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.

Polyprodrug Antimicrobials: Remarkable Membrane Damage and Concurrent Drug Release to Combat Antibiotic Resistance of Methicillin‐Resistant Staphylococcus aureus

“…Notably, the development of antibiotic resistance for MRSA was also interrogated . MRSA were serially trained in the presence of sublethal content of P 45 , QP 45 , vancomycin, and triclosan for ten cycles, the MIC values were measured after each passage (Figure d).…”

Biodegradable Antibacterial Polymeric Nanosystems: A New Hope to Cope with Multidrug‐Resistant Bacteria

“…Photodynamic approaches provided alternative approaches for therapeutic purposes . For example, protoporphyrin IX (PpIX) as a photosensitizer was explored to be encapsulated in the MSPM platform to facilitate the penetration into biofilms, and eradicate multidrug‐resistant staphylococcal infections in a murine model via photodynamic antibacterial therapy . Figure shows that the experimental group administered with PpIX‐loaded MSPMs exhibited faster recovery rate after infection with vancomycin‐resistant staphylococcal , while the differences in bacterial eradication efficacies in the groups treated with saline, vancomycin, and PpIX‐loaded SSPMs were minimal.…”

“…To curb the rise of antibiotic resistance, one approach is to reduce the administered dose of antibiotics, and enhance the bioavailability at the same time. To achieve this purpose, the conventional antibiotics can be conjugated with a variety of synthetic polymers, or encapsulated into polymeric nanoparticles (e.g., micelles, vesicles, nanogels) . The payload of conjugated or encapsulated drugs can be enriched in the bacterial infected zone, and released to kill bacteria.…”

The Dual Role of the Liver in Nanomedicine as an Actor in the Elimination of Nanostructures or a Therapeutic Target

“…is process can affect the efficacy of NPs to effectively reach their target and exert a therapeutic effect [1], as well as potentially increase the risk of unwanted liver toxicity [2]. Biodistribution studies have demonstrated that the clearance action exerted by the liver is confirmed for the majority of NP designs: polymeric NPs [3][4][5], micelles [6,7], quantum dots [8], gold NPs [9], and carbon nanotubes [10]. In this context, injected nanomaterials usually accumulate in the liver and in an amount that depends on their physiochemical properties, such as size, shape, and surface functionalization, although relatively little is understood about dynamics of NP transport at the intraorgan level [11,12].…”