Self-assembling lipid modified glycol-split heparin nanoparticles suppress lipopolysaccharide-induced inflammation through TLR4-NF-κB signaling
Self-assembling lipid modified glycol-split heparin nanoparticles suppress lipopolysaccharide-induced inflammation through TLR4-NF-κB signaling
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DOI：
10.1016/j.jconrel.2014.09.011
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发表时间：
2014-11-28
影响因子：
10.8
通讯作者：
Hashida, Mitsuru
中科院分区：
文献类型：
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作者：
Babazada, Hasan;Yamashita, Fumiyoshi;Hashida, Mitsuru
自组装肝素纳米粒作为药物、基因和显像剂的理想载体受到广泛关注。在本研究中，我们发现肝素纳米颗粒是选择性Toll样受体4（TLR-4）拮抗剂，具有比天然肝素更大的抗炎作用。更具体地说，我们开发了由乙二醇裂解肝素/D-赤鞘氨醇缀合物（NAHNP）组成的自组装纳米粒，表征了其理化性质和体外抗炎作用。与天然肝素不同，NAHNP显著抑制脂多糖诱导的MyD 88依赖性NF-κ B信号通路的激活和促炎细胞因子如小鼠巨噬细胞TNF-α的产生，IC 50 = 0.019 mg/mL。此外，我们研究了偶联物的构效关系，并确定了连接的D-β-鞘氨醇的烷基链的长度是抗炎作用的关键。NAHNP的烷基链长度的减少导致抑制活性的丧失。与这些发现一致，D-葡糖胺残基的6-O-硫酸基团对于有效抑制是必不可少的，而去除2-O-磺基和3-O-磺基以及用N-乙酰基取代N-磺基并不改变抗炎活性。因此，NAHNP将是一个有前途的候选人在急性和慢性炎症性疾病，除了药物载体的性质。(C)2014爱思唯尔有限公司版权所有。
Self-assembling heparin nanoparticles have attracted much attention as promising drug carriers for various drugs, genes and imaging agents. In the present investigation, we found that heparin nanoparticles are selective Toll-like receptor 4 (TLR-4) antagonists and have a much greater anti-inflammatory effect than native heparin. More specifically, we developed self-assembling nanoparticles composed of glycol-split heparin/D-erythrosphingosine conjugates (NAHNP), characterized their physicochemical properties and anti-inflammatory effect in vitro. Unlike native heparin, NAHNP significantly inhibited lipopolysaccharide-induced activation of MyD88-dependent NF-kappa B signaling pathway and production of pro-inflammatory cytokines such as TNF-alpha from mouse macrophages with IC50= 0.019 mg/mL. Furthermore, we investigated the structure-activity relationship of the conjugates and identified the length of attached alkyl chains of D-erythro-sphingosine to be critical for anti-inflammatory effect. Decrease in alkyl chain length of NAHNP resulted in loss of inhibitory activity. In line with these findings, 6-O-sulfate groups of D-glucosamine residue were essential for effective inhibition, while removal of 2-O-sulfo and 3-O-sulfo groups as well as replacement of N-sulfo groups with N-acetyl did not alter anti-inflammatory activity. Therefore, NAHNP would be a promising candidate in acute and chronic inflammatory disorders, in addition to the nature of a drug carrier. (C) 2014 Elsevier B.V. All rights reserved.