June 26, 2006
Drug-Loaded Nanoparticles Use Two-Pronged Approach to Kill Cancer Cells
Tumor cells that develop resistance to multiple anticancer drugs are responsible for a majority of cases in which treatment ultimately fails. In most cases of multiple drug resistance, the tumor cells have evolved the ability to produce a protein in their membrane, known as p-glycoprotein (P-gp), that pumps anticancer agents back out of the cells before the drugs can exert their toxic effects. Certain types of nanoparticles have already demonstrated they can overcome multiple drug resistance by ferrying drugs into cancer cells, bypassing this protein pump.
Now, researchers in France have come up with a new way to circumvent drug resistance. Using a lipid nanocapsule, Alf Lamprecht, Ph.D., of the University of Franche-Comté in Besançon, and Jean-Pierre Benoit, Ph.D., of the University of Angers, have created a drug delivery device that both delivers drug into a cancer cell and inhibits p-glycoprotein. This two-pronged approach successfully killed drug resistant tumor cells. The investigators report their findings in the Journal of Controlled Release.
The key ingredient in the nanocapsule is a fatty polymer known as poly(ethylene glycol)-600-hydroxystearate (PEG-HS), which the investigators used to create a water-soluble coating for the nanocapsule that would also shield the particle from uptake and elimination by immune system cells. But in two strokes of serendipity, the researchers found that once the nanocapsule enters a cell it quickly sheds its PEG-HS coating and that free PEG-HS inhibits p-glycoprotein from inside the cell. PEG-HS, which is currently used as a component in various injectable drugs and has been proven safe for human use, has no effect on p-glycoprotein when it is outside of cells.
Taking advantage of this property, the investigators used their PEG-HS-coated lipid nanocapsule to create a sustained-release formulation of etoposide, a proven anticancer drug used to treat testicular cancer and some forms of lung cancer but is particularly prone to multiple drug resistance. They then tested the drug-loaded nanocapsule on glioblastoma cells expressing p-glycoprotein. The results of these experiments showed that smaller nanocapsules were more effective than larger ones, but that all the PEG-HS nanocapsules loaded with etoposide were able to overcome drug resistance and kill the cultured tumor cells. Additional tests conducted on non-malignant astrocytes, another type of brain cell, found that the drug-loaded nanocapsules were far less toxic to these healthy cells than they were to the brain tumor cells.
This work is detailed in a paper titled, “Etoposide nanocarriers suppress glioma cell growth by intracellular drug delivery and simultaneous P-glycoprotein inhibition.” An abstract of this paper is available through PubMed.