Conjugation to a Dendrimer Reduces Anti-Cancer Drug Toxicity

Cancer researchers have found a way to dramatically lower the toxicity of the major anticancer drug doxorubicin (DOX) by conjugating it to a biodegradable dendrimer, a regularly branched molecule whose structure resembles the branches of a tree.

Investigators at the University of California, Berkeley (USA), and the University of California, San Francisco (USA), prepared an asymmetric biodegradable polyester dendrimer containing 8-10 wt % DOX. The design of the dendrimer carrier optimized blood circulation time through size and molecular architecture, drug loading through multiple attachment sites, solubility through PEGylation, and drug release through the use of pH-sensitive hydrazone linkages.

Groups of laboratory mice that had been injected with colon cancer cells were treated with DOX, dendrimer-DOX, or Doxil (a commercially available version of liposome encapsulated DOX). Results published in the November 7, 2006, issue of the Proceedings of the [U.S.] National Academy of Sciences showed that a single intra venous injection of dendrimer-DOX eight days after tumor implantation caused complete tumor regression and 100% survival of the mice over the 60-day experiment. No cures were achieved in tumor-implanted mice treated with free DOX at its maximum tolerated dose, drug-free dendrimer, or dendrimer-DOX in which the DOX was attached by means of a stable carbamate bond. The anti-tumor effect of dendrimer-DOX was similar to that of an equimolar dose of Doxil.

"There is nothing better than comparing a drug against what works in people, and in our tests in mice, the new technique cured 100% of the mice, performing at least as well as the liposomal drug,” said contributing author Dr. Jean Fréchet, professor of chemistry and chemical engineering at the University of California, Berkeley. "We think the new technique has many advantages over liposome delivery. Liposomes can break in the bloodstream, increasing the chance of side effects. The doxorubicin-dendrimer has little or no impact until it penetrates a cell, which eliminates the chance of drug side effects.”



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University of California, Berkeley
University of California, San Francisco