Low-adhesive, Positively Charged Nanocapsule for the Treatment of Drug-resistant Bacterial Biofilm Infection

Liu, CH (Liu, Chen-hui)^[ 1 ] ; Cao, JJ (Cao, Jing-jing)^[ 1 ] ; Zhao, Y (Zhao, Yu)^[ 1 ] ; Zheng, CX (Zheng, Chun-xiong)^[ 1 ] ; Zheng, YD (Zheng, Ya-dan)^[ 1 ] ; Liu, Q(Liu, Qi)^[ 1 ] ; Zhang, ZZ (Zhang, Zhan-zhan)^[ 1 ] ; Liu, Y (Liu, Yang)^[ 1 ]

ACTA POLYMERICA SINICA, 2019, 50(3): 300-310

DOI: 10.11777/j.issn1000-3304.2019.18220

Abstract

Microbes with the biofilm mode of growth are highly resistant against antibiotics partially due to the ineffective antibiotic penetration to the depth of a biofilm where the bacteria reside and proliferate. To enhance the penetration of antibiotics, we herein demonstrated a delivery nanocapsule that could deliver antibiotics deeply into the deep layer of the biofilm and release the antibiotics inside. The delivery nanocapsule performs a core-shell structure. The core is formed via nanoprecipitation with two different types of antibiotics in the presence of an acid-liable polymer, which allows the effective release of the antibiotics in response to the acidic environment when reaching the deep layer of the biofilm. The shell of the delivery nanocapsule is synthesized by co-polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) and N-(3-Aminopropyl) methacrylamide hydrochloride (APM) to form a cationic and protein adsorption-resistant film encapsulating around the core. Such a core-shell structure could effectively reduce the diffusion resistance of the delivery nanocapsule into the biofilm, resulting in an enhanced penetration capability. Confocal laser scanning macroscopy (CLSM) imaging demonstrated that the nanocapsule could efficiently penetrate into the mature biofilms formed by S. aureus ATCC12600(GFP). Moreover, such nanocapsules could load multiple drugs simultaneously, allowing the spontaneously co-delivery of various types of antibiotics into the biofilm. Exemplified with piperacillin and tazobactam, the co-delivery of the two types of antibiotics with the nanocapsule resulted in the synergetic therapeutic effect on the beta-lactam resistance bacteria of S. aureus ATCC43300, achieving an efficient eradication of the bacteria embedded in the biofilm. In conclusion, the nanocapsule-based delivery system assisted with antibiotics in penetrating into the deep layer of biofilm and released the antibiotics in response to the acidic environment of the biofilm. Compared to directly applying antibiotics to the biofilm, the delivery of antibiotics with the nanocapsule exhibited more effective penetration and accumulation deeply inside the layer, achieving a more efficient eradication of the residual bacteria in the biofilm.