Laboratoire de Biologie Tissulaire Et Ingénierie Thérapeutique, UMR5305, CNRS/Université, Lyon 1, Lyon, France.
Adjuvatis, 7 passage du Vercors, 69007, Lyon, France.
J Nanobiotechnology. 2021 Jan 7;19(1):12. doi: 10.1186/s12951-020-00760-w.
After the golden age of antibiotic discovery, bacterial infections still represent a major challenge for public health worldwide. The biofilm mode of growth is mostly responsible for chronic infections that current therapeutics fail to cure and it is well-established that novel strategies must be investigated. Particulate drug delivery systems are considered as a promising strategy to face issues related to antibiotic treatments in a biofilm context. Particularly, poly-lactic acid (PLA) nanoparticles present a great interest due to their ability to migrate into biofilms thanks to their submicronic size. However, questions still remain unresolved about their mode of action in biofilms depending on their surface properties. In the current study, we have investigated the impact of their surface charge, firstly on their behavior within a bacterial biofilm, and secondly on the antibiotic delivery and the treatment efficacy.
Rifampicin-loaded PLA nanoparticles were synthetized by nanoprecipitation and characterized. A high and superficial loading of rifampicin, confirmed by an in silico simulation, enabled to deliver effective antibiotic doses with a two-phase release, appropriate for biofilm-associated treatments. These nanoparticles were functionalized with poly-L-lysine, a cationic peptide, by surface coating inducing charge reversal without altering the other physicochemical properties of these particles. Positively charged nanoparticles were able to interact stronger than negative ones with Staphylococcus aureus, under planktonic and biofilm modes of growth, leading to a slowed particle migration in the biofilm thickness and to an improved retention of these cationic particles in biofilms. While rifampicin was totally ineffective in biofilms after washing, the increased retention capacity of poly-L-lysine-coated rifampicin-loaded PLA nanoparticles has been associated with a better antibiotic efficacy than uncoated negatively charged ones.
Correlating the carrier retention capacity in biofilms with the treatment efficacy, positively charged rifampicin-loaded PLA nanoparticles are therefore proposed as an adapted and promising approach to improve antibiotic delivery in S. aureus biofilms.
在抗生素发现的黄金时代之后，细菌感染仍然是全球公共卫生的主要挑战。生物膜生长模式是导致目前治疗方法无法治愈的慢性感染的主要原因，因此必须研究新的策略。颗粒药物递送系统被认为是解决生物膜环境中抗生素治疗相关问题的一种有前途的策略。特别是，聚乳酸（PLA）纳米粒子由于其亚微米尺寸能够迁移到生物膜中而具有很大的优势。然而，由于其表面特性，关于它们在生物膜中的作用模式仍存在一些问题尚未解决。在本研究中，我们研究了表面电荷对其在细菌生物膜内的行为以及抗生素递送和治疗效果的影响。
通过纳米沉淀合成了载利福平的 PLA 纳米粒子，并对其进行了表征。通过计算机模拟证实，高表面载利福平能够实现有效的抗生素剂量递送，并具有两相释放，适合生物膜相关治疗。这些纳米粒子通过表面涂层用阳离子肽聚-L-赖氨酸进行功能化，诱导电荷反转而不改变这些颗粒的其他物理化学性质。与带负电荷的纳米粒子相比，带正电荷的纳米粒子在浮游和生物膜生长模式下能够与金黄色葡萄球菌更强地相互作用，导致纳米粒子在生物膜厚度中的迁移速度减慢，并提高这些阳离子粒子在生物膜中的保留能力。虽然在冲洗后，利福平在生物膜中完全无效，但带正电荷的载利福平 PLA 纳米粒子的保留能力增加与未涂层的带负电荷的载利福平 PLA 纳米粒子相比，具有更好的抗生素疗效。
将载体在生物膜中的保留能力与治疗效果相关联，带正电荷的载利福平 PLA 纳米粒子因此被提出作为一种改进的、有前途的方法，以改善金黄色葡萄球菌生物膜中的抗生素递送。
