Li Yinghuan, Gao Lei, Tan Xi, Li Feiyang, Zhao Ming, Peng Shiqi
Beijing area major laboratory of peptide and small molecular drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
School of Biomedical Engineering, Capital Medical University, 10 Xitoutiao, You An Men, Beijing 100069, PR China.
Biochim Biophys Acta. 2016 Aug;1858(8):1801-11. doi: 10.1016/j.bbamem.2016.04.014. Epub 2016 Apr 23.
The clathrin-mediated endocytosis is likely a major mechanism of liposomes' internalization. A kinetic approach was used to assess the internalization mechanism of doxorubicin (Dox) loaded cationic liposomes and to establish physiology-based cell membrane traffic mathematic models. Lipid rafts-mediated endocytosis, including dynamin-dependent or -independent endocytosis of noncaveolar structure, was a dominant process. The mathematic models divided Dox loaded liposomes binding lipid rafts (B) into saturable binding (SB) and nonsaturable binding (NSB) followed by energy-driven endocytosis. The intracellular trafficking demonstrated early endosome-late endosome-lysosome or early/late endosome-cytoplasm-nucleus pathways. The three properties of liposome structures, i.e., cationic lipid, fusogenic lipid, and pegylation, were investigated to compare their contributions to cell membrane and intracellular traffic. The results revealed great contribution of cationic lipid DOTAP and fusogenic lipid DOPE to cell membrane binding and internalization. The valid Dox in the nuclei of HepG2 and A375 cells treated with cationic liposomes containing 40mol% of DOPE were 1.2-fold and 1.5-fold higher than that in the nuclei of HepG2 and A375 cells treated with liposomes containing 20mol% of DOPE, respectively, suggesting the dependence of cell type. This tendency was proportional to the increase of cell-associated total liposomal Dox. The mathematic models would be useful to predict intracellular trafficking of liposomal Dox.
网格蛋白介导的内吞作用可能是脂质体内化的主要机制。采用动力学方法评估载有多柔比星（Dox）的阳离子脂质体的内化机制，并建立基于生理学的细胞膜转运数学模型。脂质筏介导的内吞作用，包括非小窝结构的发动蛋白依赖性或非依赖性内吞作用，是一个主要过程。数学模型将载有Dox的脂质体与脂质筏的结合（B）分为可饱和结合（SB）和非可饱和结合（NSB），随后是能量驱动的内吞作用。细胞内转运显示出早期内体-晚期内体-溶酶体或早期/晚期内体-细胞质-细胞核途径。研究了脂质体结构的三个特性，即阳离子脂质、促融合脂质和聚乙二醇化，以比较它们对细胞膜和细胞内转运的贡献。结果显示阳离子脂质DOTAP和促融合脂质DOPE对细胞膜结合和内化有很大贡献。用含有40mol%DOPE的阳离子脂质体处理的HepG2和A375细胞细胞核中的有效Dox分别比用含有20mol%DOPE的脂质体处理的HepG2和A375细胞细胞核中的有效Dox高1.2倍和1.5倍，表明存在细胞类型依赖性。这种趋势与细胞相关的总脂质体Dox的增加成正比。该数学模型将有助于预测脂质体Dox的细胞内转运。
