The National Cancer Institute on Tuesday formally launched its alliance for nanotechnology and oncology, a $144.3 million, five-year initiative to develop and apply nanotechnology to cancer prevention, detection, diagnosis and treatment.

"We are struck with the potential of nanotechnology to exponentially improve progress against cancer," National Institutes of Health Deputy Director Ann Barker told reporters at a press briefing. They are so struck, in fact, that Under Secretary of Commerce for Technology Philip Bond told reporters that, with plans to invest $961 million, the government will put "twice as much in nanotechnology this year alone as it did in the peak year of the Human Genome Project."

Will all that money affect the future of nanotechnology, when current efforts, after all, have been resulting in nanoscale therapeutics in the broadest sense for quite some time?

The answer might come from nanotechnology's strong engineering roots.

"We are talking about nano-objects that are not made by molecular biology and living cells," Richard Smalley, professor at Rice University and winner of the 1997 Nobel Prize in chemistry for his discovery of buckminsterfullerene (C60), said in a separate scientist briefing. "And yet they are on the nanometer scale, so they can be intimately associated with the machinery of life."

Smalley admits that scientists' ability to engineer at the nanoscale is, so far, "rather primitive," compared to the sophisticated molecular biology tools that have been developed over the past few decades. Improving that ability is one goal of the initiative.

Mauro Ferrari, special expert to the NCI on nanotechnology and professor at Ohio State University, added that, to some degree, nanotechnology's novelty is based on "the notion of being able to assemble multiple functionalities." For example, a nanoparticle for injection and delivery of a cancer drug would need to be able to conjugate to the drug, to deliver it to the right place and release it at the right time, which are "extraordinarily complex" tasks in their own right.

"The difficulty is that there are great scientists trained in great disciplines - this doesn't fall in any of them," said Ferrari, who described himself as having "a Purple Heart in the interdisciplinary wars." To develop successful nanotechnology applications, researchers need to possess "the technical ability to make the thing, as well as the biological wisdom to really identify what it is that you need. The great challenge is to be able to integrate those two visions."

Therapeutic Applications: Gumming Up The Works'

Nanotechnology's effects on improving cancer therapeutics are expected to be mainly indirect, through enabling more targeted drug delivery that would in turn allow the deployment of more toxic agents. Samuel Wickline, professor of medicine, physics and biomedical engineering at Washington University, described perfluorocarbon nanoscale emulsions as an example of an agent that could be simultaneously used for imaging, targeting and drug delivery.

"You can paste a whole bunch of different things onto it" he said, "You might put targeting ligands on it. . . you might put drugs on it, or you might put imaging agents on it."

However, there also is research showing that nanoagents might be used as therapeutics. Research groups focusing on drug delivery and diagnostic applications of nanoscale agents are concerned with biocompatibility - that is, desperately trying to avoid cytotoxic effects of the particles themselves. In contrast, researchers that want to use nanoagents as therapeutics attempt to harness such cytotoxic effects. In a paper titled "Folate-mediated cell targeting and cytotoxicity using thermoresponsive microgels," scientists at the Georgia Institute of Technology and Purdue University recently reported on one such potential therapeutic application.

In the paper, which was published in the Aug. 25, 2004, issue of the Journal of the American Chemical Society, Satish Nayak and his colleagues reported on the use of hydrogel nanoparticles to destroy cancer cells in culture. The researchers constructed the particles in a core-shell structure; core and shell are the same basic polymer, but conjugated to different molecules - in that case, a fluorophore for tracking in the core and folic acid for targeting in the shell.

In general, "Core-shell synthesis allows you to make particles with orthogonal or complementary chemistries that are well-localized within the particle," said Andrew Lyon, associate professor at Georgia Tech's School of Chemistry and Biochemistry and senior author. "In general, core-shell synthesis is going to allow for a lot of variability and multifunctionality in targeting drugs."

The nanoparticles were conjugated to folic acid, a B vitamin that is necessary for cell division and therefore a favorite nutrient of cancer cells. The researchers then exposed KB cells, an epithelial cancer cell line that easily can be induced to express high levels of folate receptors, to the folate-conjugated microgels. The cells did indeed take up the conjugated nanoparticles, which accumulated in the cytosol.

In a second step, the researchers then heated up the cell cultures, from 27oC to 37oC. At the higher temperature (normal body temperature), the nanogel clumped, destroying the cells it had entered. The exact mechanism by which that occurred was not clear, but the hypothesis is that as the particles aggregate, they caused "protein adsorption and denaturation and disrupt normal cellular pathways," Lyon told BioWorld Today. "Basically, it's gumming up the works."

While the specific temperatures provide an obvious clue that the material is not ready for in vivo testing, the fact that the material shows temperature-dependent state changes is encouraging to the researchers, who are currently attempting to move the temperature at which this state change occurs into a more useful range.

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