March 13, 2006
Multifunctional Dendrimer for Cancer Therapy
Paclitaxel, the active ingredient in Taxol™ and Abraxane™, is a powerful but non-selective anticancer agent that triggers programmed cell death, or apoptosis, in cells exposed to this drug. In an effort to improve the drug’s selectivity for cancer cells over healthy cells, and to create a single agent that can both image and treat malignant cells, investigators at the University of Michigan have linked paclitaxel, a fluorescent imaging agent, and a tumor-targeting agent to a dendrimer. Initial experiments have shown that this multifunctional, nanoscale drug delivery construct does discriminate between healthy and malignant cells.
A team of investigators led by István Majoros, Ph.D., and James Baker Jr., M.D., reported its work on the development and characterization of this multifunctional nanoscale device in the journal Biomacromolecules. Dendrimers are spherical, highly branched polymers. Their well-defined size, relative ease of synthesis, and chemically modifiable surface makes them promising multifunctional nanoparticles for delivering both imaging agents and anticancer drugs to tumor cells. The goal of the current work, in fact, was to create a “working, proof-of-principle example,” of a single dendrimer containing targeting, imaging, and therapeutic functions.
To produce their test nanodelivery system, the investigators started with a so-called fifth generation PAMAM dendrimer. Precise chemical and physical characterization of this particular dendrimer provided detailed information on how best to attach the three different kinds of molecules – targeting agent, imaging agent, and therapeutic agent – in optimal proportions to the surface of the dendrimer. The investigators chose folic acid as the tumor-targeting agent, the fluorescent dye known as fluorescein isothiocyanate as the imaging agent, and paclitaxel as the therapeutic agent.
Following synthesis and characterization of this tri-functional nanoparticle, the investigators tested its targeting and cell-killing properties using two sets of cancer cells: one that expresses the folic acid receptor, and one that does not. This experiment showed that only the cells containing the folic acid receptor took up the dendrimer, an event that was seen easily thanks to the fluorescent imaging agent attached to the dendrimer. The dendrimer construct was highly toxic to these cells. In contrast, the dendrimer construct had no effect on the cells without the folic acid receptor. Similarly, neither type of cell showed any ill effects when exposed to a dendrimer that contained the targeting agent and imaging agent but no paclitaxel. Based on these results, the investigators will now conduct tests to determine if these promising initial results are seen when this multifunctional dendrimer is given to animals with tumors that overexpress folic acid receptors.
This work, which was funded by the National Cancer Institute, is detailed in a paper titled, “PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality.” An abstract of this paper is available through PubMed.