Nanotech medicines held up by lack of particle characterization.

A. CAVANAGH, WELLCOME IMAGES

Nanotechnology has invaded the world of biomedicine over the past decade, with scientists increasingly using nanoparticles as potential vehicles for delivering drugs to specific tissues.

Yet the particles are often so poorly understood that their chances of making it off the laboratory bench and into the clinic are being damaged, experts warned at the first international workshop on nanotech medicines held by the European Medicines Agency (EMA) in London earlier this month. They say there is too little rigorous measurement of the particles’ basic properties, such as size, shape and surface area. “Characterization is the biggest challenge to this field,” Simon Holland, director of process understanding and control at pharmaceutical company GlaxoSmithKline (GSK), headquartered in London, told the conference.

Nanomedicine draws on both biology and materials science, but communication between the two fields has not always been good enough. “In the earlier days, the communities that characterized and the communities that did the cell biology were very different,” says Kenneth Dawson, a chemist at University College Dublin and director of Ireland’s Centre for BioNano Interactions. The situation is slowly improving, he adds — at least for ‘pristine’ nanoparticles in the laboratory.

But in the messy biological system of the bloodstream or the cell, the precise form of the nanoparticles is often something of a black box. “Everybody accepts that as an academic community we haven’t been characterizing enough,” says Dawson. “In the absence of that you’ll never get a drug approval licence.”

The EMA, which serves a regulatory function similar to that of the US Food and Drug Administration, has approved 18 nanomedicine products so far, most of which are very simple, says Dawson. For example, medicinal liposomes — tiny droplets of a drug encased in lipids — are temporary assemblages that are designed to break apart in the body.

But smarter nanomedicines with more complex properties are in the pipeline. Liposomes might be coated with polyethylene glycol (PEG) molecules to prevent them from coagulating, for example. The liposomes’ ability to deliver a drug will then depend on how many PEG chains there are per particle, and what proportion of those chains are linked to each other. Without characterization of these details, explains Dawson, there would be no way to determine whether a nanomedicine fails a clinical trial because the drug itself is ineffective, or because its carrier is coagulating too much.

Sizing up nanoparticles, even in their pristine state, can prove a problem. Holland noted that in a recent GSK project, the size of drug particles was measured by laser diffraction. But whereas one method of analysing the data gave a median particle size of 740 nanometres, an alternative approach indicated 130 nanometres. Such a large difference could drastically alter drug activity, and there would be no way of pursuing a drug approval application until it was resolved, says Dawson.

SOURCE: NIH REPORT

As funding pours into the field (see ‘A small revolution’) attempts are under way in both Europe and the United States to characterize nanoparticles in biological systems. One such problem is that nanoparticles aggregate proteins at their surfaces to form ‘protein coronas’, which can drastically affect their behaviour. Jim Riviere, director of the Center for Chemical Toxicology Research and Pharmacokinetics at North Carolina State University in Raleigh, and his colleagues recently proposed a biological surface adsorption index that would characterize the corona on the basis of a range of factors, including the distribution of electrons in the nanoparticles, proteins and solvent (X.-R. Xia, N. A. Monteiro-Riviere and J. E. Riviere Nature Nanotechnol. 5, 671–675; 2010). “I personally think we really can’t understand a lot about the biological fate of these materials until we develop and validate metrics that actually correlate to biological fate,” says Riviere.

Riviere’s approach just tackles one of many issues, however. “This is a fiercely debated topic these days,” says Justin Teeguarden, a senior scientist at Pacific Northwest National Laboratory in Richland, Washington. “Asking for a gold standard for the community right now is like asking microbiologists what the gold standard for characterizing bacteria should be a few years after microscopes became available.”

Nanotech medicines held up by lack of particle characterization.

Daniel Cressey

A. CAVANAGH, WELLCOME IMAGES

Nanotechnology has invaded the world of biomedicine over the past decade, with scientists increasingly using nanoparticles as potential vehicles for delivering drugs to specific tissues.

Yet the particles are often so poorly understood that their chances of making it off the laboratory bench and into the clinic are being damaged, experts warned at the first international workshop on nanotech medicines held by the European Medicines Agency (EMA) in London earlier this month. They say there is too little rigorous measurement of the particles’ basic properties, such as size, shape and surface area. “Characterization is the biggest challenge to this field,” Simon Holland, director of process understanding and control at pharmaceutical company GlaxoSmithKline (GSK), headquartered in London, told the conference.

Nanomedicine draws on both biology and materials science, but communication between the two fields has not always been good enough. “In the earlier days, the communities that characterized and the communities that did the cell biology were very different,” says Kenneth Dawson, a chemist at University College Dublin and director of Ireland’s Centre for BioNano Interactions. The situation is slowly improving, he adds — at least for ‘pristine’ nanoparticles in the laboratory.

But in the messy biological system of the bloodstream or the cell, the precise form of the nanoparticles is often something of a black box. “Everybody accepts that as an academic community we haven’t been characterizing enough,” says Dawson. “In the absence of that you’ll never get a drug approval licence.”

The EMA, which serves a regulatory function similar to that of the US Food and Drug Administration, has approved 18 nanomedicine products so far, most of which are very simple, says Dawson. For example, medicinal liposomes — tiny droplets of a drug encased in lipids — are temporary assemblages that are designed to break apart in the body.

But smarter nanomedicines with more complex properties are in the pipeline. Liposomes might be coated with polyethylene glycol (PEG) molecules to prevent them from coagulating, for example. The liposomes’ ability to deliver a drug will then depend on how many PEG chains there are per particle, and what proportion of those chains are linked to each other. Without characterization of these details, explains Dawson, there would be no way to determine whether a nanomedicine fails a clinical trial because the drug itself is ineffective, or because its carrier is coagulating too much.

Sizing up nanoparticles, even in their pristine state, can prove a problem. Holland noted that in a recent GSK project, the size of drug particles was measured by laser diffraction. But whereas one method of analysing the data gave a median particle size of 740 nanometres, an alternative approach indicated 130 nanometres. Such a large difference could drastically alter drug activity, and there would be no way of pursuing a drug approval application until it was resolved, says Dawson.

SOURCE: NIH REPORT

As funding pours into the field (see ‘A small revolution’) attempts are under way in both Europe and the United States to characterize nanoparticles in biological systems. One such problem is that nanoparticles aggregate proteins at their surfaces to form ‘protein coronas’, which can drastically affect their behaviour. Jim Riviere, director of the Center for Chemical Toxicology Research and Pharmacokinetics at North Carolina State University in Raleigh, and his colleagues recently proposed a biological surface adsorption index that would characterize the corona on the basis of a range of factors, including the distribution of electrons in the nanoparticles, proteins and solvent (X.-R. Xia, N. A. Monteiro-Riviere and J. E. Riviere Nature Nanotechnol. 5, 671–675; 2010). “I personally think we really can’t understand a lot about the biological fate of these materials until we develop and validate metrics that actually correlate to biological fate,” says Riviere.

Riviere’s approach just tackles one of many issues, however. “This is a fiercely debated topic these days,” says Justin Teeguarden, a senior scientist at Pacific Northwest National Laboratory in Richland, Washington. “Asking for a gold standard for the community right now is like asking microbiologists what the gold standard for characterizing bacteria should be a few years after microscopes became available.”