Abstract
HypothesispH-responsive aminolipid self-assemblies are promising platforms for the targeted delivery of antimicrobial peptides (AMPs), with the potential to improve their therapeutic efficiency and physico-chemical stability. ExperimentspH-sensitive nanocarriers based on dispersed self-assemblies of 1,2-dioleoyl-3-dimethylammonium-propane (DODAP) with the human cathelicidin LL-37 in excess water were characterized at different pH values using small-angle X-ray scattering, cryogenic transmission electron microscopy, and dynamic light scattering. Fluorescence and electrophoretic mobility measurements were used to probe the encapsulation efficiency of LL-37 and the nanocarriers’ surface potential. FindingsUpon decreasing pH in the DODAP/water systems, normal oil-in-water emulsions at pH ≥ 5.0 transitioned to emulsions encapsulating inverse hexagonal and cubic structures at pH between 4.5 and 4.0, and mostly positively-charged vesicles at pH < 4.0. These colloidal transformations are driven by the protonation of DODAP upon pH decrease. The larger lipid-water interfacial area provided by the DODAP self-assemblies at pH ≤ 4.5 allowed for an adequate encapsulation efficiency of LL-37, favouring the formation of vesicles in a concentration-dependent manner. Contrary, LL-37 was found to dissociate from the emulsion droplets at pH 6.0. The knowledge on the pH-triggered self-assembly of LL-37 and DODAP, combined with the results on peptide release from the structures contribute to the fundamental understanding of lipid/peptide self-assembly. The results can guide the rational design of future pH-responsive AMP delivery systems.
Highlights
This study reports the design and characterization of pHresponsive nanocarriers based on the self-assembly of the aminolipid dioleoyl-3-dimethylam monium-propane (DODAP) with the human cathlecidin antimicrobial peptide (AMP) LL-37 (Fig. 1)
The results indicate that LL-37 is still predominantly encapsulated in the DODAP dispersions at pH 4.5 despite the electrostatic repulsion from the positive surface potential of the DODAP self-assemblies (Fig. 7) and the decrease in LL-37 amphiphilicity caused by the loss of its ahelicity in solution (Fig. S15 in the Supporting Information (SI)).[57]
Conclusion pH-responsive nanocarriers based on self-assemblies of DODAP with LL-37 in excess water were designed and characterized
Summary
Antimicrobial peptides (AMPs) have attracted increasing attention as the next-generation alternatives to conventional antibiotics due to reduced development of bacterial resistance.[1,2,3] these short, positively-charged, and predominantly amphiphilic peptides possess broad-spectrum antibacterial activity, it is recognized that their cytotoxicity, low physico-chemical stability, and limited bioavailability are the main weaknesses that limit their clinical success.[4,5,6,7]The delivery of AMPs using pH-responsive nanocarriers is a promising strategy to protect the peptides from enzymatic degradation and selectively target their antimicrobial activity to the sites of infection with abnormal pH values, while avoiding off-target side effects.[8,9,10,11] As such, dispersed self-assemblies of amphiphilic lipids, especially the non-lamellar liquid crystalline phases, are emerging as effective drug delivery platforms due to their high loading capacity for hydrophobic, hydrophilic, and amphiphilic molecules.[12,13,14,15,16] The features of these nanostructures are strongly influenced by the molecular geometry and composition of their building blocks.[17,18] Their packing within the selfassemblies can depend on the characteristics of the amphiphilic molecules and their surrounding environmental conditions, including the local pH values, rendering these structures stimuliresponsive.[19,20,21,22,23,24] The pH-responsiveness may be exploited for the design of advanced drug delivery systems targeting specific local pH levels in the body that could trigger the release of peptide cargo or switch the antimicrobial activity of the nanocarriers. [11,20,25,26] Such abnormal pH environments can be conveniently found in infected tissues[27,28,29,30,31] or chronic[32,33,34] and acute wounds.[33]. The delivery of AMPs using pH-responsive nanocarriers is a promising strategy to protect the peptides from enzymatic degradation and selectively target their antimicrobial activity to the sites of infection with abnormal pH values, while avoiding off-target side effects.[8,9,10,11] As such, dispersed self-assemblies of amphiphilic lipids, especially the non-lamellar liquid crystalline phases, are emerging as effective drug delivery platforms due to their high loading capacity for hydrophobic, hydrophilic, and amphiphilic molecules.[12,13,14,15,16] The features of these nanostructures are strongly influenced by the molecular geometry and composition of their building blocks.[17,18] Their packing within the selfassemblies can depend on the characteristics of the amphiphilic molecules and their surrounding environmental conditions, including the local pH values, rendering these structures stimuliresponsive.[19,20,21,22,23,24] The pH-responsiveness may be exploited for the design of advanced drug delivery systems targeting specific local pH levels in the body that could trigger the release of peptide cargo or switch the antimicrobial activity of the nanocarriers.
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