Eradication of Multidrug‐Resistant Staphylococcal Infections by Light‐Activatable Micellar Nanocarriers in a Murine Model

Abstract

Bacterial infections are mostly due to bacteria in their biofilm mode-ofgrowth, making them recalcitrant to antibiotic penetration. In addition, the number of bacterial strains intrinsically resistant to available antibiotics is alarmingly growing. This study reports that micellar nanocarriers with a poly(ethylene glycol) shell fully penetrate staphylococcal biofilms due to their biological invisibility. However, when the shell is complemented with poly(β-amino ester), these mixed-shell micelles become positively charged in the low pH environment of a biofilm, allowing not only their penetration but also their accumulation in biofilms without being washed out, as do single-shell micelles lacking the pH-adaptive feature. Accordingly, bacterial killing of multidrug resistant staphylococcal biofilms exposed to proto porphyrin IX-loaded mixed-shell micelles and after light-activation is superior compared with single-shell micelles. Subcutaneous infections in mice, induced with vancomycin-resistant, bioluminescent staphylococci can be eradicated by daily injection of photoactivatable protoporphyrin IX-loaded, mixed-shell micelles in the bloodstream and light-activation at the infected site. Micelles, which are not degraded by bacterial enzymes in the biofilm, are degraded in the liver and spleen and cleared from the body through the kidneys. Thus, adaptive micellar nanocarriers loaded with lightactivatable antimicrobials constitute a much-needed alternative to current antibiotic therapies.

Antimicrobial synergy of monolaurin lipid nanocapsules with adsorbed antimicrobial peptides against Staphylococcus aureus biofilms in vitro is absent in vivo

“…Release of AMPs from ML-LNCs is controlled by shifting the adsorption-desorption equilibrium in reply to changes in AMP concentration in suspension, as demonstrated here through the measurement of zeta potentials and unlike operative in most drug release systems, that are pH controlled or light activated [24,25]. ML-LNCs without AMPs were effective in killing staphylococci in a planktonic and biofilm mode of growth, but DPK-060 and LL-37 on their own did not.…”

A dynamic covalent polymeric antimicrobial for conquering drug‐resistant bacterial infection

“…Since numerous pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α and anti-inflammatory IL-10 play an important role in the progression of bacterial infection disease, the capability of different treatment groups to regulate these cytokines was therefore studied. [25] As shown in Figure 4, the PM@Van@Cur could significantly decrease the levels of IL-1β, IL-6, and TNF-α and increase the amount of IL-10 compared with any other treatment groups, signifying that our combination therapy based on dynamic covalent polymeric antimicrobials had superior inflammatory cytokine regulation ability to the other mono-therapy, contributing to alleviate the infection-induced inflammation.…”

Encapsulation of Photothermal Nanoparticles in Stealth and pH-Responsive Micelles for Eradication of Infectious Biofilms In Vitro and In Vivo

“…In order to compare penetration and accumulation, encapsulated PDA-ICG-NPs were first loaded with Nile red. Previously Nile red-loading has been demonstrated not to affect the properties of PEG or PEG-PAE micelles [15]. PDA-ICG-NPs encapsulated in PEG micelles were unable to target, penetrate, and accumulate in 48 h grown S. aureus biofilms in vitro, neither at pH 5.0 nor at pH 7.4 (Figure 3a).…”