April 3, 2006
Dendrimer Nanoparticle Overcomes Drug Resistance in Tumor Cells
Investigators at Wayne State University have found that attaching the cancer drug methotrexate to a dendrimer nanoparticle can overcome the resistance to this drug that some cancer cells develop. The researchers also found that this potentially beneficial effect is not seen with all dendrimer nanoparticles.
Reporting its work in the journal Bioconjugate Chemistry, a team of investigators led by Rangaramanujam Kannan, Ph.D., prepared two different dendrimer-methotrexate combinations. In one formulation, the investigators used a dendrimer that had free carboxylic acid groups at the multiple ends of the branched dendrimer polymer. The researchers called this conjugate A. The second formulation, named conjugate B, comprised a dendrimer with free amino groups at the ends of the polymer. The researchers then attached the drug methotrexate to these reactive free ends.
When tested for their tumor-killing properties, the two dendrimer-methotrexate formulations produced markedly different results. Conjugate A was more toxic to all cancer cells than either free methotrexate or conjugate B. But more importantly, conjugate A was the only formulation that was able to kill cells that were resistant to free methotrexate. More remarkable to the investigators was the fact that the resistant cells will not take up free methotrexate, but did take up conjugate A.
Additional experiments revealed that linking methotrexate to the dendrimer had no effect on the way in which this drug kills cells. Rather, the increased cell-killing activity of conjugate A was the result of increased uptake of methotrexate.
This work is detailed in a paper titled, "Activity of dendrimer-methotrexate conjugates on methotrexate-sensitive and -resistant cell lines." An investigator now at Rutgers State University also participated in this study. An abstract of this paper is available through PubMed.