November 13, 2006
Nanoparticle-Arsenic Combination Makes for More Potent Anticancer Agent
Arsenic trioxide, one of most promising drugs for treating acute promyelocytic leukemia, could achieve broader use if encapsulated in lipid-based nanoparticles designed to release their cargo inside tumor cells. That is just one of the findings from work conducted by Thomas O’Halloran, Ph.D., and colleagues at Northwestern University’s Nanomaterials for Cancer Diagnostics and Therapeutics Center for Cancer Nanotechnology Excellence (CCNE). This work appears in the Journal of the American Chemical Society.
O’Halloran’s team is not alone in attempting to encapsulate arsenic trioxide into lipid-based nanoparticles. It is, however, the first to develop a method of loading large amounts of this anticancer drug into nanoparticles and getting the drug to remain trapped within the nanoparticle until released inside tumors.
The key to developing a stable nanoparticle formulation, the Northwestern team found, was to first load the nanoparticles with metal salts such as nickel acetate, cobalt acetate, copper acetate, or zinc acetate and then add arsenic trioxide. As soon as arsenic trioxide crosses into the nanoparticle, it forms an insoluble complex with the metal ions that are already there. Equally as important, this process produces acetic acid that diffuses out of the nanoparticle. As this molecule leaves the nanoparticle, it drives more arsenic trioxide into the nanoparticle, further increasing the amount of active drug encapsulated within the nanoparticle. The researchers were able to observe the accumulation of the active anticancer agent within nanoparticles using transmission electron microscopy and x-ray analysis.
The investigators note that although this nanoparticle is stable for over six months when refrigerated at neutral pH, it rapidly releases its cargo when subjected to the acidic, or low pH, conditions inside tumor cells. The rate and amount of drug release depends significantly on which metal was used initially to load arsenic trioxide into the nanoparticles. The researchers note that though none of the metals they used in this study showed any toxic effect in these preliminary experiments, it may be possible that certain metals could have synergistic effects when combined with arsenic trioxide. Further experiments are needed to test for such effects.
In one experiment designed to test whether the entrapped drug could still kill tumor cells, the researchers found that the nanoparticle formulation still retains cytotoxicity, though longer exposure times were needed to produce the same level of cell killing as they obtained using free arsenic trioxide.
Acute promyelocytic leukemia is a variant of acute myeloid leukemia (AML) that occurs primarily in young children and accounts for approximately 1 percent of childhood leukemias. This particular form of cancer results when chromosomes 15 and 17 undergo an abnormal exchange of genetic information between themselves.
This work, which was funded by the National Cancer Institute’s Alliance for Nanotechnology in Cancer, is detailed in a paper titled, “Lipid encapsulation of arsenic trioxide attenuates cytotoxicity and allows for controlled anticancer drug release.” An abstract of this paper is available through PubMed.