Web Date: October 10, 2013
Making Lipoprotein Nanoparticles In Less Time
In the bloodstream, high-density lipoproteins (HDLs), commonly known as “good cholesterol,” ferry cholesterol away from the plaques that build up on the insides of blood vessels, which lead to blockages and hardening of the arteries. Because of HDL’s ability to home in on these cardiovascular lesions, scientists think that it might also make a good delivery vehicle for drugs or imaging agents. Now, researchers have found a way to make large numbers of HDL nanoparticles quickly and easily using a microfluidics device, opening the door for testing therapies using the nanoparticles (ACS Nano 2013, DOI: 10.1021/nn4039063).
For treating cardiovascular diseases, such as hardened arteries, doctors often prescribe statin drugs. These compounds lower cholesterol levels, and some have anti-inflammatory effects. But many researchers would like to find more effective cardiovascular treatments, says Zahi A. Fayad of Mount Sinai Hospital, in New York City. For example, statins and other drugs might work better if doctors could target the agents directly to cardiovascular lesions using HDLs, he says.
One problem with using HDLs in therapies is that it is difficult to produce sufficient amounts of the lipoprotein particles. The conventional method for synthesizing HDL nanoparticles requires multiple steps and takes about 22 hours to complete. Also the size of the nanoparticles often varies from one batch to the next.
So Fayad collaborated with Robert Langer and YongTae Kim at Massachusetts Institute of Technology to develop a microfluidics device for the large-scale synthesis of HDL nanoparticles. In the device’s microfluidic channel, a unique, controlled flow pattern efficiently mixes lipids with apolipoprotein A-1 (ApoA-1) to produce HDL, says Kim, now at Georgia Institute of Technology.
The microfluidics device, made of the polymer polydimethylsiloxane, has three inlet channels. The researchers add lipids plus imaging or therapeutic agents to the central channel and ApoA-1 to the two outer channels. When the streams meet, they produce two whirlpool-like patterns, called microvortices, within a wide channel downstream of the inlets. “These two identical microvortices create strong mixing that usually cannot happen in microfluidic devices,” Kim says.
After optimizing conditions like the flow rate and the concentrations of the various solutions, the researchers could produce HDL nanoparticles of uniform size—8 to 9 nm in diameter—at a rate of 420 mg of particles per hour. The conventional HDL-synthesis method yields only about 120 mg of HDL in 22 hours.
The team used the device to incorporate hydrophobic molecules into HDL nanoparticles, including the anti-inflammatory drug simvastatin, gold nanocrystals for computed tomography imaging, and iron oxide for magnetic resonance imaging. The researchers think that HDL nanoparticles containing imaging agents might help pinpoint plaques in arteries, offering new ways to diagnose atherosclerosis noninvasively.
“The uniformity of the particles produced is impressive and reminiscent of traditional chemical synthesis,” says Samuel K. Sia of Columbia University. He thinks the method will help researchers test HDL therapies in animal models or the clinic. Fayad and his colleagues are now planning to test therapeutic HDL nanoparticles made with their synthesis technique in large animal models of atherosclerosis, such as rabbits and pigs.
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