Formulation of pH-responsive PEGylated nanoparticles with high drug loading capacity and programmable drug release for enhanced antibacterial activity

In the current global crisis of antibiotic resistance, delivery systems are emerging to combat resistant bacteria in a more efficient manner. Despite the significant advances of antibiotic nanocarriers, many challenges like poor biocompatibility, premature drug release, suboptimal targeting to infection sites and short blood circulation time are still challenging. To achieve targeted drug delivery and enhance antibacterial activity, here we reported a kind of pH-responsive nanoparticles by simply self-assembly of an amphiphilic poly(ethylene glycol)-Schiff-vancomycin (PEG-Schiff-Van) prodrug and free Van in one drug delivery system. The acid-liable Schiff base furnished the PEG-Schiff-Van@Van with good storage stability in the neutral environment and susceptible disassembly in response to faintly acidic condition. Notably, on account of the combination of physical encapsulation and chemical conjugation of vancomycin, these nanocarriers with favorable biocompatibility and high drug loading capacity displayed a programmed drug release behavior, which was capable of rapidly reaching high drug concentration to effectively kill the bacteria at an early period and continuously exerting an bacteria-sensitive effect whenever needed over a long period. In addition, more Schiff-base moieties within the PEG-Schiff-Van@Van nanocarriers may also make great contributions on promoting the antimicrobial activity. Using this strategy, this system was designed to have programmable structural destabilization and sequential drug release due to changes in pH that were synonymous with bacterial infection sites, thereby presenting prominent antibacterial therapy both in vitro and in vivo. This work represents a synergistic strategy on offering important guidance to rational design of multifunctional antimicrobial vehicles, which would be a promising class of antimicrobial materials for potential clinical translation. One drug delivery system with combination of physical encapsulation and chemical conjugation endows PEG-Schiff-Van@Van nanoparticles with high drug loading capacity and pH-responsive drug release behavior, thus achieving the programmable antibiotics release for targeted antimicrobial activity. [Display omitted] •Simple method to prepare pH-responsive PEGylated vancomycin prodrug.•Physicochemical synergistic combination endows the nanoparticles with high drug loading and programed release behavior.•It can achieve high drug concentration to kill the bacteria in early