Self-assembled drug delivery systems. Part 8: In vitro/in vivo studies of the nanoassemblies of cholesteryl-phosphonyl gemcitabine

[Display omitted] A lipid derivative of gemcitabine (Gem), cholesteryl-phosphonyl gemcitabine (CPNG) was synthesized in this study. The amphiphilicity of CPNG was confirmed using a Langmuir monolayer method. Nanoassemblies were formed when the mixture of CPNG and a long-circulating material, CHS-PEG1500 (9:1, mol/mol) were injected into water. The nanoassemblies could be spherical vesicles according to the transmission electron microscopic images. Their mean size was 71.1nm and the zeta potential was −17.6mV. CPNG maintained stable in the weakly acidic and neutral environments although mouse plasma quickly degraded CPNG. The cytotoxicity of the nanoassemblies was 3–6 folds of Gem's cytotoxicity on five human cancer cell lines including 95C, 95D, A549, SW620, PANC-1 probably because of the phosphonyl substitution and amphiphilicity of CPNG. CPNG mainly distributed into the mononuclear macrophage system (including liver and spleen) after bolus intravenous administration of the nanoassemblies into mice though the expected significant long-circulating effect was not shown. The nanoassemblies with the high dose of CPNG showed the statistically higher in vivo anticancer effect than Gem. This study indicates that the N-substituted lipid derivative of Gem and the true long-circulating function are necessary for preparing a successful nanoassembly of Gem.