Doxorubicin-Loaded Dendrimer Offers Hope for Colon CA

Here’s another excellent example of the promise of nanotechnology. Doxorubicin, bound to a specially designed polymer, has displayed a good therapeutic effect and less toxicity than free doxorubicin in mice models.
From UC Berkley press office:

… a powerful cancer drug, doxorubicin, enveloped in a large polymer produced a 100 percent cure in mice with induced colon cancer, while all mice treated with the drug doxorubicin only died. The doxorubicin-polymer combination proved as effective as a liposomal therapy – doxorubicin encapsulated in fat bubbles called liposomes – now used to treat several types of cancer in humans.
“There’s nothing better than comparing a drug against what works in people, and in our tests in mice, the new technique cured 100 percent of the mice, performing at least as well as the liposomal drug,” said Jean Fréchet, professor of chemistry and chemical engineering at UC Berkeley and a researcher at Lawrence Berkeley National Laboratory…
Fréchet, however, saw an advantage with branching polymers instead of linear polymers. Called dendrimers because of their tree-like structure, they don’t pass through filtration pores in the kidney for the same reason that it’s hard to force a tree branch though a hole. Tests show a half life in the body – the time it takes for half the drug to be eliminated or degraded – of up to 30 hours, versus a few minutes for pure doxorubicin. A linear polymer with the same half life would be impractical, Fréchet said.
In addition, Fréchet based the dendrimer polymers on a chemical structure, a polyester, that is degraded naturally inside the body, which prevents its accumulation.
“Our contribution to this field was to recognize that polymer architecture makes a difference, and Jean’s contribution was to recognize that polyester is a great backbone for doing this,” Szoka said. [Dr. Frank Szoka is a professor of pharmaceutical chemistry at UCSF –ed.]
Fréchet and his UC Berkeley graduate students synthesized a branching polyester polymer they refer to as a “bowtie” dendrimer because it has two halves that branch out from a center where they’re tied together. The team chemically attached up to 32 doxorubicin molecules to one side of the bowtie, and a smaller number of linear chains to the other half, which wrapped around the package like a hairball protecting the drug.
The mice were injected with colon cancer cells, and several days later with doxorubicin, doxorubicin-dendrimer or Doxil. Though the latter two cured the mice, the group did not address long term toxicity, which would require tests in larger animals. Doxorubicin is known to be toxic to the heart after repeated use, though liposome encapsulation seems to prevent this.
“Much less drug goes to the heart with the dendrimer and the liposome, so I would predict there would be much less cardial toxicity with the dendrimer also,” Szoka said.
One advantage of the dendrimer over liposomes is that the therapy can be delivered via one injection, while liposome treatment is by intravenous infusion. Both deliver a higher dose of drug – three to four times as much – than can be achieved with doxorubicin alone, since the drug is so toxic. Thus, attachment to the dendrimer considerably reduces its side-effects.
One big disadvantage of the dendrimer is that it requires laborious synthesis, but Fréchet already is at work on a new chemical process that could solve that problem, making synthesis relatively inexpensive.

More…
NCI’s Alliance for Nanotechnology in Cancer: Single-Dose Drug-Loaded Dendrimer Cures Mice of Colon Cancer
Flashback: Temperature-Sensitive Doxorubicin Nanoparticles