Multifunctional lipid-based nanocarriers with antibacterial and anti‐inflammatory activities for treating MRSA bacteremia in mice

Abstract

Background Bacteremia-induced sepsis is a leading cause of mortality in intensive care units. To control a bacterial infection, an immune response is required, but this response might contribute to organ failure. Kidneys are one of the main organs affected by bacteremia. Combination therapies with antibacterial and anti-inflammatory effects may be beneficial in treating bacteremia. This study aimed to develop nanostructured lipid carriers (NLCs) loaded with ciprofloxacin and rolipram that exert a combination of anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-inflammatory effects. Retinol was incorporated into the nanoparticles to transport retinol-binding protein 4 (RBP4) to the kidneys, which abundantly express RBP receptors. The NLCs were fabricated by high-shear homogenization and sonication, and neutrophils were used as a model to assess their anti-inflammatory effects. Mice were injected with MRSA to establish a model of bacteremia with organ injury. Results The mean nanoparticle size and zeta potential of the NLCs were 171 nm and − 39 mV, respectively. Ciprofloxacin (0.05%, w/v) and rolipram (0.02%) achieved encapsulation percentages of 88% and 96%, respectively, in the nanosystems. The minimum bactericidal concentration of free ciprofloxacin against MRSA increased from 1.95 to 15.63 µg/ml when combined with rolipram, indicating a possible drug-drug interaction that reduced the antibacterial effect. Nanoparticle inclusion promoted the anti-MRSA activity of ciprofloxacin according to time-kill curves. The NLCs were found to be largely internalized into neutrophils and exhibited superior superoxide anion inhibition than free drugs. Retinol incorporation into the nanocarriers facilitated their efficient targeting to the kidneys. The NLCs significantly mitigated MRSA burden and elastase distribution in the organs of MRSA-infected animals, and the greatest inhibition was observed in the kidneys. Bacterial clearance and neutrophil infiltration suppression attenuated the bacteremia-induced cytokine overexpression, leading to an improvement in the survival rate from 22% to 67%. Conclusions The dual role of our NLCs endowed them with greater efficacy in treating MRSA bacteremia than that of free drugs.

Novel silver metformin nano-structure to impede virulence of Staphylococcus aureus

“…Similarly, Li et al (2020) showed that in an in vitro cytotoxicity experiments revealed that FTP NPs were less toxic to mammalian cells than PMET, and in vivo intravenous injection of FTP NPs revealed no acute toxicity. In another study reported by Liao et al (2021), it was found that treatment with nanostructured lipid carriers (NLCs) encapsulating both ciprofloxacin and rolipram significantly reduced MRSA count in mice liver and kidneys compared with the free drugs. In addition, Mekkawy et al (2017) observed much higher antibacterial activity, as well as wound healing promotion of Na CMC hydrogel loaded with PEG-coated AgNPs as compared to silver sulfadiazine cream using MRSA-infected wound mice model.…”

Nanobiotics against antimicrobial resistance: harnessing the power of nanoscale materials and technologies

“…Furthermore, nanocarriers decrease the apparent volume distribution, in turn allowing maximum tolerated dose and causing bacterial cell death at much lower antibiotic concentrations and thus expanding the spectrum of action against MDR bacteria. Various biopolymers including proteins, carbohydrates and lipids have been used to synthesize nanocarriers with promising antibacterial activities [144]. For example, linalool-functionalized hollow mesoporous silica spheres efficiently improved the bactericidal activities of the organic component against both Gram-negative (E. coli) and Gram-positive (S. aureus) bacteria by breaking the cell membrane structure [145].…”

Advances in Nanostructures for Antimicrobial Therapy

“…Coating the NP surface with a biocompatible polymer (e.g., polyethylene glycol (PEG)) prolongs the blood circulation time by preventing opsonization and reducing absorption by the reticuloendothelial system. For example, rifamipicin (RIF) in a mannose and PEG-coated graphene oxide NC is increasingly endocytosed into macrophages via the mannose receptor, thereby increasing the concentration of RIF in macrophages infected with M. tuberculosis [ 97 ], encapsulated VAN into the pillar [ 5 ] arenes covered with mannose are taken up by MRSA-infected macrophages, in which VAN is subsequently released due to the acidic pH and the presence of cathepsin B [ 98 ] or NLCs containing ciprofloxacin (CIP) and rolipram coated with retinol to ensure active transport of NLCs via retinol-binding protein 4 to the kidney for the treatment of bacteremia [ 99 ]. Dicloxacillin-loaded and CS-coated liposomes have been proven to be a promising NC with increased antibiotic delivery to MRSA [ 100 ].…”