Development of heparin-based nanoparticles with multi-functional biological properties intended for rheumatoid arthritis therapy

开发具有多功能生物学特性的肝素纳米颗粒，用于类风湿性关节炎治疗

• 批准号: 23659022
• 负责人: YAMASHITA Fumiyoshi
• 金额: $ 2.41万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659022/
• 关键词: ドラッグデリバリー; ヘパリンナノ粒子; 関節リウマチ; マクロファージ; 炎症性サイトカイン; TLR-4

This study aimed to develop a nano-sized drug carrier consisting of heparin, which has a variety of biological functions, and apply it to rheumatoid arthritis therapy. First, we conjugated native heparin or partially ring-opened heparin with sphingosine. These sphingosine-heparin conjugates form a self-assembling nanoparticle in water, which has the diameter of 120-200 nm and the ζpotential of -50 to -60 mV. Although inflammatory cytokines were produced following stimulation of mouse peritoneal macrophages with lipopolysaccharides, co-presence of the sphingosine-heparin conjugates, even without any drugs, significantly reduced the cytokine production. On the other hand, sphingosine-heparin conjugates were not effective against poly I:poly C-induced TNF-α production, suggesting that the conjugates act selectively on the TLR4/NF-κB pathway. In the mouse model of type II collagen-induced arthritis, the sphingosine-heparin conjugates, especially that derived from partially ring-opened heparin, showed remarkable anti-inflammatory effects.

本研究旨在研制一种具有多种生物学功能的肝素纳米药物载体，并将其应用于类风湿关节炎的治疗。首先，我们将天然肝素或部分开环肝素与鞘氨醇结合。这些鞘氨醇-肝素缀合物在水中形成自组装纳米颗粒，其具有120-200 nm的直径和-50至-60 mV的电势。虽然产生炎症细胞因子的小鼠腹腔巨噬细胞与脂多糖刺激后，鞘氨醇-肝素共轭物的共存，即使没有任何药物，显着减少细胞因子的产生。另一方面，鞘氨醇-肝素缀合物对poly I：poly C诱导的TNF-α产生无效，表明缀合物选择性地作用于TLR 4/NF-κB途径。在II型胶原诱导的关节炎的小鼠模型中，鞘氨醇-肝素缀合物，特别是源自部分开环肝素的鞘氨醇-肝素缀合物，显示出显著的抗炎作用。

项目成果

スフィンゴシン結合両親媒性ヘパリンによるナノ粒子の調整と物性評価

鞘氨醇偶联两亲性肝素纳米粒的制备及物性评价

• 发表时间: 2013
• 作者: 福岡美帆; Hasan Babazada;山下富義;橋田 充
• 通讯作者: 橋田 充

ヘパリンナノパーティクルの物性及び免疫抑制効果の検討

肝素纳米颗粒的物理性质和免疫抑制作用的检查

• 发表时间: 2012
• 作者: Hasan Babazada;福岡美帆; 山下富義;橋田 充
• 通讯作者: 橋田 充

Mechanisms of anti-inflammatory effect of heparin-sphingosine nanoparticles in activated macrophages in vitro

肝素-鞘氨醇纳米粒对活化巨噬细胞的体外抗炎作用机制

• 发表时间: 2013
• 作者: Hasan Babazada; 福岡美帆; 山下富義;橋田 充
• 通讯作者: 橋田 充

Immunosuppressive effect of heparin nanoparticles on activated macrophages in primary culture

肝素纳米颗粒对原代培养物中活化巨噬细胞的免疫抑制作用

• 发表时间: 2012
• 作者: Hasan Babazada;Miho Fukuoka;Fumiyoshi Yamashita;Mitsuru Hashida
• 通讯作者: Mitsuru Hashida