Lipid rafts-mediated endocytosis and physiology-based cell membrane traffic models of doxorubicin liposomes.
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.
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.
Yinghuan
Y
Li
School of Biomedical Engineering, Capital Medical University, 10 Xitoutiao, You An Men, Beijing 100069, PR China.
Lei
L
Gao
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.
Xi
X
Tan
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.
Feiyang
F
Li
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; Faculty of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: mingzhao@bjmu.edu.cn.
Ming
M
Zhao
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. Electronic address: sqpeng@bjmu.edu.cn.
Shiqi
S
Peng
D001692:Biological Transport; D002412:Cations; D002460:Cell Line; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D008081:Liposomes; D008561:Membrane Fusion; D008563:Membrane Lipids / Q000737:chemistry; D021962:Membrane Microdomains / Q000502:physiology*; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000737:chemistry
D002412:Cations; D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D008563:Membrane Lipids; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; C506643:liposomal doxorubicin; C094877:dioleoyl phosphatidylethanolamine; D011092:Polyethylene Glycols; D004317:Doxorubicin; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane
Endosomal escape; Internalization; Intracellular trafficking; Lipid raft; Liposomes; Membrane binding