Hosain Md Zahangir, Yuzuriha Kazuki, Takeo Masafumi, Kishimura Akihiro, Murakami Yoshihiko, Mori Takeshi, Katayama Yoshiki
Graduate School of Systems Life Sciences , Kyushu University , 744 Motooka, Nishi-ku , Fukuoka 819-0395 , Japan . Email:
Department of Applied Chemistry, Faculty of Engineering , Kyushu University , 744 Motooka, Nishi-ku , Fukuoka 819-0395 , Japan.
Medchemcomm. 2017 Jun 2;8(7):1514-1520. doi: 10.1039/c7md00174f. eCollection 2017 Jul 1.
Inflammatory activation of macrophages is a key factor in chronic inflammatory diseases such as ulcerative colitis. The excessive production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) by macrophages causes oxidative stress during the inflammatory response and exaggerates inflammatory lesions in ulcerative colitis. Inhibition of the inflammatory activation of macrophages is a promising treatment for chronic inflammatory diseases. Here, we prepared self-filling polymer-lipid hybrid nanoparticles (PST-PLNPs) consisting of poly dl-lactic acid as a hydrophobic biodegradable polymer core encapsulating α-tocopherol (T) and phosphatidylserine (PS) both on the surface and interior of the particle. We confirmed the anti-inflammatory response of these hybrid nanoparticles in activated murine macrophages. PS has anti-inflammatory effects on macrophages by modulating the macrophage phenotype, while α-tocopherol is an antioxidant that neutralizes ROS. We found that PS-containing (PS-PLNPs) and PS plus α-tocopherol-containing (PST-PLNPs) polymer-lipid hybrid nanoparticles significantly increased the viability of lipopolysaccharide (LPS)-treated macrophages compared with phosphatidylcholine-containing PLNPs. PST-PLNPs had a better effect than PS-PLNPs, which was attributed to the synergy between PS and α-tocopherol. This synergic action of PST-PLNPs reduced NO and pro-inflammatory cytokine (IL-6) production and increased anti-inflammatory cytokine (TGF-β1) production when incubated with activated macrophages. Thus, these self-filling biodegradable polymer-lipid hybrid nanoparticles (PST-PLNPs) containing anti-oxidant and anti-inflammatory molecules might be potential alternative drug carriers to liposomes and polymeric nanoparticles for the treatment of chronic inflammatory diseases such as ulcerative colitis.
巨噬细胞的炎症激活是溃疡性结肠炎等慢性炎症性疾病的关键因素。巨噬细胞过量产生活性氧（ROS）/活性氮（RNS）会在炎症反应期间导致氧化应激，并加剧溃疡性结肠炎中的炎症损伤。抑制巨噬细胞的炎症激活是治疗慢性炎症性疾病的一种有前景的方法。在此，我们制备了自填充聚合物-脂质杂化纳米颗粒（PST-PLNPs），其由聚dl-乳酸作为疏水可生物降解聚合物核心组成，该核心在颗粒的表面和内部均包裹α-生育酚（T）和磷脂酰丝氨酸（PS）。我们证实了这些杂化纳米颗粒在活化的小鼠巨噬细胞中的抗炎反应。PS通过调节巨噬细胞表型对巨噬细胞具有抗炎作用，而α-生育酚是一种中和ROS的抗氧化剂。我们发现，与含磷脂酰胆碱的PLNPs相比，含PS的（PS-PLNPs）和含PS加α-生育酚的（PST-PLNPs）聚合物-脂质杂化纳米颗粒显著提高了脂多糖（LPS）处理的巨噬细胞的活力。PST-PLNPs的效果优于PS-PLNPs，这归因于PS和α-生育酚之间的协同作用。当与活化的巨噬细胞一起孵育时，PST-PLNPs的这种协同作用降低了NO和促炎细胞因子（IL-6）的产生，并增加了抗炎细胞因子（TGF-β1）的产生。因此，这些含有抗氧化和抗炎分子的自填充可生物降解聚合物-脂质杂化纳米颗粒（PST-PLNPs）可能是脂质体和聚合物纳米颗粒的潜在替代药物载体，用于治疗溃疡性结肠炎等慢性炎症性疾病。
