It’s a dilemma pharmaceutical researchers have been grappling with for decades. How do you ensure a sufficient therapeutic dose of your drug reaches the correct tissues without killing harmless, healthy cells in the process?
Cancer treatment is often offered as an example of where targeted drug delivery is particularly pertinent. By targeting anti-cancer drugs to just the tumour, healthy cells could potentially remain untouched, reducing the toxic side effects of chemotherapy. But drug targeting has applications in many other areas of the human body, from crossing the heavily protected blood-brain barrier to homing in on an unstable plaque in the cardiovascular system and preventing a life-threatening stroke.
Achieving targeted delivery on the nano-scale
So how can targeted drug delivery actually be achieved? Breaking down the drug or the drug carrier into nanoscale elements is one technique that is becoming increasingly widespread across the pharmaceutical industry.
"When you break down either the drug or the drug carrier into a nano-size, there is a huge increase in surface area and this is important in terms of reactivity," said Richard Moore, scientific director at the UK-based Institute of Nanotechnology.
"If you can target these nanoscale drugs as well, you will need less of the drug, which is important when you’re talking about drugs that can have harmful side effects such as cytotoxic drugs used in cancer treatment."
There are many ways in which nanoscale drugs can be targeted. "Tumours typically have a disorganised vasculature, which is leaky in places. You can take advantage of this with drug particles of the right size because they can pass out through these leaky blood vessels and into the tumour. That’s one of the non-active ways of delivering drugs to a tumour," said Moore.
A more active targeting technique is to attach biomolecules such as antibodies to the nanoscale drug particles which then bind to specific sites on the surface of cancer cells.
"By understanding how cells work, you can find a variety of tricks to get as much of the drug as possible inside your cell of choice," Moore added.
Nano drugs – what’s available?
Pharmaceutical and biotechnology companies have really started capitalising on the potential of nanotechnology-enabled drug delivery. Indeed, Moore said that in 2010 there were at least 30 drugs listed as being on or close to the market that boasted some form of nanoscale delivery system.
Ranging from systems using polymeric nanoparticles to nanoshells, nanocrystals to quantum dots, the variety of different nanotechnologies being employed across the pharmaceutical industry only continues to increase.
"A very important aspect of this is that drugs have a certain patent life time before they face competition from generic drug companies. So if pharmaceutical companies can reformulate useful drug molecules for new applications they can often extend their useful lifetimes," Moore explained.
"Because of the extremely high cost of drug development, drug companies are very interested in adding value and patent extension to existing high value drugs using novel delivery methods."
Three companies that have recently released innovative nanoscale drug delivery systems are Alkermes Contract Pharma Services (formerly Elan Drug Technologies), Bind Biosciences and Selecta Biosciences. Ireland-based Alkermes offers a nanoscale carrier system for drugs based on the company’s proprietary nanocrystal technology, while Selecta’s targeted tolerogenic Synthetic Vaccine Particles are designed to induce antigen-specific immune tolerance to a wide array of relevant antigens, including small molecules, peptides, oligosaccharides and proteins.
Finally, Bind Biosciences has developed nanoparticles that deliver cancer drugs more precisely to malignant cells and help drugs circulate longer in the body. Biodegradable polymers surrounding the drug allow it to diffuse slowly into the bloodstream, while a coating of polyethylene glycol, a molecule with water-like properties, helps the particle evade detection by the immune system.
A sprinkling of ligands designed to bind to the target cells make sure the particle’s payload reaches its destination.
A long way to go
For Moore, the industry has only really scratched the surface of nanotechnology’s potential so far, and inventor, entrepreneur and former MIT researcher Geoffrey von Maltzahn agrees.
Nanoscale drugs are still only able to deliver on average 2% of the drug into the target tissues, with the remaining 98% going elsewhere. "This tells you quite clearly that we have a long way to go when we think about truly selectively delivering toxic therapeutics to sites of cancer formation," said von Maltzahn.
This is where the next generation of researchers comes into play. Von Maltzahn’s team at MIT, for example, has developed a new drug delivery technique whereby two different types of nanoparticles communicate with one another to improve drug delivery.
"We took inspiration from systems in the human body – for example, how immune cells in our blood talk to each other to find and treat disease. We’re trying to emulate that with synthetic particles so that when one particle gets to the site of disease it can communicate that event to expedite the subsequent arrival of other nanoparticles," he said.
"In our case, the implementation of communication into these systems improved drug delivery by about 40 fold relative to systems without them, but that doesn’t mean the technology is ready to put on the shelf and be made available to cancer patients," he emphasised.
"I would compartmentalise our work as the next generation of how these sorts of systems can be designed. It’s the beginning of a new way of thinking about designing therapeutics, but very much still something that has a lot of hard work to be done in the lab to make it robust."
The testing of systems using new approaches to nanotechnology or new types of nanomaterials is a crucial part of the picture. "The body does its best to reject anything it’s not used to so if you’re using novel materials, there is a lot of safety testing to be done to determine the fate of these materials in the human body.
The material might deliver the drug, but does the carrier stay around? Is it excreted? Is it broken down by the liver? Does it biodegrade in the body? Does it transform into something else? There’s a lot of work to determine what actually happens to some of these materials," said Moore.
While the pharmaceutical industry clearly has some way to go before drugs using nanoscale delivery systems are widely available to patients, there is no doubt that a select few companies and researchers are making significant progress in improving drugs’ ability to target diseased cells without damaging their healthy counterparts.
Although research like von Maltzahn’s is very much part of the next generation, companies like Bind, Selecta and Alkermes have the potential to quickly and effectively begin to make a real difference in patient care.