A health worker treats a small child

What nanomedicines will do for us - eventually

Pharmaceutical giants have promised consumers an army of nanorobots capable of curing'a whole host of diseases. As we await these medical breakthroughs, a different form of nano-sized health aid called nanomedicine is emerging.

Last year saw the medical industry announce a flurry of exciting developments in the world of nanomedicine. These included banishing annoyances such as athlete's foot, treating advanced ovarian cancer and delivering HIV drugs at lower doses with the same effect, through to advancing our pharmokinetics knowledge and regenerating human organs without the controversial use of embryonic stem cells. But when can we expect these discoveries to start delivering benefits to patients?

No longer the futuristic ideal of science fiction, nanomedicine, which is the application of nanotechnologies in a healthcare setting, is fast becoming fact. Some nanomedicines are already in use, and with over 200 companies established in this field and 38 products available worldwide, more will soon emerge to improve treatment for a wide range of diseases as well as our understanding and control of how drugs work in the body.

To date, the majority of nanomedicine's benefits have involved the use of nanoparticles to improve the behaviour and efficacy of drugs, as well as how they are delivered.

Many of the latest research developments in nanomedicine are demonstrating how we can overcome some of the difficulties experienced by normal medical approaches, such as debilitating side-effects or the body's inability to absorb drugs well enough to gain any benefit from them. Recent years have also seen many diseases and disorders develop a resistance to antibiotics and other drugs traditionally used to treat them, and nanomedicine is leading the way in addressing this problem.

Healthcare researchers have known for many years that identifying illness or disease in its very early stages can help prevent progression and improve the patient's chances of survival. Many diseases show no visible symptoms until they reach an advanced stage, by which time it's often too late for treatment to have any real impact.

The human body does, however, produce evidence of problems at the molecular level much earlier on. Nanomedicine is expected to deliver real improvements quite quickly in diagnostics. By using nanotechnologies to study and identify individual molecules, healthcare professionals can diagnose diseases in time to improve the patient's prognosis; and by using nanomedicines to treat them the outcome can also be improved.

While the early years of research into nanomedicines were plagued by issues of toxicity and concerns about the environmental impact of nanoscale materials, more recent research and improvements to the development processes have shown that they can be produced in a way that is non-toxic to humans. Some nanomedicines can even benefit the environment by recycling materials such as plastic bottles into nanofibre molecules that kill off infected cells while leaving healthy ones alone.

Fighting fungus

Worldwide, over a billion people a year suffer from fungal infections. Many experience simple irritations such as athlete's foot, but at the other end of the scale there are life-threatening fungal blood infections.

The breakthrough that researchers from the Institute of Bioengineering and Nanotechnology in Singapore, working with a team from IBM, have made with their new nanomedicine, which uses common plastic bottles made from polyethylene terephthalate, has caused much excitement in the clinical world.

In a project nicknamed 'Ninjas vs Superbugs', which has brought together research from supercomputing, green chemistry and the healthcare industry, the team has used an organic catalytic process to engineer the plastic bottles into non-toxic, biocompatable, nanofibre molecules that attack fungal infections that have become antibiotic resistant. The new nanomedicine is 1,000 times smaller than a grain of sand and the researchers believe that it can be used to target and kill off just the infected cells without causing any damage to healthy cells.

It does this by creating an electrical charge on the nanoparticles which is attracted only to the fungi cells. The nanoparticles then rip through the fungi cells' membrane walls and destroy them, so they are killed off before they can become immune to the nanomedicine. The nanoparticles then safely biodegrade and disappear from the body.

It is expected that this breakthrough will have applications beyond fungus fighting, with potential to attack MRSA superbug cells and cancer cells. It could also be used in deodorants, toothpastes and other hygiene products as well as a way to kill off the bacteria that grow on contact lenses, meaning users could wear them for longer.

Better HIV drug delivery

At the University of Liverpool, Andrew Owen, professor of pharmacology, who is also chair of the British Society for Nanomedicine, has been working in collaboration with Steve Rannard, professor of chemistry, on research funded by the Engineering and Physical Sciences Research Council into solid drug nanoparticle formulations of HIV drugs.

Prof Owen says: "Our research has shown that drugs formulated in this way are better able to cross intestinal cells and are better absorbed into the body when given orally to preclinical species."

