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Nanotechnology successfully used to halt atherosclerotic plaque growth in animal model.

A research team showed that a nanotherapeutic medicine can halt the growth of artery plaque cells resulting in the fast reduction of the inflammation that may cause a heart attack, according to a study led by researchers from Icahn School of Medicine at Mount Sinai.  In just one week the team showed that their novel cell proliferation-specific approach successfully suppressed atherosclerotic plaque growth and inflammation in mice engineered to mimic human vascular disease.  Atherosclerosis is a major cause of death around the globe, and the team state that their new nanomedicine strategy offers a new way to reduce the number of heart attacks and strokes.  The opensource study is published in the journal Science Advances.

Building upon previous studies by their Massachusetts General Hospital research collaborators which found that macrophage proliferation dictates atherosclerosis-related vessel wall inflammation, the research team applied a nanomedicine strategy with a molecule of ‘good cholesterol,’ or high-density lipoprotein (HDL), a naturally occurring shuttle that travels from the liver to arteries. The research team took advantage of HDL’s natural travel routes, loading it with the widely-used cholesterol-lowering medication called simvastatin (Zocor), which it shuttles into arterial walls.

The simvastatin-loaded nanoparticles, named S-HDL, work by targeting inflamed immune cells called macrophages within high-risk arterial plaques. These macrophages become laden with cholesterol and start proliferating in plaques, thereby increasing inflammation. This lipid-driven inflammatory process drives atherosclerotic plaque buildup and rupture leading to a heart attack or stroke.

Since patients hospitalized after heart attack or stroke have a high recurrence rate of up to 20 percent within three years, the researchers also tested the possible benefits of adding an eight-week regimen of oral statins after the one-week S-HDL nanotherapy. Mice study results showed superior long-term therapeutic benefits of a combined total nine-week S-HDL and oral statins regimen, by first rapidly reducing plaque inflammation and then continuously keeping it suppressed.

The researchers envision their S-HDL nanomedicine therapy could be translated quickly to human clinical trials as a short-term infusion therapy for heart attack and stroke patients to rapidly suppress plaque inflammation, which can be sustained using current standard of care oral statin medication.

The team state that nanotherapeutically inhibiting local macrophage proliferation is possible and medical teams can effectively apply it to treat inflammation inside arteries. The researchers surmise that the data findings demonstrate that the two-step regimen not only reduces macrophage accumulation but also reduces the expression of key genes linked to inflammation in this cell type.

The researchers look forward to translating their promising mice study findings to larger animal models and human clinical trials in the not to distant future.

Source:  The Mount Sinai Health System 

Study summary.  (A) First, we investigated the mechanisms by which statin-loaded HDL nanoparticles (S-HDL) reduce plaque inflammation. Blood Ly-6Chigh monocyte targeting, monocyte recruitment, plaque phenotype, macrophage proliferation, macrophage emigration, and macrophage inflammation were investigated by flow cytometry, MRI, latex bead–based in vivo cell tracking, laser capture microdissection, and mRNA profiling. (B) To evaluate S-HDL’s translational potential, we combined one-week S-HDL intervention with an eight-week oral statin treatment. Plaque macrophage accumulation, macrophage phenotype, plaque phenotype, and toxic effects on the liver were evaluated in Apoe−/− mice fed a high-cholesterol diet (HCD) for 26 weeks.   Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation.  Mulder et al 2015.
Study summary. (A) First, we investigated the mechanisms by which statin-loaded HDL nanoparticles (S-HDL) reduce plaque inflammation. Blood Ly-6Chigh monocyte targeting, monocyte recruitment, plaque phenotype, macrophage proliferation, macrophage emigration, and macrophage inflammation were investigated by flow cytometry, MRI, latex bead–based in vivo cell tracking, laser capture microdissection, and mRNA profiling. (B) To evaluate S-HDL’s translational potential, we combined one-week S-HDL intervention with an eight-week oral statin treatment. Plaque macrophage accumulation, macrophage phenotype, plaque phenotype, and toxic effects on the liver were evaluated in Apoe−/− mice fed a high-cholesterol diet (HCD) for 26 weeks. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. Mulder et al 2015.

 

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