A groundbreaking study has demonstrated the reversal of diet-induced disease in obese mice through the targeted delivery of medication directly to the liver using a nanogel carrier, significantly mitigating the risk of side effects.
This innovative research has unveiled a potential method for treating a range of diseases, including fatty liver disease, type 2 diabetes, and high cholesterol, by encapsulating drugs within nanogels.
“Approximately one hundred million Americans suffer from obesity and related cardiometabolic disorders,” highlights S. Thai Thayumanavan, a biomedical engineer and chemist from the University of Massachusetts Amherst in the US. “We became quite excited about this research.”
The nanogel functions as a delivery system for a synthetic thyroid hormone drug known as a thyromimetic. Thyroid hormones play a crucial role in regulating the liver’s metabolism. However, systemic administration of thyromimetics often diminishes their efficacy and leads to adverse effects.
Thayumanavan and his team realized the need for targeted drug delivery to the liver to avoid potential complications. They ingeniously developed nanogels with negatively charged (anionic) surfaces that could be specifically directed to liver cells known as hepatocytes.
“We devised a remarkably straightforward approach, utilizing our proprietary invention – nanogels designed for selective hepatocyte delivery in the liver,” Thayumanavan explains.
The thyromimetic axitirome was encapsulated within anionic nanogels (ANGs) and administered via abdominal injection to obese and control mice daily for a five-week period. The obese mice had been subjected to a high-fat, high-sugar, and high-cholesterol diet for 24 weeks before the treatment.
Thayumanavan remarks, “The treated mice completely shed the weight they had gained, and we observed no adverse side effects.”
Remarkably, despite continuing their high-density food diet, the mice not only returned to their normal weight but also witnessed a drop in cholesterol levels, accompanied by a reduction in harmful liver inflammation.
Thayumanavan elaborates, “We have initiated the reverse cholesterol transport pathway, which leads to reduced cholesterol levels. We believe that the activation of fat oxidation and an increase in metabolic rate contribute to the weight loss, but further research is required to confirm this.”
Following hepatocyte uptake of ANGs, axitirome is released as the liver cell environment breaks down the nanogel’s bonds. The drug subsequently binds to a protein that regulates gene expression.
The ability of ANG-mediated axitirome to reverse weight gain without causing widespread changes in thyroid hormone levels indicates the promise of thyromimetics in addressing metabolic conditions like obesity, a significant public health concern.
It is worth noting that mice administered axitirome maintained their appetite for their high-density food diet, an observation that differs from human experiences with another type of weight loss drug.
Thayumanavan cautions that there is substantial development work to bridge the gap between mice and humans, but there is optimism that it may eventually lead to the development of a novel drug.
Building upon the nanogel technologies pioneered by his laboratory, Thayumanavan has co-founded Cyta Therapeutics, a startup with a primary objective of developing innovative delivery platforms to precisely target drugs within the body.