Multifunctional polymer nanoparticles pass critical in vivo test

In an effort to overcome the drug resistance that often occurs in cancer, a team of investigators has developed a nanoparticle made of a blend of polymers that first releases a powerful anticancer drug and then delivers an agent that tricks a drug-resistant cell into committing suicide. Now, tests in mice with human breast cancer have shown that these blended nanoparticles are effective in maintaining high levels of both drugs in the vicinity of tumors.

Mansoor Amiji, Ph.D., Principal Investigator, Nanotherapeutic Strategy for Multidrug-Resistant Tumors Platform Partnership at Northeastern University, led the research team that reported on this study in the journal Molecular Pharmaceutics. This platform partnership is part of the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer.

In a previous study, Dr. Amiji and his collaborators showed that the combination of the anticancer drug paclitaxel and a molecule known as ceramide was able to kill drug-resistant breast cancer cells growing in culture. Ceramide is a naturally occurring compound that cells produce to trigger apoptosis (programmed cell death) when the cells suffer irreversible damage, such as when they are exposed to an anticancer drug. Tumor cells that have developed drug resistance are able to destroy ceramide before it triggers the apoptosis pathway.

In the current study, these two drugs were encapsulated in a single nanoparticle made of two polymers. One polymer, known as poly(beta-amino ester) (PbAE), dissolves rapidly in the acidic environment inside tumor cells, and the researchers used that polymer to encapsulate paclitaxel. The second polymer, poly(d,l-lactide-co­-glycolide) (PLGA), dissolves far more slowly under the same conditions, affording a means of encapsulating ceramide for release after a time delay, when a drug-resistant cell will be trying to avoid apoptosis.

The researchers injected these nanoparticles into mice with human breast tumors. They then measured drug concentrations both in blood and in the vicinity of the tumors. The results showed that this blended nanoparticle was able to sustain high levels of the drugs in the mice and that, as a result, the drugs accumulated in the tumors. This study was not intended to determine whether the drugs had the desired therapeutic effect; those data will come from studies that are now under way.

This work, which is detailed in the paper "Biodistribution and Pharmacokinetic Analysis of Paclitaxel and Ceramide Administered in Multifunctional Polymer-Blend Nanoparticles in Drug Resistant Breast Cancer Model," was supported by the NCI Alliance for Nanotechnology in Cancer. Investigators from the Massachusetts General Hospital, University of Pittsburgh, and the Fox Chase Cancer Center also participated in this study. An abstract of this paper is available at the journal's Web site.View abstract.