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1/15/2007 9:26:16 AM
Dendrimers Improve Cancer Drug Uptake and Antitumor Activity

With an eye toward developing a delivery vehicle for anticancer agents that are poorly soluble in water, a research team at Boston University and the Research Triangle Institute (RTI) has developed a biocompatible dendrimer that wraps itself around water-insoluble drugs. The investigators have used this dendrimer to create water-soluble formulations of three promising anticancer agents belonging to the camptothecin family, which also includes the widely used drugs topotecan and irinotecan. This research is reported in the journal Cancer Research.

David Kroll, Ph.D., of RTI, and Mark Grinstaff, Ph.D., at Boston University, led the team of investigators developing water-soluble dendrimers as drug delivery vehicles. In this instance, the researchers created a dendrimer by polymerizing the natural products succinic acid and glycerol. This dendrimer readily formed stable complexes with three different water-insoluble camptothecins. The encapsulation process increased the water solubility of the drugs by approximately 10-fold.

Tests with four types of cultured cancer cells showed that the dendrimer-drug complexes were readily taken in by the cells. When compared to free drug, up to 16 times more of the encapsulated drug accumulated inside cells within two hours.

More importantly, cultured tumor cells retained a greater percentage of the drug when it was delivered using the dendrimer, a finding that the investigators noted came as a surprise. In one experiment, for example, about 50 percent of the dendrimer-complexed drug that had accumulated within 30 minutes remained in the cell some 32 hours later. In contrast, only 35 percent of the free drug that had accumulated within the first 30 minutes remains inside the cells after 32 hours. Cytotoxicity assays showed that increase in drug accumulation translated into improved potency at killing cancer cells.

This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, “Dendrimer-encapsulated camptothecins: increased solubility, cellular uptake, and cellular retention affords enhanced anticancer activity in vitro.” Investigators from Duke University and Duke University Medical Center also participated in this study. An abstract of this paper is available through PubMed.

View abstract.

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