Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
School of Science, Monash University Malaysia, Subang Jaya 47500, Selangor, Malaysia.
ACS Biomater Sci Eng. 2022 Oct 10;8(10):4196-4206. doi: 10.1021/acsbiomaterials.1c00807. Epub 2021 Aug 31.
Pretomanid and MCC7433, a novel nitroimidazopyrazinone analog, are promising antitubercular agents that belong to the bicyclic nitroimidazole family. Despite possessing high cell permeability, they suffer from poor aqueous solubility and require specialized formulations in order to be orally bioavailable. To address this limitation, we investigated the use of mesoporous silica nanoparticles (MCM-41) as drug carriers. MCM-41 nanoparticles were synthesized using a sol-gel method, and their surface was further modified with amine and phosphonate groups. A simple rotary evaporation method was used to incorporate the compounds of interest into the nanoparticles, leading to a high encapsulation efficiency of ≥86% with ∼10% loading (w/w). An overall significant improvement of solubility was also observed, and the pharmacological activity of pretomanid and MCC7433 was fully retained when tested in vitro against using these nanocarriers. Amino-functionalized MCM-41 nanoparticles were found to enhance the systemic exposure of MCC7433 in mice (1.3-fold higher ) compared to MCC7433 alone. The current work highlights the potential of using nanoparticles such as mesoporous silica as a carrier for oral delivery of poorly soluble antibacterial agents against tuberculosis.
苯并噁嗪酮类似物替莫硝唑和 MCC7433 是具有前景的抗结核药物，属于双环硝基咪唑类。尽管它们具有较高的细胞通透性，但水溶性差，需要特殊的制剂才能口服生物利用。为了解决这个问题，我们研究了介孔硅纳米颗粒（MCM-41）作为药物载体的用途。MCM-41 纳米颗粒采用溶胶-凝胶法合成，其表面进一步用胺和膦酸基团进行修饰。采用简单的旋转蒸发法将感兴趣的化合物掺入纳米颗粒中，实现了≥86%的高包封效率（w/w）和 10%的载药量。还观察到溶解度的显著整体提高，并且当使用这些纳米载体在体外针对进行测试时，替莫硝唑和 MCC7433 的药理活性得到了完全保留。与单独的 MCC7433 相比，氨基功能化的 MCM-41 纳米颗粒被发现可提高 MCC7433 在小鼠体内的全身暴露量（高 1.3 倍）。目前的工作强调了使用介孔硅等纳米颗粒作为载体口服递送至结核病的水溶性差的抗菌剂的潜力。
