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 Å. 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. Triethylammonium squalenoyl‐gemcitabine monophosphate self‐assembles into unilamellar liposomes of about one hundred nanometres in size. These nanoassemblies displayed a pronounced anticancer effect on leukaemia cell lines including a gemcitabine‐resistant cell line with down‐regulation of deoxycytidine kinase enzyme.