Synthesis and in vitro Cytotoxic Activity on Human Anaplastic Thyroid Cancer Cells of Lipoamino Acids Conjugates of Gemcitabine

Lipophilic derivatives of the antitumor drug gemcitabine (GEM) with the potential for improving drug loading in lipid-based colloidal carriers, like liposomes or lipid nanoparticles, are described. GEM free base was conjugated to lipoamino acids bearing an alkyl side chain of different length, by either a carbodiimide-assisted or an ethylchloroformiate-assisted coupling reaction, to obtain N(4)-acyl GEM derivatives. These compounds retained the same in vitro cell growth inhibitory activity of the parent drug against two lines of human anaplastic thyroid cancer cells. Stability studies suggested that the observed activity was due mainly to intact derivatives and not to released GEM. Accordingly, these amphiphilic derivatives can be proposed in a further step for the encapsulation in liposomes or lipid nanocarriers, to achieve as a final goal an improvement of the pharmacokinetics and therapeutic activity of GEM.