Abstract
HypothesispH-responsive nanocarriers have the potential to provide targeted delivery of antimicrobial peptides (AMPs) to sites of bacterial infection with typically abnormal pH levels in the body. However, the local pH of the infected sites varies substantially among different infection-related diseases, calling for the development of delivery systems capable of targeting local pathological conditions in an adjustable pH range. ExperimentsIn this study, a highly versatile pH-responsive nanocarrier platform, based on dispersions of oleic acid (OA) and glycerol monooleate (GMO) self-assemblies with the human cathelicidin AMP LL-37, was designed and characterized. FindingsA detailed pH-composition phase diagram was constructed from small angle X-ray scattering and cryogenic transmission electron microscopy data. In addition, the protonation state and apparent pKa of OA embedded in these nano-self-assemblies were investigated by electrophoretic mobility measurements at different pHs and found to be strongly dependent on nanocarrier composition. By varying composition of these nanocarriers, the apparent pKa of embedded OA molecules could be tuned from 7.8 to 6.3, shifting the range of nanocarriers' pH-response. The study advances our fundamental understanding of self-assembly and pH-responsiveness in lipid-peptide systems containing monounsaturated long-chain fatty acids. The results may guide the future design of highly adaptable nanocarriers for patient-optimized pH-targeted AMP delivery.
Highlights
In light of the global rise of multi-drug-resistance among pathogenic bacteria, antimicrobial peptides (AMPs) are widely regarded as promising alternatives to conventional antibiotics, and are attracting growing interest owing to their broad-spectrum antimicrobial activity [1,2,3,4,5]
This study demonstrates the formation and characterization of pH-responsive LL-37 nanocarriers based on mixtures of OA and GMO
In absence of GMO, this F127-stabilized OA/LL-37 dispersion displayed a Small angle X-ray scattering (SAXS) curve with Bragg reflection spacings characteristic for a micellar cubic Fd3m phase with aFd3m of about 14.2 nm, in agreement with our previous investigations [44]
Summary
In light of the global rise of multi-drug-resistance among pathogenic bacteria, antimicrobial peptides (AMPs) are widely regarded as promising alternatives to conventional antibiotics, and are attracting growing interest owing to their broad-spectrum antimicrobial activity [1,2,3,4,5]. Our research group has recently reported on the self-assembly of oleic acid (OA) with human cathelicidin-derived AMP LL-37 in excess water, demonstrating the potential use of the produced nanoparticles as smart nanocarriers with pH-responsive structures [12,44]. Their pH sensitivity is attributed to the protonation state of OA, which modulates the electrostatic interactions among the embedded fatty acid molecules depending on the pH [12,33,44]. The experimental findings allow constructing partial ternary OA/GMO/LL-37 composition-pH phase diagrams that may guide the future design of highly tunable pH-responsive AMP nanocarriers for pH-targeted delivery
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