Uptake mechanism and intracellular destiny of liposomes in RES

RES中脂质体的摄取机制和细胞内命运

• 批准号: 05671783
• 负责人: HARASHIMA Hideyoshi
• 金额: $ 1.47万
• 依托单位: The University of Tokushima, Faculty of Pharmaceutical Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05671783/
• 关键词: Drug delivery system; Pharmacokinetics; Liposomes; Opsonin; Complement receptor; Saturation; Diameter

The objective of this study is to clarify the relationship between uptake mechanism of liposomes by the reticuloendothelial system (RES) and the intracellular destiny of liposomes. The saturation manner of liposome uptake by the liver was examined kinetically in rats. The saturation characteristics of liposomes by the liver was explained well with the area under the curve of blood concentration and not by the blood concentration itself. New model was postulated for this saturation kinetics as "satiated model". The kinetic analysis revealed that there were at least two kinds of uptake pathways in liver, one is the high clearance/low capacity and low clearance/high capacity pathway. The uptake mechanism of liposomes by the liver was then examined under the isolated perfused liver system, and the contribution of complement receptor mediated phagocytosis was shown. The activation of complement system was dependent on the size of liposomes and the enhanced uptake by the liver resulted from the size dependent opsonization of liposomes. This complement receptor mediated uptake pathway corresponded to the high clearance/low capacity pathway. The effect of liposome dose on the intracellular degradation of liposomes in RES was also investigated. There were at least two kinds of degradation processes in the liver. This heterogeneity in the degradation of liposomes can be explained by both "Sorting Model" which assumes the heterogenous degradation processes and "Traffic Jam Model" which assumes the heterogenous transport processes. The intracellular transport of liposomes into acidic compartment was analyzed under peritoneal macrophages using pH-sensitive dye and it was clarified that the dose of liposomes influenced the transport processes of liposomes before fusion with lysosomes, which supported the "Traffic Jam Model".

本研究的目的是阐明网状内皮系统（RES）摄取脂质体的机制与脂质体的细胞内命运之间的关系。用动力学方法研究了脂质体在大鼠肝脏中的饱和摄取方式。用血药浓度曲线下面积较好地解释了脂质体在肝脏中的饱和特性，而不是血药浓度本身。提出了一种新的饱和动力学模型--“饱和模型”。动力学分析表明，肝脏中至少存在两种摄取途径，一种是高清除/低容量途径，另一种是低清除/高容量途径。然后在离体灌流的肝脏系统下检查肝脏对脂质体的摄取机制，并显示补体受体介导的吞噬作用的贡献。脂质体对补体系统的激活依赖于脂质体的大小，脂质体的大小依赖性调理作用导致肝脏对补体系统的摄取增强。这种补体受体介导的摄取途径对应于高清除率/低容量途径。同时考察了脂质体剂量对脂质体在RES细胞内降解的影响。在肝脏中至少有两种降解过程。脂质体降解的这种异质性可以通过假设异质性降解过程的“分选模型”和假设异质性转运过程的“交通堵塞模型”来解释。在腹腔巨噬细胞下使用pH敏感染料分析脂质体进入酸性区室的细胞内转运，并且阐明了脂质体的剂量影响脂质体与溶酶体融合之前的转运过程，这支持了“交通堵塞模型”。

项目成果

Hideyoshi Harashima, Noriko Hirai and Hiroshi Kiwada.: "Kinetic modeling of liposome degradation in peritoneal macrophages." Biopharm.Drug Disposit.16. 113-123 (1995)

Hideyoshi Harashima、Noriko Hirai 和 Hiroshi Kiwada.：“腹膜巨噬细胞中脂质体降解的动力学模型。”

Hideyoshi Harashima et al.: "Kinetic modeling of liposome degradation in peritoneal macrophages" Biopharmaceutics and Drug Disposition. 16. 113-123 (1995)

Hideyoshi Harashima 等人：“腹膜巨噬细胞中脂质体降解的动力学模型”生物药剂学和药物处置。

Hideyoshi Harashima et al.: "Kinetic modeling of liposome degradation in peritoneal macrophages." Biopharmaceutics and Drug Disposition. 16. 113-123 (1995)

Hideyoshi Harashima 等人：“腹膜巨噬细胞中脂质体降解的动力学模型。”

Yumi Morioka et al.: "Effect of liposome dose on the intracellular degradation of liposomes." Drug Delivery System. 45. 27-35 (1996)

Yumi Morioka 等人：“脂质体剂量对脂质体细胞内降解的影响”。

Hideyoshi Harashima et al.: "Kinetic analysis of AUC-dependent saturable clearance of liposomes:Mathematical description of AUC dependency." J.Pharmacokin.Biopharm.21. 299-308 (1993)

Hideyoshi Harashima 等人：“脂质体 AUC 依赖性饱和清除率的动力学分析：AUC 依赖性的数学描述。”