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| Fantastic voyage |
16-Jul-2007 |
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Once firmly in the realm of science fiction, nanotechnology is fast becoming a medical reality
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so fast that regulators are struggling to catch up.
By Bianca Nogrady
IN the classic 1960s science fiction film Fantas
tic Voyage, a medical team is shrunk to micrometre size and injected into the body of a dying scientist, with the mission of removing the blood clot that threatens to claim his life. They have just one hour to complete their task before the miniaturisation process reverses and they are restored to full size.
The story is one of countless nano-sized scenarios that have kept sci-fi fans enthralled for decades. But, while miniaturisation of entire humans is unlikely in the foreseeable future, nanotechnology has now moved from fiction into fact. Dramatic advances in the field promise extraordinary benefits for numerous areas of medicine — including cancer therapy and diagnostics —but they also raise unique safety concerns.
The applications of nanotechnology across science and industry are likely to be incredibly broad, but what they all have in common is the minute scale they operate on: 1-100 nanometres, just billionths of a metre.
In the field of medicine alone, researchers in Australia and around the world are using nanotechnology to develop more efficient, targeted drug delivery systems; more bioavailable and efficacious pharmaceuticals; more effective vaccines; stronger and safer biomaterials; and more accurate diagnostic systems (see box, page 21).
With nanotechnology products already starting to hit the market, therapeutic regulatory bodies are still coming to grips with this unique new technology. Australia’s Therapeutic Goods Administration has identified nanotechnology as presenting “substantial policy and scientific challenges to the TGA into the future”.
“One of the key concerns raised by many commentators in the public arena is that of the potentially unique hazards associated with nanomaterials and the capacity of existing regulatory paradigms to adequately identify and manage those risks,”the TGA says.
So what makes nanotechnology different? Professor Brian Priestly, head of the Australian Centre for Human Health Risk Assessment, says the technology is unique because the properties of even the most stable, well-understood materials change when brought down to the nanoscale.
“It’s really two things which cause nanotechnology to stand out,” Professor Priestly says. “Whether the particles might get to where you wouldn’t expect them to get to, and the reaction of the body.”
For example, at a larger size, a substance might not be absorbed well by the body. At the nanoscale, however, the surface area of a particle relative to its mass is much greater, making it more reactive and more soluble, which increases absorption.
The qualities that make nanotechnology potentially hazardous are precisely those that offer the therapeutic benefits.
One example of how the capacity for greater absorption is being exploited is a transdermal insulin delivery system being developed by Australia’s Interstitial NanoSystems, a spin-off from Nanotechnology Victoria. The company has developed a patch that is coated with about 110,000 tiny needles, 80-120 microns in length, that protrude just through the skin surface into the interstitial fluid but without reaching nerve endings or blood vessels. The key ingredients are the nano-sized insulin particles attached to the needles, says Dr Bob Irving, Nanotechnology Victoria’s director of delivery and sensing.
“Usually, insulin is delivered as a solution and injected,” Dr Irving says. “The key with nanoparticles is because [the insulin] is particulate, and the particles are attached to the needle, we are able to deliver a high concentration from a much smaller patch.”
The nanoscale also means increased solubility and therefore increased efficacy, Dr Irving says. “You’re not going to have particles whizzing around the body, they’re delivered into the interstitial fluid and dissolved.”
While this increased reactivity works in favour of delivering drugs such as insulin, the same principle means normally benign substances such as gold and silver become more reactive at the nanoscale level.
Another unique, and potentially dangerous, aspect of nanoscale particles is their ability to get to parts larger particles can’t reach, Dr Peter Binks, CEO of Nanotechnology Victoria, says.
For example, nanoparticles may travel where larger particles cannot, such as through the skin and across the blood-brain barrier.
“There’s two edges to that sword because if a particle is going to cross the blood-brain barrier that couldn’t have done so before, we’ve got to work out is that going to be a bad thing,” Dr Binks says. “But it might well allow us to deliberately get particles across the blood-brain barrier that we haven’t been able to before.” This could present new ways of treating neurological diseases such as Alzheimer’s disease, for example, he says.
Nanotechnology is not just about making existing therapeutic molecules smaller. Another burgeoning area is about creating designer nanoscale particles that have the ability to interact with cell surface receptors, either to deliver a drug or exert a therapeutic effect themselves.
VivaGel — a vaginal microbicide — is one such designer nanomolecule, developed by Australian company Starpharma. The active ingredient is a tiny particle 2-3 nanometres across, called a dendrimer, which is built from scratch using synthetic, organic polymers, says Mr Paul Barrett, Starpharma’s vice-president of business development.
“The dendrimer is a small particle like a little tumbleweed, and its purpose is to bond to proteins in the coatings of viruses and prevent those viruses fusing with human cells,” Mr Barrett says. In this case, the dendrimer is designed to interact with HIV and HSV viral particles, and prevent infection, but without crossing the vaginal membrane and entering the blood. The product has undergone phase one clinical trials and extensive safety testing.
Mr Barrett says there is also growing evidence that it may act as a contraceptive.
Nanoscale molecules can also act as a vehicle for a therapeutic substance, and be coupled with an antibody or ligand that enables the vehicle to bond with a very specific site to deliver their therapeutic content.
Australian company pSivida is developing a silicon-based nanostructure called BioSilicon that is structured to create ‘nano-pores’. The pores are designed to be filled with small molecules, proteins and even vaccine ingredients, allowing for controlled, targeted drug release. The silicon itself is designed to safely biodegrade in body fluids.
