title: Self-assemblies of 5'-cholesteryl-ethyl-phosphoryl zidovudine.
abstract: Anti-HIV prodrugs are recently focused on due to their ability of self-assembly, macrophage targeting, and enhanced antiviral effects. Here, an amphiphilic prodrug of zidovudine, an anti-HIV nucleoside analogue, 5'-cholesteryl-ethyl-phosphoryl zidovudine (CEPZ) was synthesized. CEPZ showed some unique physicochemical properties. The solubility of CEPZ in the noncompetitive solvents chloroform and tetrahydrofuran (THF) was very high based on the hydrogen bonds between zidovudine groups, though CEPZ was sparing soluble in alcohols and almost insoluble in water. The typical amphiphilic property of CEPZ was demonstrated according to the Langmuir monolayers at the air/water interface. The LogP of CEPZ was high to 13.78, indicating the high hydrophobicity of amphiphilic CEPZ similar to phospholipids. Homogenous and stable self-assemblies were formed with the mean size of 128.7nm and the zeta potential of -35.4mV after injecting the CEPZ-in-THF solution into water. Hydrophobic interaction between the cholesteryl moieties of CEPZ could drive molecular self-assembly and lead to the formation of spherical vesicles. CEPZ self-assemblies showed strong stability even under high temperature and gravity probably due to the high surface charge. CEPZ was very slowly degraded in neutral solutions (e.g., pH 7.4), but fast in acid solutions (e.g., pH 5.0) and some tissue homogenates. CEPZ was quickly eliminated from the circulation and distributed into the mononuclear phagocyte system (MPS) including the liver, spleen and lung after bolus intravenous administration of CEPZ self-assemblies to mice. The MPS targeting effect of CEPZ self-assemblies makes them become a promising self-assembled drug delivery system to eradicate the HIV hidden in the macrophages.
authors.affiliation: Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, PR China; Pharmaceutical College of Henan University, Kaifeng 475004, PR China.
authors.forename: Lina
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, PR China; Pharmaceutical College of Henan University, Kaifeng 475004, PR China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, PR China; Pharmaceutical College of Henan University, Kaifeng 475004, PR China.
authors.forename: Pingju
authors.initials: P
authors.lastname: Ge
authors.affiliation: Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, PR China; Pharmaceutical College of Henan University, Kaifeng 475004, PR China. Electronic address: jinyg@139.com.
authors.forename: Yiguang
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002460:Cell Line; D002788:Cholesterol Esters / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008253:Macaca mulatta; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008956:Models, Chemical; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D014018:Tissue Distribution; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: C000614922:5'-cholesteryl-ethyl-phosphoryl zidovudine; D019380:Anti-HIV Agents; D002788:Cholesterol Esters; D011355:Prodrugs; D012997:Solvents; D015215:Zidovudine
keywords: Anti-HIV; Langmuir monolayer; Macrophage; Phosphorylation; Prodrug; Self-assembly; Zidovudine