title: Self-assembled drug delivery systems. Part 4. In vitro/in vivo studies of the self-assemblies of cholesteryl-phosphonyl zidovudine.
abstract: An amphiphilic prodrug of anti-HIV nucleoside analogue, cholesteryl-phosphonyl zidovudine (CPNZ) was synthesized. An aqueous suspension containing CPNZ self-assemblies was obtained through injecting the ethanol solution of CPNZ and cholesteryl succinyl poly(ethylene glycol) 1500 (20:1, mol/mol) into water under agitation. Hydrophobic interaction may be the driving force of molecular self-assembly. The self-assemblies were nanoscale with approximately 100nm in size, and remained stable for a long time. Degradation of CPNZ self-assemblies was investigated in various environments including buffered solutions, plasma and rabbit tissue homogenates. CPNZ was degraded very slowly in neutral solutions but rapidly in various plasma with the half-lives (t(1/2)) of less than 20h. Tissue homogenates degraded CPNZ with varied rates depending on enzyme activity. CPNZ self-assemblies showed potent anti-HIV activity on MT4 cell model, the anti-HIV 50% effective concentration (EC(50)) of which was 1nM, only equal to 1/5 of AZT EC(50). CPNZ was rapidly eliminated from circulation and distributed into the mononuclear phagocyte system (MPS) including liver, spleen and lung after bolus intravenous administration of CPNZ self-assemblies followed slowly elimination. The possible products include AZT-5'-H-phosphonate, AZT and their derivatives. The MPS-targeted effect and high anti-HIV activity of CPNZ self-assemblies make them become a promising self-assembled drug delivery system (SADDS).
authors: Department of Pharmaceutical Chemistry, Beijing Institute of Radiation Medicine, PR China. jin_yiguang@yahoo.com.cn
authors: Yiguang
authors: Y
authors: Jin
authors: Lei
authors: L
authors: Xing
authors: Ying
authors: Y
authors: Tian
authors: Miao
authors: M
authors: Li
authors: Chunsheng
authors: C
authors: Gao
authors: Lina
authors: L
authors: Du
authors: Junxing
authors: J
authors: Dong
authors: Hongxuan
authors: H
authors: Chen
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002788:Cholesterol Esters / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D016503:Drug Delivery Systems; D004355:Drug Stability; D005260:Female; D015497:HIV-1 / Q000187:drug effects*; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D063065:Organophosphonates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013154:Spleen / Q000378:metabolism; D013501:Surface-Active Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013737:Testis / Q000378:metabolism; D014018:Tissue Distribution; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D002788:Cholesterol Esters; D063065:Organophosphonates; D011355:Prodrugs; D013501:Surface-Active Agents; C546229:cholesteryl-phosphonyl zidovudine; D015215:Zidovudine; D002784:Cholesterol