Molecular self-assembly of amphiphilic cyclic phosphoryl gemcitabine with different N-fatty acyl tails and enhanced anticancer effects of the self-assembled nanostructures

Abstract Molecular self-assembly of nucleosides is important, and the self-assembled nanostructures may be used for drug delivery and targeting. Gemcitabine (GEM) is an important anticancer nucleoside analog though deactivation and multi-drug resistance frequently happen. Four N-fatty acyl derivatives of cyclic phosphoryl GEM were prepared based on the theory of self-assembled drug delivery systems and the HepDirect prodrug technique wherein the prodrug could be degraded by the cytochrome P 450 isozymes in hepatocytes to release active drugs. They are cyclic phosphoryl N-octyl gemcitabine (CPOG), cyclic phosphoryl N-dodecanoyl gemcitabine (CPDG), cyclic phosphoryl N-hexadecanoyl gemcitabine (CPHG), and cyclic phosphoryl N-octadecanoyl gemcitabine (CPODG). Their amphiphilicity and self-assembling property were explored. The self-assembled nanostructures of them were prepared and simulated. The in vitro anticancer activities of the nanostructures were investigated. The derivatives formed the Langmuir monolayers at the air/water interface, though their surface pressure–molecular area isotherms were different with dependency of the length of lipid chains. The derivatives self-assembled into the vesicular or rice-like nanostructures based on the hydrophobic interaction between lipid chains when injected into water, in accordance with the results of computer simulation. The nanostructures showed higher anticancer effects on HepG2 cells than GEM. The nanostructures are promising anticancer nanomedicines.