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タイトル: Self-assembling lipid modified glycol-split heparin nanoparticles suppress lipopolysaccharide-induced inflammation through TLR4-NF-κB signaling.
著者: Babazada, Hasan
Yamashita, Fumiyoshi  kyouindb  KAKEN_id
Yanamoto, Shinya
Hashida, Mitsuru  kyouindb  KAKEN_id
著者名の別形: 橋田, 充
キーワード: Inflammation
Heparin nanoparticles
Toll-like receptors
Desulfation
Macrophage
Nuclear factor-κB
発行日: 28-Nov-2014
出版者: Elsevier B.V.
誌名: Journal of controlled release
巻: 194
開始ページ: 332
終了ページ: 340
抄録: 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-erythro-sphingosine 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-κB signaling pathway and production of pro-inflammatory cytokines such as TNF-alpha from mouse macrophages with IC50=0.019mg/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.
著作権等: © 2014 Elsevier B.V.
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
URI: http://hdl.handle.net/2433/191264
DOI(出版社版): 10.1016/j.jconrel.2014.09.011
PubMed ID: 25234820
出現コレクション:学術雑誌掲載論文等

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