Nucleoside analogs such as cytarabine and gemcitabine are powerful anticancer agents, but a simple chemical modification that causes them to assemble into stable nanoparticles could make them even more valuable in the treatment of a wide variety of cancers.
This new technique appears to work with virtually any nucleoside analog and has the net effect of improving the pharmacological behavior of this class of compounds. This research appears in the journal Nano Letters.
A research team headed by Patrick Couvreur, Ph.D., at the CNRS in Châtenay-Malabry, France, found that attaching the molecule squalene to any one of several nucleoside analogs triggered a self-assembly process that creates nanoparticles that are stable in biological fluids. Squalene is a naturally occurring, water-insoluble compound involved in synthesizing steroid hormones. Linking this molecule to a water-soluble nucleoside analog causes the resulting conjugates to form a core-shell nanostructure, with the nucleoside analogs creating an outer layer that shields the squalene portion from the surrounding aqueous environment.
Tests using cultured tumor cells showed that a squalene-gemcitabine conjugate was up to eight times more potent as an anticancer agent compared to unmodified gemcitabine. In addition, these in vitro studies showed that the squalene-gemcitabine conjugate was able to kill cells that had developed resistance to gemcitabine. The researchers attribute the improved anticancer activity, in both normal and resistant cells, to the fact that the conjugate is poorly metabolized by the enzymes that normally detoxify nucleoside analogs.