Stimuli-Responsive Miktoarm Polymer-Based Formulations for Fisetin Delivery and Regulatory Effects in Hyperactive Human Microglia
Stimuli-Responsive Miktoarm Polymer-Based Formulations for Fisetin Delivery and Regulatory Effects in Hyperactive Human Microglia
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DOI：
10.1002/mabi.202200174
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发表时间：
2022-07-29
影响因子：
4.6
通讯作者：
Kakkar, Ashok
中科院分区：
文献类型：
--
作者：
Baghbanbashi, Mojhdeh;Yong, Hui Wen;Kakkar, Ashok
支化的星星聚合物在增强纳米载体递送生物活性亲脂剂的功效方面提供了令人兴奋的机会。它表明，可以利用星星聚合物结构，以产生软纳米粒子的囊泡形态与精确定位的刺激敏感的化学实体。使用合成接合构建AB（2）（A = PEG，B = PCL）组合物的两亲性星形，在A和B臂的核心连接处具有/不具有氧化应激或还原响应单元。非瑟酮是一种天然黄酮类化合物，具有显著的抗炎和抗氧化特性，但由于其水溶性差，临床价值有限。在人小胶质细胞（HMC 3）中分别和组合评价聚合物囊泡和非瑟酮，以显示i）聚合物囊泡是否有毒; ii）非瑟酮是否降低活性氧（ROS）的丰度;和iii）非瑟酮是否调节ERK 1/2的活化。这些信号分子和途径与炎症过程和细胞存活有关。非瑟酮，无论是纳入和非纳入聚合物囊泡，减少ROS和ERK 1/2磷酸化脂多糖处理的人小胶质细胞，正常化过度的氧化应激和ERK介导的信号。
Branched star polymers offer exciting opportunities in enhancing the efficacy of nanocarriers in delivering biologically active lipophilic agents. It is demonstrated that the star polymeric architecture can be leveraged to yield soft nanoparticles of vesicular morphology with precisely located stimuli-sensitive chemical entities. Amphiphilic stars of AB(2) (A = PEG, B = PCL) composition with/without oxidative stress or reduction responsive units at the core junction of A and B arms, are constructed using synthetic articulation. Fisetin, a natural flavonoid with remarkable anti-inflammatory and antioxidant properties, but of limited clinical value due to its poor aqueous solubility, is physically encapsulated into miktoarm star-derived aqueous polymersomes. Polymersomes and fisetin are evaluated separately, and in combination, in human microglia (HMC3), to show if i) polymersomes are toxic; ii) fisetin reduces the abundance of reactive oxygen species (ROS); and iii) fisetin modulates the activation of ERK1/2. These signaling molecules and pathways are implicated in inflammatory processes and cell survival. Fisetin, both incorporated and nonincorporated into polymersomes, reduces ROS and ERK1/2 phosphorylation in lipopolysaccharide-treated human microglia, normalizing excessive oxidative stress and ERK-mediated signaling.