pH-Responsive, Charge-Reversing Layer-by-Layer Nanoparticle Surfaces Enhance Biofilm Penetration and Eradication.
pH-Responsive, Charge-Reversing Layer-by-Layer Nanoparticle Surfaces Enhance Biofilm Penetration and Eradication.
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DOI：
10.1021/acsbiomaterials.3c00481
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发表时间：
2023-06
影响因子：
5.8
通讯作者：
Elad Deiss‐Yehiely;Gerardo Cárcamo-Oyarce;Adam G. Berger;K. Ribbeck;P. Hammond
中科院分区：
文献类型：
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作者：
Elad Deiss‐Yehiely;Gerardo Cárcamo-Oyarce;Adam G. Berger;K. Ribbeck;P. Hammond
盘伏在生物膜内的微生物可以承受高出1000倍浓度的抗生素，部分原因是黏性的细胞外基质会隔离和减弱抗菌活性。与单独的游离药物相比，基于纳米颗粒（NP）的治疗方法可以帮助在整个生物膜中传递更高的局部浓度，从而提高疗效。规范的设计标准表明，带正电的纳米颗粒可以多价结合阴离子生物膜成分，并增加生物膜的渗透。然而，阳离子颗粒是有毒的，并且在体内循环中很快被清除，限制了它们的使用。因此，我们试图设计pH响应NPs，使其表面电荷从负变为正，以响应降低的生物膜pH微环境。我们合成了一系列依赖ph的可水解聚合物，并采用逐层（LbL）静电组装方法以这些聚合物为最外表面制备了生物相容性NPs。NP电荷转化率由聚合物亲水性和侧链结构决定，在实验时间范围内从数小时到无法检测。电荷转化率越来越快的LbL NPs更有效地穿透并积累在野生型（PAO1）和突变型过表达生物量（ΔwspF）的铜绿假单胞菌生物膜中。最后，妥布霉素，一种已知被阴离子生物膜成分捕获的抗生素，被加载到LbL NP的最后一层。与最慢的电荷转换NP和游离妥布霉素相比，最快的电荷转换NP的ΔwspF集落形成单位减少了3.2倍。这些研究为生物膜穿透NPs的设计提供了一个框架，这些NPs响应基质相互作用，最终增加了抗菌剂的有效递送。
Microbes entrenched within biofilms can withstand 1000-fold higher concentrations of antibiotics, in part due to the viscous extracellular matrix that sequesters and attenuates antimicrobial activity. Nanoparticle (NP)-based therapeutics can aid in delivering higher local concentrations throughout biofilms as compared to free drugs alone, thereby enhancing the efficacy. Canonical design criteria dictate that positively charged nanoparticles can multivalently bind to anionic biofilm components and increase biofilm penetration. However, cationic particles are toxic and are rapidly cleared from circulation in vivo, limiting their use. Therefore, we sought to design pH-responsive NPs that change their surface charge from negative to positive in response to the reduced biofilm pH microenvironment. We synthesized a family of pH-dependent, hydrolyzable polymers and employed the layer-by-layer (LbL) electrostatic assembly method to fabricate biocompatible NPs with these polymers as the outermost surface. The NP charge conversion rate, dictated by polymer hydrophilicity and the side-chain structure, ranged from hours to undetectable within the experimental timeframe. LbL NPs with an increasingly fast charge conversion rate more effectively penetrated through, and accumulated throughout, wildtype (PAO1) and mutant overexpressing biomass (ΔwspF) Pseudomonas aeruginosa biofilms. Finally, tobramycin, an antibiotic known to be trapped by anionic biofilm components, was loaded into the final layer of the LbL NP. There was a 3.2-fold reduction in ΔwspF colony forming units for the fastest charge-converting NP as compared to both the slowest charge converter and free tobramycin. These studies provide a framework for the design of biofilm-penetrating NPs that respond to matrix interactions, ultimately increasing the efficacious delivery of antimicrobials.