This biodegrading feature is one way around another concern Professor Priestly has about nanotechnology, which is how the body might react to the presence of nanoparticles. “Once it gets into tissues, any particulate matter that doesn’t dissolve will need to be cleared by normal immune-type mechanisms, such as macro-phages, and these can generate local toxic effects,” he says.
However Dr Krassen Dimitrov, group leader at the Australian Institute for Bioengineering and Nanotechnology at the University of Queensland, believes the size of nanoparticles can avoid this. “Because they’re so small, they’re not really a target of the immune system and can be cleared out through the urinary system,”he says.
Not all nanotechnology in medicine presents such safety concerns. Nanotechnology-based diagnostics is another hot area and, because it doesn’t involve injecting or applying an active ingredient in vivo, a much less controversial one. Dr Dimitrov believes nanotechnology could transform medical diagnostics in the next 5-10 years.
The biggest advantage it has to offer is miniaturisation of diagnostic technology, allowing diagnostic tests to be performed at the bedside, or on the battlefield, for far less cost.
“Diagnostics has traditionally been a very cost-sensitive market,” Dr Dimitrov says. “That’s why nanotechnology can make a huge difference because, when you miniaturise, you reduce the amount of reagent that is needed, for example. There is a lower cost per component.”
Dr Dimitrov is working on a novel diagnostic method that uses a ‘nano-barcode’ to label target substances in a blood sample. “The molecules in a droplet of blood can be detected with much higher sensitivity once you go to the nanoscale,” he says.
“If you have some molecule in your circulation that you want to detect and quantify, you can attach these nanobarcodes to the molecules [using conventional antibodies].” An electronic barcode ‘reader’ then reads the barcodes and counts exactly how many of that particular molecule are present in the sample.
One example of how this might be used is for an STI screen, where a simple finger-prick test could target a panel of 20 different pathogens and immediately identify if the patient is positive and even tell if the pathogen has any level of antibiotic resistance.
“The revolution is that you can detect each individual molecule in the drop of blood,” Dr Dimitrov says. This accuracy comes solely from the miniaturisation, not the specificity of the test.
However, some diagnostic nanotechnologies do involve injecting substances into a patient. American company Nanospectra Biosciences is developing a method of imaging and targeting tumours more accurately using gold-coated nanospheres made of silica. Once injected into the blood, these nanospheres collect in tumours because of their leaky blood vessels. When excited with a near-infrared laser, the gold coating either emits light, enabling the location of the tumour to be pinpointed accurately, or absorbs light that is converted into heat, destroying the tumour tissue. Animal studies have so far not indicated any toxicity or immune effects from the nanoshells, and the company is about to test them in human patients.
But while silicon and gold are known, well-studied and relatively benign substances, the challenge for regulatory authorities is to identify when the miniaturisation of these substances may introduce new and potentially hazardous properties.
“Basically what we’re saying is that it is sometimes very difficult to work out exactly when the toxicity profile of a nanomaterial has changed from a larger bulk-type material,” Professor Priestly says.
This poses a particular problem from the regulatory perspective, especially if a nano-engineered therapeutic is merely a scaled-down version of an existing drug or material that is already in common use.
“The issue is when products come into the regulatory system that are based on a chemical which is already in use, it may not get the same type of scrutiny as a nanomaterial unless it is flagged,”Professor Priestly says. For example, many drug delivery nanostructures are based on simple carbon nanotubes that wouldn’t necessarily trigger regulatory interest because they are based on a non-toxic material, he says.
While these are unique issues, Starpharma’s vice-president of development and regulatory affairs Mr Jeremy Paull says existing regulatory process are well set up to handle the new technology. “[VivaGel] is a pharmaceutical and the existing regulatory pathway for pharmaceuticals is incredibly rigorous,” Mr Paull says. “There is a lot of safety testing, a lot of pre-clinical work and a lot of clinical work, so we have found that existing regulations, particularly in the US and also Australia, are absolutely adequate for this sort of development program.”
Unlike with genetically modified organisms, many governments are wholeheartedly embracing nanotechnology, and investing enormous amounts of money into developing their nanotechnology capabilities. And while a nano-robot or miniaturised medical team might be a little far-fetched, Dr Binks believes nanotechnology holds great promise for the field of medicine. “It’s got potential,” he says. “I don’t want to tell you that it’s going to solve all human ailments, but there are some things that we can do in nanotechnology that are really going to make a difference.”
FROM LITTLE THINGS, BIG THINGS GROW
Medical applications of nanotechnology could include:
* A patch delivering nanoscale insulin molecules that are far more soluble and therefore better absorbed.
* A designer organic nanostructure called a dendrimer that bonds to viral surface proteins and prevents viruses such as HIV and HSV fusing with human cells.
* Nanoscale biomarkers for cardiovascular disease and cancer with enhanced fluorescence to improve imaging of plaques and cancer cell clusters.
* Gold-coated silicon nanoshells that are injected into the bloodstream and accumulate in the leaky microvessels of tumours, where near-infrared laser stimulates them to either emit light for more accurate imaging, or absorb light and generate heat to kill tumour cells.
* 'Nano-barcodes' that can be attached to conventional antibodies and used to label target molecules in a fingerprick blood sample, allowing rapid and extremely accurate tests.
* Porous silicon nanostructures to be used as a biodegradable drug delivery device.
* Silver nanotechnology coatings for invasive medical devices to reduce risk of bacterial infection.
Source: Medical Journal of Australia 2007; 186:189-91.
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