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Efficient Targeting of Adipose Tissue Macrophages in Obesity with Polysaccharide Nanocarriers
Liang Ma1, Tzu-Wen Liu1, Matthew A Wallig1
1Department of Materials Science and Engineering, ‡Micro and Nanotechnology Laboratory, §Division of Nutritional Sciences, ∥Department of Pathobiology, ⊥Beckman Institute for Advanced Science and Technology, #Department of Bioengineering, □Department of Molecular and Integrative Physiology and University of Illinois Cancer Center, and ⬡Department of Animal Sciences, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
Abstract:
Obesity leads to an increased risk for type 2 diabetes, heart disease, stroke, and cancer. The causal link between obesity and these pathologies has recently been identified as chronic low-grade systemic inflammation initiated by pro-inflammatory macrophages in visceral adipose tissue. Current medications based on small-molecule drugs yield significant off-target side effects with long-term use, and therefore there is a major need for targeted therapies. Here we report that nanoscale polysaccharides based on biocompatible glucose polymers can efficiently target adipose macrophages in obese mice. We synthesized a series of dextran conjugates with tunable size linked to contrast agents for positron emission tomography, fluorophores for optical microscopy, and anti-inflammatory drugs for therapeutic modulation of macrophage phenotype. We observed that larger conjugates efficiently distribute to visceral adipose tissue and selectively associate with macrophages after regional peritoneal administration. Up to 63% of the injected dose remained in visceral adipose tissue 24 h after administration, resulting in >2-fold higher local concentration compared to liver, the dominant site of uptake for most nanomedicines. Furthermore, a single-dose treatment of anti-inflammatory conjugates significantly reduced pro-inflammatory markers in adipose tissue of obese mice. Importantly, all components of these therapeutic agents are approved for clinical use. This work provides a promising nanomaterials-based delivery strategy to inhibit critical factors leading to obesity comorbidities and demonstrates a unique transport mechanism for drug delivery to visceral tissues. This approach may be further applied for high-efficiency targeting of other inflammatory diseases of visceral organs.
Insights
Nanoscale glucose polymers efficiently target pro-inflammatory macrophages in visceral fat, offering a novel therapy for obesity-related diseases. This targeted approach reduces inflammation and minimizes side effects, paving the way for improved treatment strategies.
Area of Science:
- Biomaterials Science
- Nanomedicine
- Immunology
Background:
- Obesity is linked to chronic low-grade inflammation, driven by pro-inflammatory macrophages in visceral adipose tissue.
- This inflammation is a key factor in developing type 2 diabetes, heart disease, stroke, and cancer.
- Current small-molecule drugs for obesity comorbidities have significant long-term side effects, necessitating targeted therapies.
Purpose of the Study:
- To develop and evaluate nanoscale polysaccharides for targeted delivery to adipose macrophages in obese mice.
- To investigate the efficacy of these nanoconjugates in modulating macrophage phenotype and reducing inflammation.
- To establish a novel nanomaterial-based strategy for treating obesity-related pathologies.
Main Methods:
- Synthesis of dextran nanoconjugates with tunable sizes, incorporating contrast agents, fluorophores, and anti-inflammatory drugs.
- Regional peritoneal administration of nanoconjugates in obese mice.
- Assessment of tissue distribution, macrophage targeting, and reduction of pro-inflammatory markers using imaging and molecular techniques.
Main Results:
- Larger nanoconjugates demonstrated efficient distribution to visceral adipose tissue, selectively targeting macrophages.
- Up to 63% of the injected dose remained in visceral adipose tissue after 24 hours, with higher local concentration than in the liver.
- A single dose of anti-inflammatory nanoconjugates significantly reduced pro-inflammatory markers in obese mice.
Conclusions:
- Nanoscale glucose polymers provide a promising targeted delivery system for adipose macrophages.
- This approach effectively reduces inflammation associated with obesity and its comorbidities.
- The use of clinically approved components and a unique visceral targeting mechanism highlights the potential for treating inflammatory diseases.
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