By Tiffany O'Callaghan
Foldable, flexible microparticles modelled on red blood cells may hold a key to the development of longer-acting, better-targeted drugs, and could even open up the possibility of making synthetic blood, according to a new study.
Researchers already know that particle structure affects how well a drug is distributed throughout the body and how long it circulates in the bloodstream. Smaller particles tend to circulate longer because they can more easily pass through tiny blood vessels, for example. For the most part, research and design have focused on particle size and shape. Now, by creating microparticles mimicking red blood cells, a team at the University of North Carolina at Chapel Hill have underscored the difference that flexibility makes. The research is published online today in The Proceedings of the National Academy of Sciences USA.
Chemistry graduate student Timothy Merkel worked with chemist Joseph DeSimone and colleagues to create hydrogel microparticles with characteristics modelled on mouse red blood cells. Using a technique developed in DeSimone's lab, known as particle replication in nonwetting templates (PRINT), the hydrogel was pushed into moulds by a roller, creating discs just 6 micrometres in diameter.
By varying the chemical composition of the particles, the researchers created red blood cell mimics with four different degrees of 'deformability'.
It has long been speculated that the deformability of particles influences how long they circulate and where they are distributed in the body. Red blood cells are equipped for longevity and have an average lifespan of 120 days. As they age, they become stiffer and less capable of passing through the tiny vascular structures in the spleen, where they're ultimately removed.
Although previous studies have examined deformability in particles modelled on red blood cells, this study also used a live-animal model to analyse the synthesized hydrogel red blood cell mimics. The flexibility and high biocompatibility of hydrogel polymers has made them increasingly popular in biochemical research. "We're the first to test this in a living system," Merkel says.
In two analyses, Merkel and his colleagues found that the most flexible particles consistently circulated for longer. In the first experiment, the particles moved through a model that required the 6-micrometre discs to squeeze through openings half their diameter (see video).
In a subsequent experiment, the researchers injected the particles into the bloodstream of live mice and monitored their distribution every two seconds for two hours using a laser-scanning microscope. In both experiments, they found that the least flexible particles got bumped out of circulation the fastest, while the springiest discs persisted much longer: in live mice, 30 times as long as the more rigid discs.
"That's what we expected to have happen," says Merkel of the longer circulation of flexible particles. Yet less expected was how particles with different flexibility tended to pool in different organs. After the experiment in live mice, the mice were killed and their organs examined.
The team found that the least springy particles routinely got held up at the first point at which they encountered smaller vascular structures: the lungs. "I didn't think we were going to see such a dramatic cut-off," says DeSimone.
By contrast, the team found that the majority of the most flexible microparticles ended up in the spleen -- largely bypassing the liver. That finding could have useful implications, DeSimone says. "There are lot of drugs you don't see on the market, as they get screened out because they have liver toxicity." As Merkel says, "Avoiding liver uptake could open up a large therapeutic window."
Other hydrogel researchers also praised the team's finding. "It was quite exciting to see the low level of accumulation in the liver," says Patrick Doyle, a chemical engineer at the Massachusetts Institute of Technology in Cambridge, whose research examines both the shape and deformability of hydrogel particles.
Doyle also expressed enthusiasm at the step forward this research marks for chemical engineering as a field: "I think these findings are going to spur a lot more research in this area of custom-designed microparticles for drug delivery and imaging."
DeSimone suggests that if future studies bear out his team's findings, the results could be applied in several areas, such as the manufacture of synthetic blood, development of longer-acting and better-targeted delivery of imaging agents and pharmaceuticals (including cancer drugs), and even a potential use in the removal of harmful substances. "Imagine if you were removing cholesterol," DeSimone suggests: the drug could be designed so that it acts like "an empty truck that, as it drives around getting filled up, gets triggered to be removed".
Although these preliminary findings are a promising advance, synthetic blood isn't likely to be just around the corner. Yet, DeSimone says hopefully, applications for the delivery of cancer drugs could be in early clinical trial stages within four years.