BBI Contributing Writer

The National Cancer Institute (NCI; Bethesda, Maryland) last month launched its alliance for nanotechnology and cancer, 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 (NIH; also Bethesda) 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 would put "twice as much in nanotechnology this year alone as it did in the peak year of the Human Genome Project."

So 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? One difference is 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 (Houston) 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 this ability is one goal of the initiative.

Mauro Ferrari, special expert to the NCI on nanotechnology and professor at Ohio State University (Columbus, Ohio), 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 be able 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."

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 (St. Louis), 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 (Georgia Tech; Atlanta) and Purdue University (West Lafayette, Indiana) recently reported on one such potential therapeutic application.

In the paper, which was published in the Aug. 25 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 of the study. "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 vitamin B 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 can easily 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 27^o C to 37^o C (normal body temperature). At the higher temperature, the nanogel clumped, destroying the cells it had entered. The exact mechanism by which that occurred is not clear, but the hypothesis is that as the particles aggregate, they cause "protein adsorption and denaturation and disrupt normal cellular pathways" Lyon told BBI's sister publication, 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.

Arrowhead unit gain rights to patents

In another interesting development in the nanotechnology arena last month, Arrowhead Research (Pasadena, California) reported that the California Institute of Technology (Caltech; also Pasadena) has granted exclusive rights to more than 80 new U.S. and international patents and patent applications covering microfluidic and micromachine technologies to one of its subsidiaries, Nanotechnica (Pasadena). Terms of the rights acquisitions were not released. Nanotechnica is focused on commercializing nanoscale devices such as scanning probe tips, pathogen sensors and medical diagnostics. Nanotechnica said it "seeks to establish capabilities for mass production of a variety of different, proprietary nanoscale devices and systems."

R. Bruce Stewart, president of Arrowhead, said that acquisition "further strengthens the growing portfolio of patent rights held by Arrowhead and its subsidiaries, which includes exclusive rights to over 180 U.S. and international patents and patent applications in the nanotechnology space." Dr. Yu-Chong Tai, primary inventor of the licensed technologies, is a consultant to Nanotechnica. Tai has broad experience in micromachines and microfluidics and has developed devices such as sensors, anemometers, actuators, microvalves and micromotors. He is a professor of electrical engineering at Caltech and the director of the Caltech Micromachining Laboratory.

The company's R&D team is led by Michael Roukes, PhD, chief technical officer, currently on leave from Caltech. Roukes, professor of physics, applied physics and bioengineering, is the director of the institution's Kavli Nanoscience Institute, co-founder of the Nanosystems Biology Alliance, co-founder and co-director of both the Initiative in Computational Molecular Biology and the Laboratory for Large Scale Integration of Nanostructures, and chair of the external advisory board of the nanoscience center at Harvard University (Cambridge, Massachusetts). Nanotechnica's R&D group also includes consultant Dr. Scott Fraser, the Anna L. Rosen Professor of Biology and director of Caltech's Biological Imaging Center.

Arrowhead Research describes its mission as bringing together "a mix of technologies and rights" to a suite of intellectual property and having three strategic components: forming or acquiring majority-owned subsidiaries engaged in the development and commercialization of nanoscale materials, devices and systems; funding of nanoscience research at universities in exchange for the exclusive right to commercialize resulting intellectual property; and acquisition, license and sublicense of intellectual property in the field of nanotechnology.

Arrowhead is funding three research efforts in nanotechnology at Caltech, in the areas of nanomaterials, nanoelectronics and nanobiomolecular tools. Besides Nanotechnica, it operates two other subsidiaries: Aonex Technologies, developing and commercializing proprietary semiconductor nanomaterial technology; and Insert Therapeutics, developing a proprietary nanoscale drug delivery system.

Nanotech in dental products area

In other news from the nanotech front, Competitive Technologies (CTT; Fairfield, Connecticut) reported that it has granted an exclusive option to research the manufacture and use of CTT's nanotech bone biomaterial for dental applications to what it termed "a major, diverse dental products company." Financial terms were not released.

CTT has an exclusive agreement with the University of South Carolina Research Foundation (USCRF; Columbia, South Carolina) to license and commercialize this nanotechnology – consisting of an injectible calcium phosphate-based biomaterial – from the work of Dr. Brian Genge, a research professor in the department of chemistry and biochemistry at the University of South Carolina.

Applications in this agreement are for dental use, but they also can be applied to human bones, especially related to the spine, and veterinary uses. The bone biomaterial technology is a flowable, moldable paste that conforms to and interdigitates with the host bone. It hardens itself in vivo, forming a solid, bone-like structure capable of stabilizing fractured bone within 15 minutes. The technology features a compressive strength that makes it suitable for weight-bearing and non-weight-bearing bones and is both machinable and drillable.

CTT is commercializing several technologies, including homocysteine assays, sexual dysfunction treatment, video compression and decoding technology, sunless tanning application, silicon carbide wafer testing, animated graphical password security technology, language-mastering software, specialty chemical compounds, pollution abatement process and the Therapik thermal therapy.