Researchers at Massachusetts Institute of Technology (MIT) and Brigham and Women’s Hospital in Boston, MA, have developed nanoparticles that can deliver anti-obesity drugs directly to fat tissue. Overweight mice treated with these nanoparticles lost 10% of their body weight over 25 days, without showing any negative side effects.
The drugs work by transforming white adipose tissue, which is made of fat-storing cells, into brown adipose tissue, which burns fat. The drugs also stimulate the growth of new blood vessels in fat tissue, which positively reinforces the nanoparticle targeting and aids in the white-to-brown transformation.
These drugs, which are not FDA-approved to treat obesity, are not new, but the research team has developed a new way to deliver them so that they accumulate in fatty tissues, helping to avoid unwanted side effects in other parts of the body.
'The advantage here is now you have a way of targeting it to a particular area and not giving the body systemic effects. You can get the positive effects that you’d want in terms of anti-obesity but not the negative ones that sometimes occur,' says Robert Langer, the David H. Koch Institute Professor at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research.
More than one-third of Americans are considered to be obese, and last year obesity overtook smoking as the top preventable cause of cancer death in the US, with 20% of the 600,000 cancer deaths attributed to obesity.
The advantage here is now you have a way of targeting it to a particular area and not giving the body systemic effects
Langer and Omid Farokhzad, Director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women’s Hospital, are the senior authors of the study, which appears in the Proceedings of the National Academy of Sciences this week. The paper’s lead authors are former MIT postdoc Yuan Xue and former BWH postdoc Xiaoyang Xu.
Langer and his colleagues have previously shown that promoting the growth of new blood vessels, a process known as angiogenesis, can help transform adipose tissue and lead to weight loss in mice. However, drugs that promote angiogenesis can be harmful to the rest of the body.
To try to overcome this, Langer and Farokhzad turned to the nanoparticle drug-delivery strategy they have developed in recent years to treat cancer and other diseases. By targeting these particles to the disease site, they can deliver a powerful dose while minimising the drug’s accumulation in other areas.
The researchers designed the particles to carry the drugs in their hydrophobic cores, bound to a polymer known as PLGA, which is used in many other drug delivery particles and medical devices. They packaged two different drugs within the particles: rosiglitazone, which has been approved to treat diabetes but is not widely used due to adverse side effects, and an analog of prostaglandin (a type of human hormone). Both drugs activate a cellular receptor known as PPAR, which stimulates angiogenesis and adipose transformation.
The outer shell of the nanoparticles consists of another polymer, PEG, embedded with targeting molecules that guide the particles to the correct destination. These targeting molecules bind to proteins found in the lining of the blood vessels that surround adipose tissue.
The researchers tested the particles in mice that had become obese after being fed a high-fat diet. The mice lost about 10% of their body weight, and their levels of cholesterol and triglycerides (molecules that are the main constituent of body fat in humans) also dropped. The mice also became more sensitive to insulin.
With the current system, the particles are injected intravenously, which could make this approach suitable for morbidly obese patients who are at significant risk of obesity-related diseases, Farokhzad says.
'For it to be more broadly applicable for treatment of obesity, we have to come up with easier ways to administer these targeted nanoparticles, such as orally,' he says.
The researchers also hope to find more specific adipose tissue targets for the nanoparticles, which could further reduce the possibility of side effects, and they may also investigate using other drugs with lower toxicity.