[Jan. 11, 2024: JJ Shavit, The Brighter Side of News]
A staggering one hundred million Americans suffer from obesity and related cardiometabolic disorders. (CREDIT: iStock Photo)
In a groundbreaking discovery, scientists have achieved significant weight loss in obese mice by introducing medication directly into the liver via a novel nanogel carrier. This innovative approach circumvents the issues associated with systemic drug administration, markedly reducing potential side effects.
The significance of this method becomes apparent when considering the broader picture. A staggering one hundred million Americans suffer from obesity and related cardiometabolic disorders, comments S. Thai Thayumanavan, a renowned biomedical engineer and chemist from the University of Massachusetts Amherst. "We became pretty excited about this work," he reveals.
The brilliance of this approach is encapsulated, quite literally, in the nanogel. These minuscule carriers are loaded with a synthetic thyroid hormone drug termed a thyromimetic. Essential for liver metabolism, thyroid hormones can be ineffective when taken systemically and carry adverse side effects.
"We realized we needed to deliver this drug selectively to the liver because if it goes to other places, it could cause complications," Thayumanavan explains.
By manipulating the surface charge of these nanogels, Thayumanavan and his team achieved precise targeting to liver cells, or hepatocytes. This focused delivery, a pivotal step in their method, reduces the risk of unintended consequences elsewhere in the body.
"We came up with a very simple approach, using our unique invention – nanogels that we can direct selectively to different targets," Thayumanavan continues, underscoring the customized nature of their method. "They were custom-designed for hepatocyte delivery in the liver."
To fully comprehend the gravity of their findings, it's essential to understand the process. Obese mice, subjected to a 24-week regimen of high fat, sugar, and cholesterol diets, were administered a thyromimetic called axitirome, packaged into these anionic nanogels. The treatment, delivered through abdominal injections, spanned five weeks.
A scanning electron micrograph of a section through a vein in the liver, showing red blood cells surrounded by hepatocytes (green). (CREDIT: PNAS Nexus)
The outcomes were nothing short of remarkable. "The treated mice completely lost their gained weight, and we did not see any untoward side effects," reports Thayumanavan.
Yet, it wasn't just about shedding weight. The mice, who continued their rich diets, saw normalized cholesterol levels and a significant reduction in liver inflammation. "We found that we are activating the reverse cholesterol transport pathway, which lowers cholesterol," Thayumanavan elaborates.
In vivo lipid-regulating effects of CGS-ANG in GAN diet-induced disease model. A) Schematic illustration of protocol for fully developed disease establishment in C57BL/6J mice and therapeutic study of CGS-ANG. (CREDIT: PNAS Nexus)
He further theorizes, "We believe that activation of fat oxidation and an increase in metabolic rate are causing the loss in weight, but more work needs to be done to prove that point."
Delving into the mechanics, once these nanogels permeate the hepatocytes, the liver cell environment disintegrates the bonds within the nanogel, releasing axitirome. This drug subsequently latches onto proteins pivotal for gene expression regulation.
A graphic depicting how the drug targets the liver. (CREDIT: Creative Commons)
The apparent effectiveness of the ANG-delivered axitirome, which reversed weight gain without disrupting thyroid hormone levels, indicates a promising avenue for thyromimetics in addressing metabolic diseases like obesity.
An interesting observation emerged: mice on axitirome retained their appetite for high-calorie food. This is in stark contrast to human subjects using other weight loss drugs.
"There is a significant amount of development work to be conducted between mice and humans," Thayumanavan cautions, "but we are hoping it will eventually become a drug."
Driven by the promise of the nanogel technology his lab birthed, Thayumanavan has launched a startup, Cyta Therapeutics. Their primary mission? To spearhead cutting-edge delivery platforms ensuring drugs are dispatched to their intended bodily destinations.
The exciting potential of this discovery cannot be understated. It not only offers a beacon of hope for those grappling with obesity and associated disorders but also paves the way for further advancements in drug delivery, potentially revolutionizing the treatment of metabolic diseases.
For more science news stories check out our New Discoveries section at The Brighter Side of News.
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