Efficient Targeting of Adipose Tissue Macrophages in Obesity with Polysaccharide Nanocarriers

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.

Immunomodulatory Nanosystems

“…On the contrary, M2 is a prohealing phenotype that assists in anti-inflammation process and tissue repair by enhancing the secretion of IL-10, TGF-β, and VEGF. [44,295,311,312] Activated macrophages are reckoned to participate in the inflammation and pathogenesis of RA. [310] Many nanoparticle platforms have been developed to reduce proinflammatory macrophages or regulate macrophage polarization for treatment of dysfunctional macrophage-associated diseases.…”

“…2019, 6,1900101 HA-NP CD44 and TLR4 on macrophages - [295] Dextran-dexamethasone prodrug Lectin and scavenger receptor on macrophages Esterase [44] Au NP IL-4 -- [296] MSNP IL-4 -- [297] MTC cross-linked with miRNA-146b Mannose receptor on BMDMs - [298] Silica nanoparticle conjugated with KGM -Mannose receptor on BMDMs - [299] RGD-coated Au NP protected by a magnetic nanocage -- [300] Modulation of Tregs Au NP Hyperforin -- [301] Au NP Hexapeptide -- [302] PLGA NP Protein or peptide antigens and rapamycin -- [303] PLA-PLGA NP PLP and rapamycin -- [304] Porous silicon nanoparticle Rapamycin and OVA peptide CD11c on DCs - [36] PLGA NP Anti-CD3 Ab PNAd on HEV - [42] PLGA NP Diabetogenic peptide -- [305] Iron oxide nanoparticle T1D-relevant peptide-MHC class I complexe -- [306] Iron oxide nanoparticle Diabetogenic antigen peptide-MHC class II complex -- [307] PLGA NP IL-2 and TGF-β Biotin on CD4+ T cells - [308] Obesity increases the M1 macrophage infiltration in adipose tissue and promotes the secretion of pro-inflammatory cytokines, such as TNF-α and IL-6, which lead to high risk of glucose intolerance and insulin resistance. Sci.…”

Nanomedicines for dysfunctional macrophage-associated diseases

“…This strategy successfully reduced significant liver uptake. Because of high adipose tissue specificity of the nanocarrier, single-dose was found to be effective reducing pro-inflammatory markers in the adipose tissue of obese mice [108]. …”

“…Additional implicated cells (e.g., T cells) and altered metabolic pathways are not depicted. Adapted with permission from [108]. …”

Modulating the immune system through nanotechnology

“…Similarly, the specific recognition of dextran by scavenger receptors was explored to develop an anti-inflammatory therapy. Namely, dextran NPs containing dexamethasone were used to target pro-inflammatory macrophages from obese patients [89]. On the other hand, hyaluronic acid, has been proposed as a way to specifically interact with the CD44 receptor, found in lymphocytes, among other cells [90,91].…”