Self-assembled drug delivery systems. Part 4. In vitro/in vivo studies of the self-assemblies of cholesteryl-phosphonyl zidovudine

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 ∼100 nm 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 (t1/2) of less than 20 h. 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 (EC50) of which was 1 nM, only equal to 1/5 of AZT EC50. 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).