October 23, 2006
Versatile Self-Assembling Nanoparticles Improve Drug Potency
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.
Based on these promising results, the investigators then assessed anticancer activity of squalene-modified gemcitabine in both mouse and rat models of human leukemia. In each case, 40 percent of the animals treated with the squalene-gemcitabine conjugate survived for at least 100 days after treatment. In contrast, control animals that received a placebo or unmodified gemcitabine all died from cancer within 60 days.
This work is detailed in a paper titled, “Squalenoyl nanomedicines as potential therapeutics.” Investigators from the Università degli Studi di Torino in Torino, Italy, and SPI-BIO in Fontenay-aux-Roses, France, also participated in this study. This paper was published online in advance of print publication. An abstract of this paper is available at the journal’s website.