An anti-obesity drug can be delivered selectively to the liver using a nanogel-based carrier, according to a study. Synthetic thyroid hormone mimics are promising treatments for metabolic diseases including metabolic dysfunction-associated steatohepatitis (MASH), high cholesterol, type 2 diabetes, and inflammatory liver disease; however, the molecules are not highly bioavailable or potent, which are necessary to see significant weight loss. S. Thayumanavan and colleagues designed a nanogel-based carrier with anionic moieties on the surface that directs a thyromimetic exclusively to liver cells in mice. The nanoscopic size of the carrier tends to direct the packages to the liver, which accumulates nanoparticles as part of its cleaning function. The anionic regions then target organic anion transporting polypeptides, which are over-expressed on liver cells known as hepatocytes. Once inside the hepatocyte cells, glutathione in the cells breaks the bonds of the gel’s disulfide crosslinkers, releasing the drug. The thyromimetic activates thyroid hormone beta receptor, leading to systemic lipid lowering, increased bile acid synthesis, and fat oxidation. Obese mice treated with the drug-encapsulated nanocarrier completely lost gained weight, saw their cholesterol levels drop, and saw a resolution of liver inflammation—all with little to no side effects. Nanoparticle-mediated pharmaceutical strategies may also be appropriate for other liver-based diseases, according to the authors.
PNAS Nexus
Conferring liver selectivity to a thyromimetic using a novel nanoparticle increases therapeutic efficacy in a diet-induced obesity animal model
29-Aug-2023
Steve Faraci, Roman Herrera, and S. Thayumanavan have a financial interest in Cyta Therapeutics.