Squalenoyl Gemcitabine Monophosphate: Synthesis, Characterisation of Nanoassemblies and Biological Evaluation

Trialkylammonium 4-(N)-1,1',2-trisnor-squalenoylgemcitabine monophosphate (SQdFdC-MP) salts were prepared from 1,1',2-trisnor-squalenoylgemcitabine by phosphoramidite-type chemistry. This amphiphilic molecule self-assembled into nanoassemblies of about 100 nm in size in aqueous solutions. Cryo-TEM and small-angle X-ray scattering (SAXS) investigations revealed that SQdFdC-MP molecules self-organized into unilamellar liposomes with a membrane thickness of about 70 angstrom. Such liposomal trialkylammonium SQdFdC-MP formulations displayed significant anticancer activity on leukaemia cells. These results suggested that squalene conjugates of negatively charged nucleotide analogues efficiently penetrated into tumour cells. Furthermore, triethylammonium SQdFdC-MP nanoassemblies were found to be more active than the parent nucleoside towards the L1210 10 K resistant cell line.