Since the 1950s, researchers have been trying to mimic the abilities of red blood cells. These flexible discs carry oxygen throughout the body, squeezing through the smallest capillaries to do so. But the physical characteristics of red blood cells, including their doubly concave shape, have made them difficult to copy with precision.
In research published Monday in the Proceedings of the National Academy of Sciences, a group specializing in drug delivery has found a way to create biodegradable, biocompatible particles with the size, shape, and flexibility of red blood cells. The group believes these artificial cells might be particularly effective not just for carrying oxygen but also as therapeutic and imaging agents.
“People have made over a thousand different polymers of different sizes for drug delivery. But if you look at them all together, they represent the synthetic world; the particles are nice and spherical,” says Samir Mitragotri, a chemical engineer at the University of California at Santa Barbara, who led the new work. “If you look at the biological world, nature uses all kinds of particles for delivering its own goods. Bacteria, cells, viruses are all designed to perform very specific delivery functions.”
To create the synthetic cells, Mitragotri, along with researchers at the University of Michigan, start with spherical particles made of a common polymer called poly(lactic-co-glycolic acid (PLGA), a compound known for its biocompatible and biodegradable properties. They expose the spheres to rubbing alcohol, which causes them to deflate and collapse into the dimpled shape of a red blood cell. The hard PLGA particle acts as a mold, around which the researchers can deposit layer after layer of proteins. They crosslink the proteins to get them to hold to the PLGA, then dissolve the rigid inner structure. The result is a soft, flexible protein shell the size and shape of a red blood cell. The researchers can also vary the protein coatings depending, for example adding hemoglobin, which could carry oxygen.
So far, Mitragotri has shown that the particles are flexible enough to compress and flow through capillary-sized tubes, and can be infused with drugs at just about every stage of the process. His group has also encapsulated iron-oxide nanoparticles in the synthetic cells, creating a potential contrast agent for MRIs. “One can imagine putting these particles into the blood and using them to visualize blood flow,” Mitragotri says.
“Overall, I’ve never seen anything like it. Both the concept and the fabrication methods they developed are very interesting,” says Ali Khademhosseini, a biomedical engineer at the Harvard-MIT Division of Health Sciences and Technology. “There’s an increasing appreciation about how the shape of particles is important for a variety of different things, like the hydrodynamics of particles inside fluid, or how different biological entities interact with them.”
Such flexible, potentially long-lasting particles hold great potential for drug delivery. But Mitragotri has not yet looked to see whether the synthetic cells can stand up to the most difficult test: remaining in circulation. Proving that the particles remain in the bloodstream and do not prompt an immune attack is a critical step that will require testing in animals.
“Back in 1966, I made similar [particles] that can change in shape and in size,” says artificial blood researcher Thomas Chang from McGill University in Quebec, Canada. Those cells, he says, could also squeeze through capillary tubes and were about the same size as red blood cells. The problem was that even synthetic cells one-eighth of the size of regular blood cells were purged from the blood within 30 seconds. (By the 1970s, researchers found that artificial blood particles work best at 200 nanometers or less–30 times smaller than red blood cells.) “The main thing is to show that they remain in circulation,” Chang says.
Even the most advanced synthetic particles get cleared out of the blood incredibly rapidly. “The longest circulating nanoparticle ever lasted about 24 hours, so there’s a need for developing an approach to something that can circulate in the bloodstream for a long period of time,” says Jeffrey Karp, a Harvard-MIT professor of health science and technology. But the new research could be a big step in that direction, he says, if the body keeps the synthetic cells circulating for as long as two to three months, like real red blood cells. Karp says that the production methods that Mitragotri and his colleagues used could be scaled up without much difficulty.
Assuming that the cells stand up to the circulatory test of time, “I would think that anybody who’s trying to use a nanoparticle-like system for delivery or for imaging would have good reason to go with these particles,” says Daniel Pack, a drug-delivery researcher at the University of Illinois at Urbana-Champaign.
Mitragotri says that the next step will be animal testing. He also wants to look into other ways to mimic nature’s delivery methods. “We started with red blood cells, but there are many others I can think of that might be of interest, like viruses and bacteria,” he says. “You have your synthetic world on one side, and your biological world on the other, and we want to bridge the gap as best we can between these two extremes.”