Antimicrobial peptide-gold nanoscale therapeutic formulation with high skin regenerative potential

Abstract

Chronic skin wounds affect ≈3% of persons aged >60years (Davies et al., 2007) [1]. These wounds are typically difficult to heal by conventional therapies and in many cases they get infected making even harder the regeneration process. The antimicrobial peptide (AMP) LL37 combines antimicrobial with pro-regenerative properties and thus represents a promising topical therapy to address both problems. Here, we investigated the wound healing potential of soluble and immobilized LL37 (LL37-conjugated gold nanoparticles, LL37-Au NPs), both in vitro (migration of keratinocytes) and in vivo (skin wound healing). Our results show that LL37-Au NPs, but not LL37 peptide, have the capacity to prolong the phosphorylation of EGFR and ERK1/2 and enhance the migratory properties of keratinocytes in a large in vitro wound model. We further report that both LL37 and LL37-Au NPs promote keratinocyte migration by the transactivation of EGFR, a process that seems to be initiated at the P2X7 receptor, as confirmed by chemical and genetic inhibition studies. Finally, we show in vivo that LL37-Au NPs have higher wound healing activity than LL37 peptide in a splinted mouse full thickness excisional model. Animal wounds treated by LL37-Au NPs have higher expression of collagen, IL6 and VEGF than the ones treated with LL37 peptide or NPs without LL37. Altogether, the conjugation of AMPs to NPs offers a promising platform to enhance their pro-regenerative properties.

Antimicrobial endotoxin‐neutralizing peptides promote keratinocyte migration via P2X7 receptor activation and accelerate wound healing in vivo

“…However, these studies did not show a direct involvement of the P2X7 receptor in peptide‐induced cell migration. In contrast, we provide evidence that the P2X7 receptor is mandatory for peptide‐induced keratinocyte migration which is in line with recent findings for LL‐37 (Comune et al ., ). The importance of P2X7 receptor‐mediated cell migration during wound healing in vivo remains to be established.…”

“…Thus, future studies should investigate application of Pep19-2.5 in combination with antibiotics for the treatment of infected wounds. Additionally, alternative delivery methods and formulations should be considered since conjugation of LL-37 to gold nanoparticles improved in vitro and in vivo wound healing activity compared to soluble LL-37 (Comune et al, 2017).…”

Paradoxical Bactericidal Effects of Hydrophobic Lung Surfactant Proteins and Their Peptide Mimics Using Liposome Molecular Trojan

“…2 of the LS proteins and their mimics indicating they have quite a stable backbone at them. The backbone stability is a prerequisite for novel antibacterial peptide for therapeutic use 26 . It further validates the PPI and their characteristic suggesting LS proteins and their peptide mimics could be used in future therapeutics.…”

“…Therefore, we have performed a detailed in silico analysis of the LS proteins and their peptide mimics to predict its functionality and mode of action before going into the in-depth in vitro study. The backbone stability is an important property of any AMPs to cast a long shadow on host immune system 26 . Thus, we have performed the molecular dynamic simulation of the LS proteins and their mimics in cubic water box followed by protein-protein interaction PPI study using ambiguous docking algorithms.…”

Flame-Made Calcium Phosphate Nanoparticles with High Drug Loading for Delivery of Biologics

“…LL-37 has a net positive charge at physiological conditions, is amphiphilic and can eliminate the pathogenic microbes directly via electrostatic attraction towards negatively charged bacterial membranes [30]. Upon its immobilization on nanoparticle surfaces, LL-37 exhibits bactericidal activity against various bacteria [31][32][33][34]. Braun et al [31] showed the effect of surface charge and SSA of mesoporous SiO 2 nanocarriers on loading and release of LL-37 and they investigated their antimicrobial activity against Escherichia coli 25922.…”