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Date: Monday, 29-Jan-2007
Dendrimers, highly branched, spherical polymers, have demonstrated their utility as drug and imaging agent delivery vehicles for use in detecting and treating cancer, with several dendrimer-based agents nearing human clinical trials.Now, researchers at Tel-Aviv University in Israel have developed a second-generation dendrimer that will disintegrate upon command, releasing all of its drug payload in a single dose. These so-called self-immolating dendrimers could prove useful for delivering massive, lethal doses of anticancer agents inside malignant cells. This work appears in the journal Bioconjugate Chemistry.
Doron Shabat, Ph.D., led the research team developing dendrimers designed to fall apart when a specific enzyme breaks one chemical bond at the core of the dendrimer. These dendrimers contain a water-insoluble, or hydrophobic, core surrounded by a poly(ethylene glycol), or PEG, shell. The core contains the enzyme-sensitive chemical bond, or trigger, activated by the enzyme known as penicillin-G-amidase. The investigators also attached multiple molecules of the anticancer agent camptothecin to the dendrimer.
Tests with this construct showed that it disperses readily in water and that it does fall apart when treated with its triggering enzyme, releasing free camptothecin. Tests with culture tumor cells confirmed that this dendrimer could release therapeutic doses of its drug payload, and in fact, the dendrimer-based formulation was more effective at stopping cell growth than was an equal dose of free camptothecin. In contrast, the dendrimer-formulation was incapable of inhibiting cell growth when the investigators repeated this experiment without adding the triggering enzyme. The researchers note that this type of dendrimer could be designed to release its payload only in the presence of a tumor-specific enzyme.
This work is detailed in a paper titled, "Enzymatic activation of second-generation dendritic prodrugs: Conjugation of self-immolative dendrimers with poly(ethylene glycol) via click chemistry." An abstract of this paper is available through PubMed. View abstract.
http://nano.cancer.gov