Efficient Targeting of Adipose Tissue Macrophages in Obesity with Polysaccharide Nanocarriers.
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.
Department 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.
Liang
L
Ma
Department 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.
Tzu-Wen
TW
Liu
Department 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.
Matthew A
MA
Wallig
Department 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.
Iwona T
IT
Dobrucki
Department 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.
Lawrence W
LW
Dobrucki
Department 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.
Erik R
ER
Nelson
Department 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.
Kelly S
KS
Swanson
Department 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.
Andrew M
AM
Smith
D000273:Adipose Tissue; D000818:Animals; D003924:Diabetes Mellitus, Type 2; D016503:Drug Delivery Systems; D007249:Inflammation; D008264:Macrophages; D051379:Mice; D009765:Obesity / Q000628:therapy*; D011134:Polysaccharides
D011134:Polysaccharides
PET; drug delivery; imaging; inflammation; nanomedicine; nanoparticles; targeting