Abstract
To avert the poor bioavailability of antibiotics during S. aureus biofilm infections, a series of zwitterionic nanoparticles containing nucleic acid nanostructures were fabricated for the delivery of vancomycin. The nanoparticles were prepared with three main lipids: (i) neutral (soy phosphatidylcholine; P), (ii) positively charged ionizable (1,2-dioleyloxy-3-dimethylaminopropane; D), and (iii) anionic (1,2-dipalmitoyl-sn-glycero-3-phospho((ethyl-1′,2′,3′-triazole) triethylene glycolmannose; M) or (cholesteryl hemisuccinate; C) lipids. The ratio of the anionic lipid was tuned between 0 and 10 mol %, and its impact on surface charge, size, stability, toxicity, and biofilm sensitivity was evaluated. Under biofilm mimicking conditions, the enzyme degradability (via dynamic light scattering (DLS)), antitoxin (via DLS and spectrophotometry), and antibiotic release profile was assessed. Additionally, biofilm penetration, prevention (in vitro), and eradication (ex vivo) of the vancomycin loaded formulation was investigated. Compared with the unmodified nanoparticles which exhibited the smallest size (188 nm), all three surface modified formulations showed significantly larger sizes (i.e., 222–277 nm). Under simulations of biofilm pH conditions, the mannose modified nanoparticle (PDM 90/5/5) displayed ideal charge reversal from a neutral (+1.69 ± 1.83 mV) to a cationic surface potential (+17.18 ± 2.16 mV) to improve bacteria binding and biofilm penetration. In the presence of relevant bacterial enzymes, the carrier rapidly released the DNA nanoparticles to function as an antitoxin against α-hemolysin. Controlled release of vancomycin prevented biofilm attachment and significantly reduced early stage biofilm formations within 24 h. Enhanced biocompatibility and significant ex vivo potency of the PDM 90/5/5 formulation was also observed. Taken together, these results emphasize the benefit of these nanocarriers as potential therapies against biofilm infections and fills the gap for multifunctional nanocarriers that prevent biofilm infections.
Highlights
Bacteria can colonize the surface of diseased tissues or medical devices to form biofilms, which has significant medical, social, and economic ramifications
The poor performance of antibiotics against biofilms has been attributed to limited drug diffusion and deactivation of antibiotics.[5−7] To avert the high mortality associated with biofilm infections, engineered nanocarriers increasingly constitute an advanced approach to improve the efficacy of antibiotics and overcome biofilm resistance
The blank deoxyribonucleic acid (DNA) nanoparticles were complexed with approximately 7.5−7.8 mg/mL of the lipids, and the zeta potential was examined at different pH conditions
Summary
Bacteria can colonize the surface of diseased tissues or medical devices to form biofilms, which has significant medical, social, and economic ramifications. Image Created by The Micro Art Illustrations aptamer functionalization on DNA origami nanoparticles enabled high nanostructure affinity for bacterial targets (Bacillus subtilis and Escherichia coli) compared with origami structures without the aptamers.[13] In parallel research efforts, directed growth and assembly of silver nanoparticles was achieved using polycytosine DNA.[14] These hybrids demonstrated antimicrobial activity because of the high affinity of cationic silver to the negatively charged bacteria cell wall Along these lines, the surface chemistry of DNA-based nanocarriers can be modified via complexation with lipids to promote their interaction with the EPS components of biofilms. The translational value of the formulation against cutaneous wound infections was demonstrated in a porcine explant model where a single application of the zwitterionic formulation led to a potent reduction in the bacterial bioburden within 24 h
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