Designing efficient colloidal systems for the delivery of membrane active antimicrobial peptides requires in-depth understanding of their structural and morphological characteristics. Using dispersions of inverted type bicontinuous cubic phase (cubosomes), we examine the effect of integrating the amphiphilic peptide LL-37 at different concentrations on the self-assembled structure and evaluate its bactericidal ability against Escherichia coli. Small-angle X-ray scattering, dynamic light scattering, and cryogenic transmission electron microscopy show that LL-37 integrates into the bicontinuous cubic structure, inducing colloidal transformations to sponge and lamellar phases and micelles in a concentration-dependent manner. These investigations, together with in vitro evaluation studies using a clinically relevant bacterial strain, established the composition-nanostructure-activity relationship that can guide the design of new nanocarriers for antimicrobial peptides and may provide essential knowledge on the mechanisms underlying the bacterial membrane disruption with peptide-loaded nanostructures.
Stimuli-responsive nanocarriers based on lipid self-assemblies have the potential to provide targeted delivery of antimicrobial peptides, limiting their side effects while protecting them from degradation in the biological environments. In the present study, we design and characterize a simple pH-responsive antimicrobial nanomaterial, formed through the self-assembly of oleic acid (OA) with the human cathelicidin LL-37 as a model for an amphiphilic antimicrobial peptide. Colloidal transformations from core–shell cylindrical micelles with a cross-sectional diameter of ∼5.5 nm and a length of ∼23 nm at pH 7.0 to aggregates of branched threadlike micelles at pH 5.0 were detected using synchrotron small-angle X-ray scattering, cryogenic transmission electron microscopy, and dynamic light scattering. Biological in vitro assays using an Escherichia coli bacteria strain showed high antimicrobial activity of the positively charged LL-37/OA aggregates at pH 5.0, which was not caused by the pH conditions themselves. Contrary to that, negligible antimicrobial activity was observed at pH 7.0 for the negatively charged cylindrical micelles. The nanocarrier’s ability to switch its biological activity “on” and “off” in response to changes in pH could be used to focus the antimicrobial peptides’ action to areas of specific pH in the body. The presented findings contribute to the fundamental understanding of lipid-peptide self-assembly and may open up a promising strategy for designing simple pH-responsive delivery systems for antimicrobial peptides.
The delivery of poorly water-soluble antimicrobial peptides (AMPs) that are sensitive to degradation is a major challenge in the pharmaceutical field. In this study, we design and characterize a pH-sensitive nanocarrier with the potential for delivery of AMPs and their protection from degradation. These nanobiointerfaces are prepared through the self-assembly of oleic acid (OA) with the human cathelicidin LL-37 in excess water. Advanced experimental methods including synchrotron small angle X-ray scattering, cryogenic transmission electron microscopy, and dynamic light scattering were used to characterize the OA/LL-37 self-assemblies and their structural alterations in response to changes in pH and composition. Experimental findings reveal colloidal transformations from normal emulsions via micellar cubosomes and hexosomes to vesicles upon increasing the pH from 6.0 to 8.0 at a LL-37 content around 10 wt% relative to OA. Increasing the LL-37 content to 30 wt% in OA led to diminishing of micellar cubosomes and hexosomes in this narrow pH range, favoring the formation of micelles and vesicles of various shapes and sizes. Upon increasing the pH, with the strongest effect around pH 7.5, charge repulsions among the gradually deprotonating carboxylic groups of OA modified the geometric packing of the molecules, significantly affecting the nanostructure. These detailed insights into the formation of this unique family of nanobiointerfaces and their tunable structural features may contribute to the rational design of pH-responsive antimicrobial systems for the delivery of peptides, particularly poorly water-soluble AMPs.
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