依卡托宁来评价的，与FD的口服吸收无关。未经聚乙二醇化的SPM脂质体显示出最高的药理作用，提示需要对脂质体成分和表面修饰剂进行药物特异性优化。
We investigated the feasibility of densely polyethylene glycol (PEG2000)-modified liposomes as mucuspenetrating particles (MPPs) for oral delivery of systemically absorbed peptides. The oral absorption of MPPs and mucoadhesive liposomes modified with glycol chitosan (GCS) was compared. In an in vitro artificial mucus model, the densely PEGylated liposomes showed mucus permeability. Intracellular uptake of liposomes was evaluated in a Caco-2 and mucus-secreting Caco-2/HT29 co-culture. Intracellular uptake of MPPs was unaffected by mucus in the co-culture system, whereas the cellular uptake of GCS-liposomes was lower with a mucus layer than in Caco-2 alone. Rat in vivo oral absorption of liposomes was evaluated by using fluorescein isothiocyanate dextran (FD) as a model peptide drug. Oral absorption was higher for densely PEGylated than for unmodified liposomes and was PEG-concentration dependent, but excessive PEGylation decreased FD blood concentration. PEGylated liposomes incorporating spermine (SPM) as an absorption enhancer were then designed and showed the highest in vivo absorption of FD of all tested formulations. The pharmacological effects of the oral liposomes were evaluated by using elcatonin and did not correlate with FD oral absorption. The non-PEGylated SPM liposomes showed the highest pharmacological effect, suggesting the need for drug-specific optimization of liposomal components and surface modifiers.