Gallium nanoparticles facilitate phagosome maturation and inhibit growth of virulent Mycobacterium tuberculosis in macrophages.
Gallium nanoparticles facilitate phagosome maturation and inhibit growth of virulent Mycobacterium tuberculosis in macrophages.
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DOI：
10.1371/journal.pone.0177987
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Narayanasamy P
中科院分区：
文献类型：
--
作者：
Choi SR;Britigan BE;Moran DM;Narayanasamy P
需要新的治疗方法和新药来应对日益严重的结核分枝杆菌耐药菌株问题。我们对抗耐药结核分枝杆菌和其他细胞内病原体的方法是使用已在使用的药物和正在开发的药物的纳米制剂进行靶向给药。后者包括基于镓(III)(Ga)的化合物。在目前的工作中，以这种方式制备了六种不同类型的GA和利福平纳米颗粒，以增强对感染结核分枝杆菌的巨噬细胞的靶向性。然后测试它们对完全致病株(H37Rv)或非致病株(H37Ra)结核分枝杆菌生长的抑制能力。在叶酸或甘露糖连接的嵌段共聚物中包裹镓可持续释放镓15天，并显著抑制人单核细胞来源的巨噬细胞中结核分枝杆菌的生长。树枝状大分子包裹镓或利福平的纳米制剂也显示出良好的抗结核活性。通过检测成熟的组织蛋白酶D(34 kDa，溶酶体氢酶)，纳米颗粒与含有吞噬小体的结核分枝杆菌共定位。它们还促进了吞噬小体的成熟，预计这将增加巨噬细胞介导的对有机体的杀伤力。将镓或利福平以纳米粒的形式输送到巨噬细胞中，为开发新的抗结核治疗药物提供了一条很有前途的途径。
New treatments and novel drugs are required to counter the growing problem of drug-resistant strains of Mycobacterium tuberculosis (M.tb). Our approach against drug resistant M.tb, as well as other intracellular pathogens, is by targeted drug delivery using nanoformulations of drugs already in use, as well as drugs in development. Among the latter are gallium (III) (Ga)-based compounds. In the current work, six different types of Ga and rifampin nanoparticles were prepared in such a way as to enhance targeting of M.tb infected-macrophages. They were then tested for their ability to inhibit growth of a fully pathogenic strain (H37Rv) or a non-pathogenic strain (H37Ra) of M.tb. Encapsulating Ga in folate- or mannose-conjugated block copolymers provided sustained Ga release for 15 days and significantly inhibited M.tb growth in human monocyte-derived macrophages. Nanoformulations with dendrimers encapsulating Ga or rifampin also showed promising anti-tuberculous activity. The nanoparticles co-localized with M.tb containing phagosomes, as measured by detection of mature cathepsin D (34 kDa, lysosomal hydrogenase). They also promoted maturation of the phagosome, which would be expected to increase macrophage-mediated killing of the organism. Delivery of Ga or rifampin in the form of nanoparticles to macrophages offers a promising approach for the development of new therapeutic anti-tuberculous drugs.