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Cancer nanotechnology: small, but heading for the big time

With cancer at the forefront of therapeutic applications of nanotechnology, Dan Jones investigates progress in the field.

Back in September 2004, the US National Cancer Institute (NCI) launched the Alliance for Nanotechnology in Cancer to stimulate and coordinate research in biology, engineering and materials science to push cancer nanotechnology forward. Just over 2 years on, such research is attracting increasing attention: in a round-up of last year's breakthroughs in the burgeoning field of nanotechnology from Forbes magazine, anticancer nanoparticles featured in the top five.

Nanotechnology is being applied to cancer in two broad areas: the development of nanovectors, such as nanoparticles, which can be loaded with drugs or imaging agents and then targeted to tumours, and high-throughput nanosensor devices for detecting the biological signatures of cancer. Combined, such technologies could lead to earlier diagnosis and better treatment for patients with cancer.

Spearheading efforts to expedite the clinical application of these technologies, the NCI currently funds eight Centers of Cancer Nanotechnology Excellence (CCNE) in the United States, in addition to 12 other smaller programmes. "We've pulled most of the key players in medical nanotechnology into this programme, and we're spending about US$35–40 million a year on these approaches," says Piotr Grodzinski, Director of the NCI Alliance. The NCI Alliance is actively pursuing both the therapeutic and diagnostics aspects of cancer nanotechnology and will continue until 2010, with follow-up programmes in sight. Grodzinski hopes that by then nanotechnology will have matured into a clinically useful approach.

Early signs are promising. The research highlighted in the Forbes list was conducted by a team led by Robert Langer, a chemical engineer who is Institute Professor at the Massachusetts Institute of Technology (MIT), USA, and also one of the two principal investigators for the MIT–Harvard CCNE. Langer, with Omid Farokhzad, Assistant Professor of Anaesthesia at Brigham and Women's Hospital, Boston, USA, and colleagues, uses polymeric nanoparticles coated with aptamers — RNA-based targeting moieties — to guide them towards the tumour, where they bind, enter the cells and then dissolve to spill out their contents — the anticancer drug docetaxel. The nanoparticles are also coated with polyethylene glycol (PEG) to aid their safe passage through the bloodstream and into the tumour cells. A single injection of such nanoparticles coated with aptamers that bind to prostate-membrane-specific antigen eradicated tumours in a mouse model of prostate cancer (PNAS 103, 6315–6320; 2006). "Extensive animal models show that this approach is both safe and efficacious," says Langer.

One of the key challenges in creating effective nanoparticles is targeting them to appropriate tissues and cells. Although biological targeting using aptamers or antibodies on the surface of nanoparticles is one popular option, other researchers are beginning to exploit the physical characteristics of the particles to guide them to desired locations. "The size, shape, physical properties, density and charge all affect how particles travel through the body, and whether or not they will cross biological membranes," says Mauro Ferrari, a professor of nanotechnology at the University of Texas Health Science Center, the M.D. Anderson Cancer Center, and Rice University in Houston, USA. His work shows that biological barriers such as the vascular wall dominate the distribution of injected nanoparticles in the body, even for particles that are decorated with exquisite biological recognition moieties. A judicious choice of size and shape of a nanovector particle can enhance by orders of magnitude the amount of drug delivered to the target lesion site. "I believe that the era of 'rational design' of nanoparticles has arrived, and that optimal design will occur based on principles of engineering and physics," Ferrari says.

Joseph DeSimone, professor of chemistry and chemical engineering at the University of North Carolina at Chapel Hill, USA, is putting these principles into practice. DeSimone has adapted fabrication technologies from the electronics industry to produce shape-specific organic nanoparticles. "We basically make moulds out of a really low-surface-energy fluoropolymer that allows us to synthesize truly engineered particles with desired characteristics," says DeSimone. DeSimone's engineered process allows the precise control over particle size (20 nm to >100 mum), particle shape (spheres, cylinders, discs, toroidal), particle composition (organic or inorganic, solid or porous), particle cargo (hydrophilic or hydrophobic therapeutics, biologicals, imaging agents), particle compliance (stiff, deformable) and particle surface properties (Avidin–biotin complexes, targeting peptides, antibodies, aptamers, PEG chains).

Nanoparticles are not the only way to encapsulate a drug or imaging agent into a small carrier, but DeSimone suggests that the nanotechnology approach offers crucial advantages. "With liposomes [which have previously been used to deliver drugs] you kinetically trap what cargo molecule you can, but you can't modify the amount that gets trapped," says DeSimone. "Our moulds enable us to make organic particles loaded with therapeutic cargoes at any amount — 5%, 20% or whatever we want."

DeSimone is also taking a cue from naturally occurring particles, such as red blood cells, to produce compliant nanoparticles that can deform to pass across biological barriers such as sinusoids in the spleen or the blood–brain barrier. "The ability to get through these barriers and the flow characteristics of particles — whether they flow through the centre of a capillary or along cell walls — are dictated by size, shape, surface chemistry and compliance," says DeSimone.

Liquidia Technologies Inc., based in Morrisville, North Carolina, USA, was spun-off from DeSimone's laboratory a few years ago to develop this technology platform. Right now, the company is working on feasibility studies, as well as research collaborations with some large pharmaceutical and medical device companies. "These feasibility studies will run through the rest of 2007, with the goal of focused out-licensing and joint product development deals within the next 18 months," says Luke Roush, Vice President of Business Development at Liquidia. "These studies will also provide data that will validate application of our technology platform, and help us advance knowledge about how to apply it in areas of clinical need," adds Roush.

The synergy between the therapeutic and diagnostic/monitoring applications of nanotechnology could be particularly potent. Linda Molnar, a programme officer at the NCI Alliance, sees a future in which new imaging agents, new diagnostic chips and new targeted therapies come together to facilitate a form of personalized medicine in which early and more accurate detection leads to rapid initiation of treatment, followed by diagnostic tests to see whether the patient is responding. If they do, good; if not, another therapy can be tried and the process repeated — what Molnar refers to as real-time therapeutic monitoring. "The sooner you can detect the cancer and start treatment, and know that you're treating that patient with a therapy that they respond to, the better," says Molnar. "That's why people are excited, and why people at the NCI have made such a large investment in nanotechnology for cancer."

As novel nanomedicine products move from the laboratory to the clinic, the issue of regulatory approval of these new technologies will come to the fore. In many cases these products will combine established drugs with materials already used in FDA-approved therapies, and no special provisions are in place to deal with nanomedicine at present. An FDA spokesperson said, "All nanotechnology applications will at this point fall within the existing framework for review of all products submitted to CDER [Center for Drug Evaluation and Research]; [however], CDER is discussing how nanotech products may be treated differently, if necessary."

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