LuTheryn Gareth, Ho Elaine M L, Choi Victor, Carugo Dario
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), The Botnar Research Centre, University of Oxford, Windmill Road, Oxford OX3 7HE, UK.
Faculty of Engineering and Physical Sciences, University of Southampton, University Road, Southampton SO17 1BJ, UK.
Pharmaceutics. 2023 May 13;15(5):1495. doi: 10.3390/pharmaceutics15051495.
The presence of multi-drug resistant biofilms in chronic, persistent infections is a major barrier to successful clinical outcomes of therapy. The production of an extracellular matrix is a characteristic of the biofilm phenotype, intrinsically linked to antimicrobial tolerance. The heterogeneity of the extracellular matrix makes it highly dynamic, with substantial differences in composition between biofilms, even in the same species. This variability poses a major challenge in targeting drug delivery systems to biofilms, as there are few elements both suitably conserved and widely expressed across multiple species. However, the presence of extracellular DNA within the extracellular matrix is ubiquitous across species, which alongside bacterial cell components, gives the biofilm its net negative charge. This research aims to develop a means of targeting biofilms to enhance drug delivery by developing a cationic gas-filled microbubble that non-selectively targets the negatively charged biofilm. Cationic and uncharged microbubbles loaded with different gases were formulated and tested to determine their stability, ability to bind to negatively charged artificial substrates, binding strength, and, subsequently, their ability to adhere to biofilms. It was shown that compared to their uncharged counterparts, cationic microbubbles facilitated a significant increase in the number of microbubbles that could both bind and sustain their interaction with biofilms. This work is the first to demonstrate the utility of charged microbubbles for the non-selective targeting of bacterial biofilms, which could be used to significantly enhance stimuli-mediated drug delivery to the bacterial biofilm.
慢性持续性感染中多药耐药生物膜的存在是治疗取得成功临床结果的主要障碍。细胞外基质的产生是生物膜表型的一个特征，与抗菌耐受性内在相关。细胞外基质的异质性使其具有高度动态性，即使是同一物种的生物膜，其组成也存在很大差异。这种变异性给将药物递送系统靶向生物膜带来了重大挑战，因为在多个物种中既适当保守又广泛表达的元素很少。然而，细胞外基质中细胞外DNA在各物种中普遍存在，它与细菌细胞成分一起赋予生物膜净负电荷。本研究旨在开发一种靶向生物膜的方法，通过开发一种阳离子充气微泡来增强药物递送，该微泡可非选择性地靶向带负电荷的生物膜。制备并测试了负载不同气体的阳离子和不带电微泡，以确定它们的稳定性、与带负电荷人工底物结合的能力、结合强度，以及随后它们附着在生物膜上的能力。结果表明，与不带电的微泡相比，阳离子微泡显著增加了能够与生物膜结合并维持相互作用的微泡数量。这项工作首次证明了带电微泡在非选择性靶向细菌生物膜方面的效用，可用于显著增强刺激介导的药物递送至细菌生物膜。
