A team led by Prabhas Mogue at Rutgers University in New Jersey has engineered molecules called nanolipoblockers and used them to reduce the build-up of low-density lipoproteins (LDLs, or 'bad' cholesterol).
High LDL levels are a major contributing factor in cardiovascular disease. LDLs accumulate to form hardened vascular plaques which block arteries and cause inflammation that damages surrounding tissues. The plaques and inflammation develop when oxidized LDL molecules are attacked by macrophages, the immune system cells which normally destroy infectious agents and scavenge cellular debris.
"Macrophages perform an essential role in keeping organisms healthy…[but] their interaction with highly oxidized LDL molecules has quite the opposite effect," says Mogue.
The interaction between LDL molecules and macrophages is mediated by receptors on the surface of the immune system cells which recognize the specific three-dimensional shape of LDL molecules.
The nanolipoblocker molecules synthesized by Mogue's team, in collaboration with Professor Kathryn Uhrich, compete with oxidized LDLs for the macrophage cell-surface receptor binding site, thus reducing the accumulation of LDLs by up to 75%. They consist of tailored organic chain molecules whose ends are attached to the same point, much like the spokes of a bicycle wheel, to form a structure called a micelle.
"We're…tailoring the structure of the molecule, changing groups on the ends of the chains and closely analyzing which forms of the particles bind to the different macrophage receptors," says Uhrich. "The significant finding of our study is that the nanoscale organization matters tremendously for blockage of oxidized LDL, which opens new avenues for more specific targeting of receptors."
The team are now beginning to test the approach in animals. According to Mogue, if animal testing proves to be successful, nanolipoblockers could be used to target specific sites in humans. This contrasts with the use of statins, the commonly prescribed cholesterol-lowering drugs, which reduce LDL levels throughout the body.