Hwang Jimin, Mros Sonya, Gamble Allan B, Tyndall Joel D A, McDowell Arlene
School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand.
Pharmaceutics. 2022 Feb 1;14(2):348. doi: 10.3390/pharmaceutics14020348.
Nanoparticle drug delivery systems have emerged as a promising strategy for overcoming limitations of antimicrobial drugs such as stability, bioavailability, and insufficient exposure to the hard-to-reach bacterial drug targets. Although size is a vital colloidal feature of nanoparticles that governs biological interactions, the absence of well-defined size control technology has hampered the investigation of optimal nanoparticle size for targeting bacterial cells. Previously, we identified a lead antichlamydial compound JO146 against the high temperature requirement A (HtrA) protease, a promising antibacterial target involved in protein quality control and virulence. Here, we reveal that JO146 was active against with a minimum bactericidal concentration of 18.8-75.2 µg/mL. Microfluidic technology using a design of experiments approach was utilized to formulate JO146-loaded poly(lactic--glycolic) acid nanoparticles and explore the effect of the nanoparticle size on drug delivery. JO146-loaded nanoparticles of three different sizes (90, 150, and 220 nm) were formulated with uniform particle size distribution and drug encapsulation efficiency of up to 25%. In in vitro microdilution inhibition assays, 90 nm nanoparticles improved the minimum bactericidal concentration of JO146 two-fold against compared to the free drug alone, highlighting that controlled engineering of nanoparticle size is important in drug delivery optimization.
纳米颗粒药物递送系统已成为一种有前景的策略，用于克服抗菌药物的局限性，如稳定性、生物利用度以及难以到达的细菌药物靶点暴露不足等问题。尽管尺寸是纳米颗粒的一个至关重要的胶体特性，它决定了生物相互作用，但缺乏明确的尺寸控制技术阻碍了对靶向细菌细胞的最佳纳米颗粒尺寸的研究。此前，我们鉴定出一种针对高温需求A（HtrA）蛋白酶的抗衣原体先导化合物JO146，HtrA蛋白酶是一种参与蛋白质质量控制和毒力的有前景的抗菌靶点。在此，我们发现JO146对……具有活性，最低杀菌浓度为18.8 - 75.2 µg/mL。利用基于实验设计方法的微流控技术来制备负载JO146的聚乳酸 - 乙醇酸纳米颗粒，并探究纳米颗粒尺寸对药物递送的影响。制备了三种不同尺寸（90、150和220 nm）的负载JO146的纳米颗粒，其粒径分布均匀，药物包封效率高达25%。在体外微量稀释抑制试验中，与单独的游离药物相比，90 nm的纳米颗粒使JO146对……的最低杀菌浓度提高了两倍，这突出表明纳米颗粒尺寸的可控工程在药物递送优化中很重要。
