Nanotech News

June 15, 2005

Nanoparticles Transport Cancer-Killing Drug Into Tumor Cells in Mice to Increase Efficacy, Lower Drug Toxicity

Dendrimers, spherical nanoscale polymers, have shown promise as targeted delivery vehicles for anticancer therapy. Now, researchers at the University of Michigan have shown for the first time that a targeted dendrimer can indeed deliver anticancer drugs to tumors and that this nanotechnology-based treatment is effective in treating tumors growing in living animals and in prolonging life. "This is the first study to demonstrate a nanoparticle-targeted drug actually leaving the bloodstream, being concentrated in cancer cells, and having a biological effect on the animal's tumor," says James Baker Jr., M.D., who directed the study, which was published in the journal Cancer Research.

Baker’s group, comprising researchers with expertise across a broad range of disciplines, has focused on developing multifunctional dendrimers as targeted carriers of anticancer drugs (see earlier story). Through a series of detailed chemical investigations, which included supercomputer-enabled modeling studies, Baker and his team have developed techniques to create so-called poly (amidoamine), or PAMAM, dendrimers that are capable of ferrying a host of molecules to specific places in the body. These branched polymers form compact nanoparticles of well-defined size, ranging from less than 2 nanometers in diameter to greater than 13 nanometers in diameter (click here to see video of dendrimer assembly). More importantly, the dendrimer nanoparticles developed by Baker’s group have reactive chemical groups on their surfaces that can be used to attach targeting molecules, therapeutic drugs, and imaging agents, either alone or in combination.

In the current work, the investigators used what is called a G5 dendrimer, which has a diameter of approximately 5 nanometers and room to attach as many as 110 targeting, therapeutic and imaging molecules. In this case, the investigators attached folate as a targeting molecule and methotrexate as the therapeutic agent. Folate targets a high-affinity folic acid receptor (see earlier story) that many cancer cells overexpress, and methotrexate is an effective but highly toxic anticancer drug. The researchers also attached a fluorescent molecule – either fluorescein or 6-carboxytetramethylrhodamine – to the dendrimer to act as an optical imaging agent. Adding the fluorescent probe enabled the investigators to track the dendrimer’s distribution in the body by measuring fluorescence in various tissues.

When tested in laboratory mice that had received injections of human epithelial cancer cells, the targeted, methotrexate-loaded dendrimer was 10 times more effective than methotrexate alone at delaying tumor growth. Nanoparticle treatment also proved to be far less toxic to mice than the anticancer drug alone. In the longest trial reported, which lasted 99 days, over 30 percent of the mice given the multifunctional nanoparticle survived. In contrast, all of the mice receiving free methotrexate died, either from tumor growth or from drug toxicity. Tumor growth also proceeded unabated when mice received a folate-targeted G5 dendrimer that did not contain methotrexate. The presence of a fluorescent label on the dendrimer had no effect on anti-tumor activity.

Biodistribution studies using the fluorescent tag showed that folate-targeted nanoparticles concentrated in tumors and liver, and tumor concentrations of the dendrimer remained high for four days after injection. These studies also revealed that the kidneys quickly filtered any nanoparticles that remained in circulation – they either did not bind to a target or were eventually released from their target – and eliminated them in urine. The researchers found no evidence that nanoparticles were able to leave the bloodstream and enter the brain. The nanoparticles did not appear to generate an immune response in mice in the study. Confocal microscopy studies, again utilizing the fluorescent tag on dendrimers, confirmed that the targeted nanoparticles were taken up by tumor cells.

In future research, scientists at the Michigan Nanotechnology Institute will determine the maximum therapeutic dose, in research animals, of targeted nanotherapy with methotrexate, and will complete other preliminary studies in preparation for the first human clinical trial, which Baker says is scheduled to begin within two years.

This work, which was funded by the National Cancer Institute, is detailed in a paper titled, “Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer.” The University of Michigan has filed a patent application on targeted nanoparticle technology, and a licensing agreement is currently being negotiated with Avidimer Therapeutics, a biopharmaceutical company in Ann Arbor, in which Baker holds a significant financial interest. An abstract of the paper is available on the journal’s website.
View abstract.