Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA; Department of Microbiology, Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, China.
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA.
Mater Sci Eng C Mater Biol Appl. 2019 Oct;103:109777. doi: 10.1016/j.msec.2019.109777. Epub 2019 May 21.
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.
结核病（TB）是由结核分枝杆菌（Mtb）引起的，已成为传染病中的头号杀手。提高抗结核药物在宿主细胞内杀死分枝杆菌的能力仍然是一个巨大的挑战。在这里，开发了一种创新的纳米系统来提高抗结核药物在分枝杆菌感染的巨噬细胞中的递送和分枝杆菌杀伤效果。我们采用甘露糖表面修饰来开发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表现出被巨噬细胞摄取的增加。有趣的是，与负载药物的 GO-PEG 相比，负载药物的 GO-PEG-MAN 更优先被从感染分枝杆菌的恒河猴中分离的表达甘露糖受体的粘膜 CD14 巨噬细胞摄取。同样，药物浓度在表达甘露糖受体的巨噬细胞中也明显高于不表达或低表达甘露糖受体的 T 和 B 细胞，这暗示了一种有用的巨噬细胞/甘露糖受体靶向药物递送系统与体内环境相关。同时，利福平负载的 GO-PEG-MAN（Rif@GO-PEG-MAN）显著增加了利福平的摄取，诱导巨噬细胞中利福平的浓度长时间保持较高水平。这种创新的 Rif@GO-PEG-MAN 可以很容易地进入分枝杆菌宿主细胞的溶酶体，在酸性溶酶体条件下利福平迅速释放，导致细胞进入后利福平的爆发性释放，从而更有效地杀死细胞内的分枝杆菌。最重要的是，Rif@GO-PEG-MAN 增强了细胞内利福平的递送和药代动力学，显著提高了利福平驱动的感染巨噬细胞中胞内 BCG 和分枝杆菌杆菌杀伤的效果，无论是在体外还是在体。这种创新的纳米载体方法可能有潜力提高抗结核药物的疗效并降低药物的副作用。
