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An empty self-assembled hyaluronic acid nanoparticle as a therapeutic agent for treatment of type 2 diabetes
- Author(s)
- 노준기
- Advisor
- 김욱
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2021-02
- Language
- eng
- Keyword
- Diabetes; Hyaluronic acid; Inflammation
- Alternative Abstract
- Self-assembled hyaluronic acid nanoparticles (HA-NPs) have been extensively investigated for biomedical and pharmaceutical applications as the constituent of the drug carrier for the target-specific and long-acting delivery of various chemicals and biopharmaceuticals, owing to their biocompatibility and receptor-binding properties. Here, I report novel function of an empty HA-NP itself not bearing any drug, which could be a therapeutic agent, not as a drug carrier, for the treatment of type 2 diabetes (T2D) by breaking the links between adipose tissue inflammation and insulin resistance. In part Ⅰ, I show that a drug-free HA-NP itself has therapeutic effects on adipose tissue inflammation and insulin resistance. HA-NPs inhibited not only the receptor-mediated internalization of low-molecular-weight (LMW) free HA but also LMW free HA-induced pro-inflammatory gene expression in mouse primary bone marrow-derived macrophages (BMDMs) isolated from wild-type mice, but not in CD44-null (CD44-/-) BMDMs. An in vivo biodistribution study showed the distribution of HA-NPs and their co-localization with CD44 in adipose tissues including epididymal white adipose tissues (eWATs), but these were rarely observed in the eWATs of CD44-/- mice. In addition, CD44 expression and HA-NP accumulation in the eWATs were increased in mice with diet-induced obesity (DIO) compared to lean mice. Interestingly, treatment with HA-NPs in DIO mice suppressed adipose tissue inflammation as indicated by reduced macrophage content, the production of proinflammatory cytokines and NLRP3 inflammasome activity in eWATs, leading to improved insulin sensitivity and normalized blood glucose levels. Collectively, these results suggest that an empty HA-NP itself can be a therapeutic agent for the treatment of T2D. In part Ⅱ, I identify effect of a self-assembled HA-NP on macrophage polarization into pro-inflammatory M1 and anti-inflammatory M2 types using mouse primary BMDMs and peritoneal macrophages. HA-NP suppresses the M0 to M1 polarization and M2 to M1 repolarization induced by LPS, but not the M0 to M2 polarization and M1 to M2 repolarization induced by IL-4. Through the direct interaction with Toll-like receptor 4 (TLR4), HA-NPs effectively suppressed Myd88- and TRIF-dependent LPS-induced expressions of pro-inflammatory mediators by acting as a competitive inhibitor of LPS-TLR4 interactions in macrophages. The effect of HA-NP on LPS-induced TLR4 signaling is attributed to the presence of self-assembled hydrophilic HA shell, not free HA and hydrophobic core 5β-Cholanic acid. Thus, these results identify the potential of an empty HA-NP as an effective therapeutic agent against TLR4-mediated inflammatory disorders
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 4. Theses(Ph.D)
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