Innovative Treatment for Obesity Shows Promise in Early Testing

A team of researchers has created a nanogel system that effectively targets and counteracts obesity in laboratory mice by directly administering therapeutic agents to the liver. This method mitigates potential side effects and increases the treatment’s effectiveness. Cyta Therapeutics, a newly established firm, is advancing this approach towards potential human application. The technology also holds potential for treating other diseases associated with the liver and marks a considerable step forward in precision medicine for metabolic conditions.

In research conducted at the University of Massachusetts Amherst, obese mice were able to return to normal weight levels despite continuing a high-fat diet thanks to a novel nanogel system.

S. Thai Thayumanavan, a prominent professor of chemistry and biomedical engineering at the university, spearheaded the development of a nanogel-based drug carrier in his laboratory. This carrier successfully delivered medication directly to the liver of obese mice, reversing the effects of their high-calorie diet.

“The mice shed all the weight they had gained, and we observed no negative side effects,” reported Thayumanavan. “Given the obesity and cardiometabolic disorders affecting over 100 million people in the U.S. alone, we are quite encouraged by these results.”

Pioneering Outcomes and Prospects for the Future

Cyta Therapeutics, established within the UMass Institute for Applied Life Sciences (IALS) utilizing the nanogel technology from the Thayumanavan laboratory, is engaged in the effort to adapt these discoveries for human treatment. In July, the company received the Judges’ Choice Best Startup award at the 16th annual Massachusetts Life Sciences Innovation (MALSI) Day.

S. Thai Thayumanavan is recognized for his significant contributions to chemistry and biomedical engineering at UMass Amherst. Credit: UMass Amherst

“There’s a substantial amount of development to be done in bridging the gap between mice and human subjects,” Thayumanavan points out, “but our goal is for this to become a viable medication.”

Thayumanavan, who also serves as the director of the Center for Bioactive Delivery at IALS, published these research findings with his team on August 29 in the journal Proceedings of the National Academy of Sciences NEXUS. Ruiling Wu, who pursued her doctoral studies in Thayumanavan’s laboratory and contributed significantly as the lead author of the paper, has since completed her Ph.D. in chemistry and now works with a pharmaceutical company in Boston.

Strategic Approach to Metabolic Health Issues

One of the central objectives at the center is to devise innovative means of delivering precise medications to targeted areas within the body, catering to both small and large molecular treatments.

Thyromimetics, which are compounds that emulate synthetic thyroid hormones, are contemplated as possible solutions for obesity, type 2 diabetes, high cholesterol, metabolic dysfunction-associated fatty liver disease (MASH), and other metabolic ailments. However, the critical aspect lies in targeted application. Thayumanavan’s research focused on a specific thyromimetic.

Obese mice were relieved of diet-induced obesity through a thyromimetic administered directly to the liver via a nanogel carrier. Credit: Thayumanavan Lab, UMass Amherst

“We recognized the importance of liver-specific drug delivery because non-targeted dispersal might lead to complications,” he remarked. The study demonstrated that administering the drug systematically reduced its potency, which the targeted delivery approach managed to overcome.

Research Approach and Findings

Thayumanavan’s group provided a set of mice with a high-fat, sugar, and cholesterol diet for 10 weeks, resulting in their weight doubling. A second set of mice was fed a normal diet for comparison.

Ruiling Wu, a recent Ph.D. graduate in chemistry from UMass Amherst, conducted her research in Thayumanavan’s lab. She is currently employed by a pharmaceutical company in Boston. Credit: UMass Amherst

Thayumanavan developed an innovative solution with his “IntelliGels” nanogels, uniquely designed for delivery to liver cells.

The obese mice received daily doses of the drug encased in the nanogel via intraperitoneal injection.

Upon entering the liver cells, the nanogels release the therapeutic agent when the cell’s glutathione breaks the gel’s bonds. The drug then activates the liver’s thyroid hormone beta receptors, which leads to the lowering of systemic lipids, enhanced bile acid synthesis, and increased fat oxidation.

Following a five-week regimen, the mice managed to return to their normal weight even though they continued their high-fat diet. Their cholesterol levels fell, and liver inflammation subsided.

“We were eager to uncover the mechanisms at play,” Thayumanavan says. “It appears we are stimulating the reverse cholesterol transport mechanism, resulting in cholesterol reduction. We hypothesize that the weight loss is due to activated fat burning and an elevated metabolic rate, though further investigation is necessary to confirm this.”

With a clearer understanding of the drug’s mechanism, the study suggests that drug-encased nanogels may pave the way for nanoparticle-facilitated pharmaceutical approaches to treat additional liver-centric illnesses.

Reference: “Conferring liver selectivity to a thyromimetic using a novel nanoparticle increases therapeutic efficacy in a diet-induced obesity animal model” by Ruiling Wu et al., 29 August 2023, PNAS Nexus.
DOI: 10.1093/pnasnexus/pgad252

The National Institute of General Medical Sciences provided funding for this research.

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More about Nanogel obesity treatment

• Nanogel-based obesity treatment
• UMass Amherst’s breakthrough in metabolic disorders
• Cyta Therapeutics’ innovation for liver-targeted therapy
• Thayumanavan Lab’s research on nanogels
• National Institute of General Medical Sciences funding