What this means is that it may be possible to reduce the amount of drugs given to patients while maintaining the same level of therapeutic effect, known as bioequivalence. The nanoformulations developed by Prof Owen and his collaborators have been scaled up using pharma industry-relevant processes, produced under GMP conditions, and are currently undergoing stability testing in order to move into a clinical study, which will assess the potential for bioequivalence from a lower dose. So what does this mean for HIV drug delivery in the future?

Globally, more than 35 million people are infected with the HIV virus. The majority of these infected people (70 per cent) reside in resource-limited countries in sub-Saharan Africa where HIV drug manufacturing capacity cannot keep up with demand. So if Prof Owen's nanoparticle formulations can reduce the amount of drug required per patient for effective therapy, more people could be treated with the drugs available.

"The approach may also reduce costs due to the lower amount of drug needed," says Prof Owen, "which would be of clear benefit everywhere. As far as we are aware, success in clinical trials here would lead to the first potential orally-dosed HIV nanomedicine being made available."

The research project has now moved on to assessing the stability of the nanoformulations under various conditions, which will be important to establish a shelf-life for future applications. Once the team has gathered this data, it hopes to conduct a study later this year in healthy volunteers to confirm that the benefits observed in preclinical species also occur in humans.

If all goes to plan with the human study, Prof Owen sees no reason why the new nanoformulations won't be available in the near future. "The solid drug nanoparticle formulations only contain the drug and various constituents that are already used in conventional drug formulations. Therefore, although the technology is novel, there are no new ingredients. Also, we have already successfully translated the methodology for producing the solid drug nanoparticles to kilogram scale, so if our studies in healthy volunteers can confirm the benefits then there is no reason why the formulations may not be available in the short term."

Beating advanced ovarian cancer

The survival rates for women with advanced ovarian cancer are among the lowest of all cancers and, according to Cancer Research UK's statistics, just 42.9 per cent of women are expected to survive five years or more when diagnosed at this stage.

As the symptoms are so hard to spot, sadly many women are already at this stage when their cancer is discovered. But if the success that researchers at Rutgers, the State University of New Jersey, have had with their new targeted nanomedicine approach to successfully treat mice with deadly advanced-stage ovarian cancer can be extended to humans, then that survival rate could be set to improve.

In advanced ovarian cancer, an out-of-control protein called CD44, which is encoded by a conserved gene located on chromosome 11 in humans, accelerates tumour growth and makes it resistant to drug treatment. In a recent study paper published in Clinical Cancer Research, the Rutger researchers revealed how they have used small molecules, called inhibiting RNA molecules, to attack the genes of the excess CD44 protein in isolated metastatic ovarian cancer cells.

The system was tested in mice that had a form of ovarian cancer, which they had developed by being injected with tumour tissue from ovarian cancer patients. The inhibiting RNA molecules were delivered by a nanoscale-based drug delivery system that also included the anti-cancer drug paclitaxel. The results of the tests were very encouraging as the treatment killed the cancerous cells, shrank the tumours, left healthy tissue intact and also caused fewer side-effects than conventional cancer drug therapy.

As the CD44 protein also features in many other cancers, the researchers believe their nanomedicine drug delivery may also help in treatment elsewhere. The next step is to develop a nanomedicine prototype for human consumption and to test it in clinical trials.

Regenerating organs

The use of embryonic stem cells in regenerative medicine has been a controversial issue and it's one that a team of researchers at the University of Manchester's Nanomedicine Laboratory, which is led by Professor Kostas Kostarelos and ranked as one of the best nanomedicine research laboratories in the world, look set to resolve.

In research published in the Journal of Visualized Experiments (JoVE) in December 2013, his team revealed that it has discovered a safe approach to reprogramming somatic cells into induced pluripotent stem (iPS) cells. Research in this field has been seen as a viable, and better, alternative to using embryonic stem cells.

Not only is it less controversial, it has also improved clinical outcomes for patients as - unlike the in vitro, viral method that won Dr Shinya Yamanaka and Sir John B Gurdon the 2012 Nobel Prize for Medicine - it doesn't come with the risk of uncontrolled stem cell growth into tumours. So how have they done this?

