Adipose tissue–targeted nanoparticles may improve treatment of obesity and atherosclerosis

Kanas Chan
27 Feb 2023
Adipose tissue–targeted nanoparticles may improve treatment of obesity and atherosclerosis
Dr Weiping Wang (4th from left), Prof Aimin Xu (6th from left), and their research team

Researchers from the University of Hong Kong (HKU) have developed a nanoparticle-based targeted drug delivery system that selectively transports thyroid hormone (TH) to adipose tissue, which may improve treatment of obesity and its related cardiometabolic complications by overcoming serious adverse events (AEs) associated with systematic TH administration.

Pharmacological treatments for obesity are limited as most antiobesity drugs have been withdrawn from the market due to serious AEs. TH, including triiodothyronine (T3) and thyroxine (T4), is a thermogenic activator with antiobesity potential. However, systemic TH administration not only failed to demonstrate clinical benefits in terms of weight reduction, but also led to multiorgan SAEs, including tachycardia, heart attack, muscle wasting, osteoporosis and early mortality, thereby limiting its therapeutic application. [Nat Commun 2022;13:7838; Int J Environ Res Public Health 2021;18:9434]

To minimize these AEs, the researchers developed T3-encapsulated liposomal (Lip) nanoparticles, which were conjugated with an adipose-homing peptide (PTP) to enable adipose tissue–targeted T3 delivery (PTP-Lip-T3 [PLT3]). PLT3 was compared with two systemic T3 delivery systems, including Lip-T3 (LT3), and free T3 (FT3), in high-fat diet–induced obese mouse models.

“[Results revealed that] T3 was preferentially enriched in three adipose depots and was barely detectable in nonadipose tissues [ie, heart, lung, kidney, brain, and soleus] of PLT3-treated mice, whereas T3 was widely distributed in nonadipose tissues in LT3- and FT3-treated mice,” noted the researchers. Moreover, both FT3 and LT3 led to cardiac remodelling in studied mice, including significant increases in left ventricular (LV) end-diastolic anterior and posterior wall thickness, LV end-diastolic inner dimension, LV volume and mass, and LV ejection fraction, but these pathological changes were not seen in mice receiving PLT3. These findings suggested that PLT3 can selectively deliver T3 into adipose tissues with negligible side effects.

Notably, PLT3 exhibited superior therapeutic effects, as demonstrated by significantly lower weight gain in PLT3-treated mice vs LT3-treated mice (p<0.05).

“Unexpectedly, PLT3 was substantially more potent than systemic T3 administration in reducing obesity-related cardiometabolic complications, including hypercholesterolaemia, fatty liver and atherosclerosis, independent of body weight reduction,” highlighted the researchers.

The researchers explained that systemic T3 administration failed to induce browning of white adipose tissues (WAT) due to feedback suppression of sympathetic innervation. In contrast, PLT3 treatment potently obviated this feedback suppression of adrenergic inputs and induced browning and thermogenesis of WAT, resulting in alleviation of obesity and its related cardiometabolic complications in obese mice.  

“This is the first proof-of-concept study showing that nanoparticle-based targeted delivery of TH to adipose tissue is an effective and safe [potential] pharmacotherapy for obesity and its related cardiometabolic complications,” remarked Professor Aimin Xu of the Department of Medicine, HKU. “The findings have also resolved a long-standing mystery of why systemic TH therapy failed to reduce body weight, thus reigniting the hope of using TH for common chronic disease treatment through nanoparticle-based targeted delivery.”

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