Lipid-Based Liquid Crystals As Carriers for Antimicrobial Peptides: Phase Behavior and Antimicrobial Effect

Abstract

The number of antibiotic-resistant bacteria is increasing worldwide, and the demand for novel antimicrobials is constantly growing. Antimicrobial peptides (AMPs) could be an important part of future treatment strategies of various bacterial infection diseases. However, AMPs have relatively low stability, because of proteolytic and chemical degradation. As a consequence, carrier systems protecting the AMPs are greatly needed, to achieve efficient treatments. In addition, the carrier system also must administrate the peptide in a controlled manner to match the therapeutic dose window. In this work, lyotropic liquid crystalline (LC) structures consisting of cubic glycerol monooleate/water and hexagonal glycerol monooleate/oleic acid/water have been examined as carriers for AMPs. These LC structures have the capability of solubilizing both hydrophilic and hydrophobic substances, as well as being biocompatible and biodegradable. Both bulk gels and discrete dispersed structures (i.e., cubosomes and hexosomes) have been studied. Three AMPs have been investigated with respect to phase stability of the LC structures and antimicrobial effect: AP114, DPK-060, and LL-37. Characterization of the LC structures was performed using small-angle X-ray scattering (SAXS), dynamic light scattering, ζ-potential, and cryogenic transmission electron microscopy (Cryo-TEM) and peptide loading efficacy by ultra performance liquid chromatography. The antimicrobial effect of the LCNPs was investigated in vitro using minimum inhibitory concentration (MIC) and time-kill assay. The most hydrophobic peptide (AP114) was shown to induce an increase in negative curvature of the cubic LC system. The most polar peptide (DPK-060) induced a decrease in negative curvature while LL-37 did not change the LC phase at all. The hexagonal LC phase was not affected by any of the AMPs. Moreover, cubosomes loaded with peptides AP114 and DPK-060 showed preserved antimicrobial activity, whereas particles loaded with peptide LL-37 displayed a loss in its broad-spectrum bactericidal properties. AMP-loaded hexosomes showed a reduction in antimicrobial activity.

Antimicrobial Peptides: An Emerging Category of Therapeutic Agents

“…Furthermore, controlled-release of LL-37 from MSNs has been demonstrated through incorporation into mesoporous silica membranes that offers opportunities as surface coatings for implants (Izquierdo-Barba et al, 2009). Recently, liquid crystalline lipid nanoparticles and lipid nanocapsules have been investigated for encapsulation of several cationic AMPs varying in biophysical properties, with high loading efficacy and sustained or improved antimicrobial effect observed for many of these systems, suggesting potential for drug delivery (Boge et al, 2016; Umerska et al, 2016b). Notably, in addition to stabilizing the AMP and targeting delivery and release, nanocarrier material can have antimicrobial function on its own, thereby boosting the effect of the AMP (Malmsten, 2011; Umerska et al, 2016a).…”

Pep‐Lipid Cubosomes and Vesicles Compartmentalized by Micelles from Self‐Assembly of Multiple Neuroprotective Building Blocks Including a Large Peptide Hormone PACAP‐DHA

“…Indeed, mesoporous cubic lattice architectures present strong current interest in a number of scientific fields. [5][6][7]11,[18][19][20] It is remarkable that the observed organized ladybird-like patterns with internal compartments as well as the periodic cubic lipid membrane structures ( Figure 6) mimic the biological compartmentalization in living systems. [22] On the other hand, the organizational complexity of the scaffolds involving the lipidated high-molecular weight peptide hormone is beyond the one that has been reached with small lipid-like peptide surfactants.…”

Current state of a dual behaviour of antimicrobial peptides—Therapeutic agents and promising delivery vectors

“…This can be attributed to the fusional interaction between the phospholipid membrane of liposomes and bacterial cells, [89] or the surface hydrophilicity of the vesicles, which can facilitate the association with hydrophilic bacterial cells. [91] In addition to DDS as discussed above, peptides can be incorporated within the carriers and adsorbed onto the particles' surface. [112] These particles can be typically obtained by the sonication of the charged lipids into short-lived bilayer fragments, or by the disruptive effect of PEGylated lipids on liposomes (47).…”