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首页> 外文期刊>Drug Design, Development and Therapy >Novel targeting of PEGylated liposomes for codelivery of TGF-β1 siRNA and four antitubercular drugs to human macrophages for the treatment of mycobacterial infection: a quantitative proteomic study
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Novel targeting of PEGylated liposomes for codelivery of TGF-β1 siRNA and four antitubercular drugs to human macrophages for the treatment of mycobacterial infection: a quantitative proteomic study

机译：新型靶向PEG化脂质体的TGF-β1siRNA和四种抗结核药物对人巨噬细胞的代码传递以治疗分枝杆菌感染的定量蛋白质组学研究

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Abstract: Tuberculosis (TB) is still a major public health issue in developing countries, and its chemotherapy is compromised by poor drug compliance and severe side effects. This study aimed to synthesize and characterize new multimodal PEGylated liposomes encapsulated with clinically commonly used anti-TB drugs with linkage to small interfering RNA (siRNA) against transforming growth factor-β1 (TGF-β1). The novel NP-siRNA liposomes could target THP-1-derived human macrophages that were the host cells of mycobacterium infection. The biological effects of the NP-siRNA liposomes were evaluated on cell cycle distribution, apoptosis, autophagy, and the gene silencing efficiency of TGF-β1 siRNA in human macrophages. We also explored the proteomic responses to the newly synthesized NP-siRNA liposomes using the stable isotope labeling with amino acids in cell culture approach. The results showed that the multifunctional PEGylated liposomes were successfully synthesized and chemically characterized with a mean size of 265.1 nm. The novel NP-siRNA liposomes functionalized with the anti-TB drugs and TGF-β1 siRNA were endocytosed efficiently by human macrophages as visualized by transmission electron microscopy and scanning electron microscopy. Furthermore, the liposomes showed a low cytotoxicity toward human macrophages. There was no significant effect on cell cycle distribution and apoptosis in THP-1-derived macrophages after drug exposure at concentrations ranging from 2.5 to 62.5 μg/mL. Notably, there was a 6.4-fold increase in the autophagy of human macrophages when treated with the NP-siRNA liposomes at 62.5 μg/mL. In addition, the TGF-β1 and nuclear factor-κB expression levels were downregulated by the NP-siRNA liposomes in THP-1-derived macrophages. The Ingenuity Pathway Analysis data showed that there were over 40 signaling pathways involved in the proteomic responses to NP-siRNA liposome exposure in human macrophages, with 160 proteins mapped. The top five canonical signaling pathways were eukaryotic initiation factor 2 signaling, actin cytoskeleton signaling, remodeling of epithelial adherens junctions, epithelial adherens junction signaling, and Rho GDP-dissociation inhibitor signaling pathways. Collectively, the novel synthetic targeting liposomes represent a promising delivery system for anti-TB drugs to human macrophages with good selectivity and minimal cytotoxicity.
机译：摘要：结核病（TB）仍然是发展中国家的主要公共卫生问题，药物依从性差和严重的副作用损害了它的化学疗法。这项研究旨在合成和表征新的多峰聚乙二醇化脂质体，这些脂质体包裹有临床常用的抗结核病药物，并与抗转化生长因子-β1（TGF-β1）的小干扰RNA（siRNA）连锁。新型NP-siRNA脂质体可以靶向THP-1衍生的人类巨噬细胞，后者是分枝杆菌感染的宿主细胞。评估了NP-siRNA脂质体对人类巨噬细胞中TGF-β1siRNA的细胞周期分布，凋亡，自噬和基因沉默效率的生物学影响。我们还使用细胞培养方法中的氨基酸稳定同位素标记，探索了对新合成的NP-siRNA脂质体的蛋白质组学反应。结果表明，已成功合成了多功能的聚乙二醇化脂质体，并进行了化学表征，平均粒径为265.1 nm。如通过透射电子显微镜和扫描电子显微镜观察到的，被人类巨噬细胞有效地胞吞了用抗结核病药物和TGF-β1siRNA功能化的新型NP-siRNA脂质体。此外，脂质体对人巨噬细胞显示出低细胞毒性。在浓度范围为2.5至62.5μg/ mL的药物暴露后，对THP-1衍生的巨噬细胞的细胞周期分布和凋亡均无明显影响。值得注意的是，当以62.5μg/ mL的NP-siRNA脂质体处理时，人类巨噬细胞的自噬增加了6.4倍。此外，THP-1来源的巨噬细胞中的NP-siRNA脂质体也下调了TGF-β1和核因子-κB的表达水平。机能途径分析数据显示，在人类巨噬细胞中，对NP-siRNA脂质体暴露的蛋白质组学反应涉及40多个信号传导途径，共绘制了160种蛋白质。排名前五的典型信号传导途径是真核生物起始因子2信号传导，肌动蛋白细胞骨架信号传导，上皮粘附连接的重塑，上皮粘附连接信号和Rho GDP-解离抑制剂信号传导途径。总的来说，新型合成靶向脂质体代表了抗结核药物以良好的选择性和最小的细胞毒性向人巨噬细胞递送的有希望的系统。

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