nn6b02878_si_001.pdf (1.23 MB)
Efficient Targeting of Adipose Tissue Macrophages in Obesity with Polysaccharide Nanocarriers
journal contribution
posted on 2016-06-09, 00:00 authored by Liang Ma, Tzu-Wen Liu, Matthew A. Wallig, Iwona
T. Dobrucki, Lawrence W. Dobrucki, Erik R. Nelson, Kelly S. Swanson, Andrew M. SmithObesity
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.