A breakthrough study has demonstrated the potential of nanogel-based medication delivery to effectively treat diet-induced disease.
This novel approach, which targets the liver specifically, could revolutionize the treatment of various health conditions, including fatty liver disease, type 2 diabetes, and high cholesterol.
The research team, led by biomedical engineer and chemist S. Thai Thayumanavan from the University of Massachusetts Amherst, developed a nanogel carrier equipped with negatively charged (anionic) surfaces to effectively deliver a synthetic thyroid hormone drug called a thyromimetic to hepatocytes, the liver cells responsible for maintaining metabolic balance.
“This new understanding of the mechanism means encapsulating drugs in nanogels could be an efficient method for treating these diseases in the future.”
Thayumanavan
The anionic nanogels, specifically designed for hepatocyte delivery, were loaded with a thyromimetic called axitirome and administered daily for five weeks via abdominal injection to both obese and control mice. The obese mice had been fed a high-fat, sugar, and cholesterol diet for 24 weeks prior to the treatment.
After five weeks of treatment, the obese mice receiving the anionic nanogel-delivered axitirome exhibited significant improvements in their liver health, including reduced weight gain, improved glucose metabolism, and decreased cholesterol levels. These positive outcomes were not observed in the control mice or in the obese mice receiving the axitirome without the nanogel carrier.
Researchers discovered a remarkable treatment approach that effectively reversed diet-induced obesity in mice without causing any adverse side effects. This groundbreaking discovery has the potential to revolutionize the treatment of various health conditions, including fatty liver disease, type 2 diabetes, and high cholesterol.
“The treated mice completely lost their gained weight, and we did not see any untoward side effects.”
Thayumanavan
The mice continued to maintain their high-fat, sugar, and cholesterol diet throughout the treatment, yet their weight returned to normal, their cholesterol levels dropped, and harmful levels of liver inflammation subsided.
“We found that we are activating the reverse cholesterol transport pathway, which lowers cholesterol. We believe that activation of fat oxidation and an increase in metabolic rate are causing the weight loss, but more work needs to be done to prove that point.”
Thayumanavan
The researchers developed a nanogel carrier equipped with negatively charged (anionic) surfaces to effectively deliver the thyromimetic directly to the liver cells, called hepatocytes. This targeted approach ensures that the drug reaches the site of action without causing unwanted side effects in other parts of the body.
“We came up with a very simple approach, using our unique invention – nanogels that we can direct selectively to different targets. They were custom-designed for hepatocyte delivery in the liver.”
Thayumanavan
After the nanogels enter the hepatocytes, the thyromimetic is released when the environment in the liver cells breaks down the bonds in the nanogel. The drug then binds to a protein that helps regulate the expression of genes.
One notable aspect of this treatment is that mice maintained their appetite for their high-fat, sugar, and cholesterol diet despite receiving axitirome. This is in contrast to observations in humans taking other weight loss medications, which often lead to suppressed appetite.
While significant development work remains before this approach can be translated into a human treatment, the findings provide encouraging evidence for the potential of thyromimetics in addressing obesity and related metabolic disorders.
Building upon the nanogel technologies developed in his lab, Professor Thayumanavan has co-founded a startup company, Cyta Therapeutics, dedicated to developing innovative drug delivery platforms that precisely target specific areas of the body. This approach could revolutionize the treatment of various health conditions by maximizing the efficacy of medications while minimizing potential side effects.
Abstract
Optimization of metabolic regulation is a promising solution for many pathologies, including obesity, dyslipidemia, type 2 diabetes, and inflammatory liver disease. Synthetic thyroid hormone mimics–based regulation of metabolic balance in the liver showed promise but was hampered by the low biocompatibility and harmful effects on the extrahepatic axis. In this work, we show that specifically directing the thyromimetic to the liver utilizing a nanogel-based carrier substantially increased therapeutic efficacy in a diet-induced obesity mouse model, evidenced by the near-complete reversal of body weight gain, liver weight and inflammation, and cholesterol levels with no alteration in the thyroxine (T4) / thyroid stimulating hormone (TSH) axis. Mechanistically, the drug acts by binding to thyroid hormone receptor β (TRβ), a ligand-inducible transcription factor that interacts with thyroid hormone response elements and modulates target gene expression. The reverse cholesterol transport (RCT) pathway is specifically implicated in the observed therapeutic effect. Overall, the study demonstrates a unique approach to restoring metabolic regulation impacting obesity and related metabolic dysfunctions.
https://academic.oup.com/pnasnexus/article/2/8/pgad252/7249146?login=false
