Mannosylated graphene oxide as macrophage-targeted delivery system for enhanced intracellular M. tuberculosis killing efficiency
Mannosylated graphene oxide as macrophage-targeted delivery system for enhanced intracellular M. tuberculosis killing efficiency
复制标题
甘露糖化氧化石墨烯作为巨噬细胞靶向递送系统，可增强细胞内结核分枝杆菌杀灭效率
DOI：
10.1016/j.msec.2019.109777
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发表时间：
2019-10-01
影响因子：
7.9
通讯作者：
Chen, Zheng W.
中科院分区：
文献类型：
--
作者：
Pi, Jiang;Shen, Ling;Chen, Zheng W.
由结核分枝杆菌（Mtb）引起的结核病（TB）已成为传染病中的头号杀手。提高抗结核药物杀灭宿主细胞内结核分枝杆菌的能力仍然是一个巨大的挑战。在这里，一种创新的纳米系统被开发出来，以增加mtb感染巨噬细胞的药物传递和mtb杀伤效果。我们采用甘露糖表面修饰来制备甘露糖化和聚乙二醇化氧化石墨烯（GO-PEG-MAN）。这种纳米平台在体外通过甘露糖受体介导的内吞作用被巨噬细胞摄取增加。有趣的是，负载药物的GO-PEG- man比负载药物的GO-PEG更容易被mmb感染恒河猴分离的表达甘露糖受体的粘膜CD14（+）巨噬细胞吸收。与此一致的是，巨噬细胞中的药物浓度也显著高于不表达或低表达甘露糖受体的T细胞和B细胞，这意味着巨噬细胞/甘露糖受体靶向药物递送系统与体内环境有关。同时，负载利福平的GO-PEG-MAN （Rif@GO-PEG-MAN）显著增加了利福平的摄取，在巨噬细胞中诱导利福平浓度的持续升高。这种创新的Rif@GO-PEG-MAN可以很容易地进入Mtb宿主细胞的溶酶体，利福平在酸性溶酶体条件下加速释放，导致细胞进入后利福平爆炸释放，更有效地杀死细胞内的Mtb。最重要的是，Rif@GO-PEG-MAN-enhanced细胞内利福平递送和药代动力学显著提高了利福平驱动的体外和离体杀伤感染巨噬细胞内BCG和Mtb杆菌的效果。这种创新的纳米载体方法有可能提高抗结核药物的疗效，减少药物的副作用。
Tuberculosis (TB), caused by M.tuberculosis (Mtb), has become a top killer among infectious diseases. Enhancing the ability of anti-TB drugs to kill intracellular Mtb in host cells remains a big challenge. Here, an innovative nano-system was developed to increase drug delivery and Mtb-killing efficacy in Mtb-infected macrophages. We employed mannose surface decoration to develop mannosylated and PEGylated graphene oxide (GO-PEG-MAN). Such nano-platform exhibited increased uptake by macrophages via mannose receptor-mediated endocytosis in vitro. Interestingly, drug-loaded GO-PEG-MAN was preferentially up-taken by mannose receptor-expressing mucosal CD14(+) macrophages isolated from Mtb-infected rhesus macaques than drug-loaded GO-PEG. Consistently, the drug concentration was also significantly higher in macrophages than that in T and B cells expressing no or low mannose receptor, implicating a useful macrophage/mannose receptor-targeted drug-delivery system relevant to the in vivo settings. Concurrently, rifampicin-loaded GO-PEG-MAN (Rif@GO-PEG-MAN) significantly increased rifampicin uptake, inducing long-lasting higher concentration of rifampicin in macrophages. Such innovative Rif@GO-PEG-MAN could readily get into the lysosomes of the Mtb host cells, where rifampicin underwent an accelerated release in acidic lysosomic condition, leading to explosive rifampicin release after cell entry for more effective killing of intracellular Mtb. Most importantly, Rif@GO-PEG-MAN-enhanced intracellular rifampicin delivery and pharmacokinetics significantly increased the efficacy of rifampicin-driven killing of intracellular BCG and Mtb bacilli in infected macrophages both in vitro and ex vivo. Such innovative nanocarrier approach may potentially enhance anti-TB drug efficacy and reduce drug side effects.