Protonation–Activity Relationship of Bioinspired Ionizable Glycomimetics for the Growth Inhibition of Bacteria

Abstract

Variations in physiological parameters (i.e., pH, redox potential, and ions) for distinct types of diseases make them attractive targets. Ionizable groups capable of pH-dependent charge conversion impart pH-switchable materials under acid condition through the protonation effect, which stimulates the emergence of various pH-inspired materials. However, it is confusing to distinguish preferable groups for high-efficiency drug-delivery vehicles attributing to the lack of perceiving the relationship between protonation and activity. Herein, we developed a series of bioinspired ionizable glycomimetics responses to the ambient variation from physiological environment (pH 7.4) to bacterial infectious acidic microenvironment (pH 6.0) to explore the protonation–activity relationship of various ionizable groups. The nanoparticles are coated with bacterial adhesion molecules galactose and fucose to target Pseudomonas aeruginosa. Moreover, the particle cores were composed of ionizable polymers responding to acidic microenvironment changes and entrapped antibiotic payload. Ionizable glyconanoparticles targeted bacteria and local cues as triggers to transfer payloads in on-demand patterns for the inhibition of bacteria-related infection. Significantly, we find that the nanoparticles with the pH-sensitive block of ionizable poly­(2-(diisopropylamino)­ethyl methacrylate) (pDPA) exhibit predominant bacterial adhesion and killing and growth inhibition of biofilm in acid environment (pH 6.0) due to the ionizable polymer protonation effect with more positive charge cooperated with the lectin-targeted effect of polysaccharide causing a huge bacterial aggregation and a highly favorable germicidal effect. The nanoparticles with poly­(2-(hexamethyleneimino)­ethyl methacrylate) (pHMEMA) have suboptimal antibacterial activity but advanced protonation at pH 6.3 compared to pDPA at 6.1, suggesting its selection as an applicable pH-switchable group for a slightly higher acid microenvironment like tumor (pH 6.9–6.5) because of the efficient performance after protonation than at deprotonation. On the other hand, the glycomimetic containing poly­(2-(dibutylamino)­ethyl methacrylate) (pDBA) as a pH-sensitive moiety displayed weak antimicrobial activity and superior stability before protonation (pH 4.7), which make it possible to prevent premature drug leakage, suggesting that pDBA is a good candidate to be applied to construct pH-sensitive drug-delivery carriers for the treatment of bacteria-related infection with a low acidic microenvironment. Overall, the structure–activity relationship of ionizable glycomimetics for the inhibition of bacteria signifies not only the development of a drug-delivery system but also the mechanism-dependent treatment of nanomedicine for infectious diseases.

Oxygen Self-Supplying Nanotherapeutic for Mitigation of Tissue Hypoxia and Enhanced Photodynamic Therapy of Bacterial Keratitis

“…Synthesis of 2-(β- d -galactosyloxy)­ethyl methacrylate (GEMA) and 2-(2′,3′,4′-trihydroxy- l -fucose)­ethyl methacrylate (FEMA) were followed by the method of our previous work . Briefly, galactose pentacetate (1.9 g, 5 mmol) and hydroxyethyl methacrylate (1.3 mL, 10 mmol) were mixed in CH 2 Cl 2 (30 mL).…”

Inhibition and eradication of bacterial biofilm using polymeric materials

“…Zhang's research group introduced a series of RAFT-synthesized amphiphilic ionizable glycomimetic block copolymers to explore the protonation–antibacterial activity relationship. 108 Here, three types of tertiary amine-based hydrophobic block, namely poly(2-(diisopropylamino)ethyl methacrylate) (pDPA), poly(2-(hexamethyleneimino)ethyl methacrylate) (pHMEMA) and poly(2-(dibutylamino)ethyl methacrylate) (pDBA), with p K a values of 6.0, 6.3 and 4.7, respectively, have been used to examine their antibacterial and antibiofilm performances against P. aeruginosa . In fact, these blocks were incorporated as a comonomer partner to prepare the block copolymers p(GEMA- r -FEMA)- b -pR (R = DPA, DBA or HMEMA) using the macro chain transfer agent p(GEMA- r -FEMA) [poly(2-(β- d -galactosyloxy) ethyl methacrylate-random-2-fucose ethyl methacrylate)].…”

Virus-like-inspired nanoparticles facilitate bacterial internalization for enhanced eradication of drug-resistant pathogens

“…1 AcGEMA was synthesized according to the modified literature procedure. 25,26 2-Hydroxyethyl methacrylate (2.6 mL, 20 mM) and galactose pentaacetate (3.9 g, 10 mM) were dissolved in dry DCM (20 mL) under a nitrogen atmosphere. Under ice-water bath conditions, boron trifluoride ether (7 mL, 44 mM) was slowly poured into the mixture at 25 1C for 3 h. The mixture was quenched by adding chloroform (60 mL).…”