Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, United States.
Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, United States.
Int J Pharm. 2018 Jun 10;544(1):75-82. doi: 10.1016/j.ijpharm.2018.03.058. Epub 2018 Mar 30.
Pseudomonas aeruginosa is an opportunistic gram-negative pathogen that causes a wide range of infections; it is becoming increasingly difficult to treat due to antibiotic resistance. Quorum-sensing (QS) based therapeutics, which function by disabling pathogen virulence without killing pathogens, are a promising class of drugs that may be used to treat bacterial infections without eliciting resistance development. The use of QS drugs to treat pulmonary P. aeruginosa infections, however, has been greatly limited due to the inability to deliver QS drugs at sufficiently high concentrations past physiological barriers such as pulmonary mucus. Here we apply a block copolymer-directed self-assembly process, Flash NanoPrecipitation, to develop a series of QS-active formulations that are fully water dispersible, stable, and mucus-penetrating. These formulations inhibit P. aeruginosa virulence without inhibiting cell growth. Particle size (70 nm-400 nm) and release rate (1 h-14 days) can be tuned by altering constructs' physical properties and formulation excipients. We also demonstrate, to the best of our knowledge, the first instance of a QS nanocarrier platform technology that can penetrate through human cystic fibrosis pulmonary mucus. This work highlights the need to incorporate nanoformulation strategies into the development of next-generation antimicrobial therapeutics.
铜绿假单胞菌是一种机会性革兰氏阴性病原体，可引起多种感染；由于抗生素耐药性，治疗难度越来越大。基于群体感应（QS）的治疗方法通过使病原体的毒力丧失而不杀死病原体起作用，是一类很有前途的药物，可用于治疗细菌感染而不会引起耐药性的发展。然而，由于无法将 QS 药物递送到生理屏障（如肺部粘液）以外的足够高的浓度，因此，QS 药物在治疗肺部铜绿假单胞菌感染方面的应用受到了极大的限制。在这里，我们应用一种嵌段共聚物导向的自组装工艺——快速纳米沉淀法（Flash NanoPrecipitation），开发了一系列完全可水分散、稳定且能穿透粘液的 QS 活性制剂。这些制剂可抑制铜绿假单胞菌的毒力，而不抑制细胞生长。通过改变构建体的物理性质和制剂赋形剂，可以调节粒径（70nm-400nm）和释放速率（1h-14d）。我们还证明了，就我们所知，这是第一个能够穿透人类囊性纤维化肺部粘液的 QS 纳米载体平台技术的实例。这项工作强调了需要将纳米制剂策略纳入下一代抗菌治疗药物的开发中。
