Nanoparticle 'wrapped' compound stops atherosclerosis in mice

In what may be a major leap forward in the quest for new treatments of the most common form of cardiovascular disease, scientists at Johns Hopkins University in Baltimore report they have found a way to halt the progression of atherosclerosis in a mouse model. To do so, they used a nanoparticle delivery system with a chemical that restores the animals' ability to properly handle cholesterol.

The team’s results, published online in the journal Biomaterials, builds on their recent research that previously identified glycosphingolipids (GSL) as the chief culprit behind a range of biological glitches that affect the body's ability to properly use, transport, and purge itself of vessel-clogging cholesterol.

That earlier study showed that mice on a high fat/high cholesterol diet remained free of heart disease if pretreated with the compound D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), which is a GSL inhibitor.

But the researchers were stymied because D-PDMP is rapidly metabolized and cleared in the bodies of larger animals and humans.

The newly published article reveals how the scientists overcame that hurdle: They encapsulated D-PDMP within a biodegradable polymer (composed of polyethylene glycol and sebacic acid) that was formulated into nanoparticles.

The idea worked. They determined that encapsulated D-PDMP nanoparticles were absorbed faster and lasted much longer. “Polymer-encapsulation increased the residence time of D-PDMP in the body of a treated mouse from less than 1 hour to at least 4 hours (and up to 48 hours or longer),” the authors wrote.

Most strikingly, the team reported, the increased duration of the nano version of the compound was potent enough to halt the progression of disease. “This substantially-increased in vivo longevity provided by polymer encapsulation resulted in an order of magnitude gain in efficacy for interfering with atherosclerosis and cardiac hypertrophy in apoE−/− mice fed a high fat and high cholesterol (HFHC) diet,” the researchers found.

By contrast, the team's previous research showed the drug was effective in preventing atherosclerosis but not potent enough to stop the disease from advancing.

"Our experiments illustrate clearly that while content is important, packaging can make or break a drug," said lead investigator Subroto Chatterjee, PhD, a professor of medicine and pediatrics at the Johns Hopkins University School of Medicine and a metabolism expert at its Heart and Vascular Institute. "In our study, the right packaging vastly improved the drug's performance and its ability not merely to prevent disease but to mitigate some of its worst manifestations."

In further experiments, the scientists put the genetically-altered mice on a HFHC diet for several months. Then they put the mice on different treatment regimens—one-third received the nano-packaged D-PDMP, another third were given standard D-PDMP, while the rest got placebo.

The researchers found that mice treated with placebo showed high levels of GSL and low-density lipoproteins (LDL), as well as dangerously high levels of oxidized LDL and elevated triglycerides. By contrast, animals given encapsulated D-PDMP had normal GSL and cholesterol levels as did animals treated with the standard form of the drug. However, animals treated with the free-floating form of D-PDMP required 10 times higher doses to achieve GSL and cholesterol levels as the mice given the nano-encapsulated form of the drug.

When scientists measured aortic intima media thicknessin the mice, they observed stark differences. The aortic walls of the control mice had grown thicker. Mice treated with either version of the drug fared better, but animals that got the encapsulated form of the drug had aortic intima media thicknessnearly indistinguishable from those of healthy mice fed a regular diet, according to researchers.

By giving mice the nano-encapsulated D-PDMP, the authors concluded, “disease markers of atherosclerosis and cardiac hypertrophy can be ameliorated.” In addition to treating the manifestations of cardiovascular disease, the polymer-encapsulated D-PDMP is a potential therapy for a “spectrum of diseases,” including cancer and other diseases characterized by excessive GSL biosynthesis.

Next, the researchers plan to test how the drug performs in larger mammals. D-PDMP—long used in basic research to experimentally block and study cell growth and other functions—is considered safe in animals, but its safety profile in humans is unknown, the investigators say.