According to the research paper they induced somatic cells in the livers of adult mice to transiently behave as iPS cells, by transferring four specific genes using a small, circular double-stranded piece of DNA to manipulate gene expression in cells, rather than introducing the genes through a virus.

While Yamanaka and Gurdon's Nobel Prize-winning viral approach showed some promise, its use has been limited as the in'vivo implantation of these stem cells leads to the formation of tumour-like masses. In'contrast, the technique developed by the University of Manchester team is "the only experimental technique to report the in vivo reprogramming of adult somatic cells to pluripotency using non-viral, transient, rapid and safe methods". It involves injecting large volumes of plasmid DNA to reprogram the cells and, as the plasmid DNA is short-lived, the risk of uncontrolled growth into tumours is reduced.

The team said that it chose to publish the results of its research in JoVE to "emphasise the novelty, uniqueness and simplicity of [its] procedure".

Advanced pharmokinetics

Pharmokinetics is the study of what our bodies do to the drugs we put in them. One'new device developed by Professor Kevin W Plaxco, who heads the Plaxco lab at the University of California, Santa Barbara, could transform pharmokinetic research and resulting drug delivery for patients.

Prof Plaxo says: "We have invented an analytical device that can measure the concentrations of specific small molecules such as drugs and metabolites continuously and in real time as they circulate in the blood. This is the first ever general platform that supports the continuous, real-time measurement of arbitrary small molecules in flowing blood."

For patient care in the future this means improvements in research, as this tool makes it much easier to measure drug pharmacokinetics (i.e. how fast a person metabolises/excretes a drug). "Indeed, because we don't have to keep poking in needles and collecting samples, we could, in theory, make the measurements on ambulatory, awake subjects rather than subjects restrained in bed," Prof Plaxo explains.

Secondly, it also improves clinicians' ability to calculate accurate drug doses. Current dosing calculations rely on weak, second-order predictors of each patient's pharmacokinetics (height, weight, age, etc) but the new device will allow for much greater accuracy in these calculations. "We'can actually measure patient-specific pharmacokinetics quickly and simply. This could vastly improve the accuracy with which doses are tailored to a given patient's metabolism."

The benefits don't stop there; the tool will also deliver high-precision, feedback-controlled drug delivery. "Ultimately, we envision measuring serum drug levels (or the levels of molecules indicative of the patient's response to the treatment) in real time, and using that information to deliver continuously adjusted, optimal drug doses," Prof Plaxo says.

To date, the team has measured three drugs for periods of up to four hours in test subjects. In future, they're expanding this to the detection of new molecules and to the ability to run the device for 24 hours.

But Prof Plaxco doesn't expect this tool to be available for clinical use for a while yet. "This is an unprecedented medical device. While using it as a research tool could be just a few years off, using it as a medical device for measuring pharmacokinetics on individual patients will be some years behind that. Showing that it has the robustness and accuracy to drive drug-dosing in real-time is a much longer-range goal."

Nanomedicines of the future

The advances in nanomedicine that were announced in 2013 show how this pioneering field is a strong weapon in improving how we diagnose, treat and understand diseases. As we are at such an early stage in developing nanomedicines, our knowledge and insight can only grow driving further advances that could see us make real headway in treating some of the world's most deadly diseases.

Hundreds of millions of pounds have already been invested in research in this field, and the global nanaomedicine market has been forecast to grow by 12.3 per cent a year up to 2016. Worldwide, physical and biological scientists, clinicians and healthcare professionals are excited about what it could potentially deliver. As healthcare moves from a one-size-fits-all treatment approach to more personalised care based on an individual's genetics and immune responses, nanomedicine is going to be the key to providing the tailored treatment that will improve patient care.

One of the biggest problems that nanomedicines faces is the enormous costs involved in getting the products approved and to the market. But as the big players, GlaxoSmithKline, Pfizer and Abbott Laboraties, and others of that ilk, are leading the way with bringing nanomedicines to market, they have the big budgets that can support it.

As we look ahead to the nanomedicines of the future, everyone's getting excited about the possibility of medical nanorobots, which coud be used to perform surgery on individual cells and seek out cancer cells and eliminate them. But before we can create nanorobots we have to create a new technology: molecular manufacturing. Perhaps in this field lies the next breakthrough announcement that we can expect from the nanomedicine research world.

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