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Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy.

ABSTRACT: Bacterial resistance to antibiotics has made it necessary to resort to antibiotics that have considerable toxicities. Here, we show that the cyclic 9-amino acid peptide CARGGLKSC (CARG), identified via phage display on Staphylococcus aureus (S. aureus) bacteria and through in vivo screening in mice with S. aureus-induced lung infections, increases the antibacterial activity of CARG-conjugated vancomycin-loaded nanoparticles in S. aureus-infected tissues and reduces the needed overall systemic dose, minimizing side effects. CARG binds specifically to S. aureus bacteria but not Pseudomonas bacteria in vitro, selectively accumulates in S. aureus-infected lungs and skin of mice but not in non-infected tissue and Pseudomonas-infected tissue, and significantly enhances the accumulation of intravenously injected vancomycin-loaded porous silicon nanoparticles bearing the peptide in S. aureus-infected mouse lung tissue. The targeted nanoparticles more effectively suppress staphylococcal infections in vivo relative to equivalent doses of untargeted vancomycin nanoparticles or of free vancomycin. The therapeutic delivery of antibiotic-carrying nanoparticles bearing peptides targeting infected tissue may help combat difficult-to-treat infections.

SUBMITTER: Hussain S

PROVIDER: S-EPMC6015743 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy.

Hussain Sazid S Joo Jinmyoung J Kang Jinyoung J Kim Byungji B Braun Gary B GB She Zhi-Gang ZG Kim Dokyoung D Mann Aman P AP Mölder Tarmo T Teesalu Tambet T Carnazza Santina S Guglielmino Salvatore S Sailor Michael J MJ Ruoslahti Erkki E

Nature biomedical engineering 20180122 2

Bacterial resistance to antibiotics has made it necessary to resort to antibiotics that have considerable toxicities. Here, we show that the cyclic 9-amino acid peptide CARGGLKSC (CARG), identified via phage display on Staphylococcus aureus (S. aureus) bacteria and through in vivo screening in mice with S. aureus-induced lung infections, increases the antibacterial activity of CARG-conjugated vancomycin-loaded nanoparticles in S. aureus-infected tissues and red ...[more]

PMID: 29955439

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Project description:As the threat of antimicrobial-resistant bacteria compromises the safety and efficacy of modern healthcare practices, the search for effective treatments is more urgent than ever. For centuries, silver (Ag) has been known to have antibacterial properties and, over the past two decades, Ag-based nanoparticles have gained traction as potential antimicrobials. The antibacterial efficacy of Ag varies with structure, size, and concentration. In the present study, we examined Ag nanoparticles (AgNPs) for their antimicrobial activity and safety. We compared different commercially-available AgNPs against gram-negative Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and gram-positive Staphylococcus aureus methicillin-resistant and susceptible strains. The most effective formula of AgNPs tested had single-digit (μg/mL) minimum inhibitory concentrations against gram-negative multidrug-resistant clinical bacterial isolates with novel and emerging mechanisms of resistance. The mode of killing was assessed in E. coli and was found to be bactericidal, which is consistent with previous studies using other AgNP formulations. We evaluated cytotoxicity by measuring physiological readouts using the Caenorhabditis elegans model and found that motility was affected, but not the lifespan. Furthermore, we found that at their antibacterial concentrations, AgNPs were non-cytotoxic to any of the mammalian cell lines tested, including macrophages, stem cells, and epithelial cells. More interestingly, our experiments revealed synergy with clinically relevant antibiotics. We found that a non-toxic and non-effective concentration of AgNPs reduced the minimum inhibitory concentrations of aminoglycoside by approximately 22-fold. Because both aminoglycosides and Ag are known to target the bacterial ribosome, we tested whether Ag could also target eukaryotic ribosomes. We measured the rate of mistranslation at bactericidal concentration and found no effect, indicating that AgNPs are not proteotoxic to the host at the tested concentrations. Collectively, our results suggest that AgNPs could have a promising clinical application as a potential stand-alone therapy or antibiotic adjuvants.

Project description:One major problem with the overuse of antibiotics is that the microorganisms acquire resistance; thus the dose must be increased unsustainably. To overcome this problem, researchers from around the world are actively investigating new types of antimicrobials. Zinc oxide (ZnO) nanoparticles (NPs) have been proven to exhibit strong antimicrobial effects; moreover, the Food and Drugs Administration (FDA) considers ZnO as GRAS (generally recognized as safe). Many essential oils have antimicrobial activity and their components do not generate resistance over time. One of the drawbacks is the high volatility of some components, which diminishes the antimicrobial action as they are eliminated. The combination of ZnO NPs and essential oils can synergistically produce a stronger antimicrobial effect, and some of the volatile compounds can be retained on the nanoparticles' surface, ensuring a better-lasting antimicrobial effect. The samples were characterized with X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV-Vis), and thermal analysis (TG-DSC) coupled with analysis of evolved gases using FTIR. The ZnO NPs, with a size of ~35 nm, exhibited a loading between 1.44% and 15.62%-the lower values were specific for limonene-containing oils (e.g., orange, grapefruit, bergamot, or limette), while high values were obtained from cinnamon, minzol, thyme, citronella, and lavender oils-highlighting differences among non-polar terpenes and alcohol or aldehyde derivatives. The antibacterial assay indicated the existence of a synergic action among components and a high dependency on the percentage of loaded oil. Loaded nanoparticles offer immense potential for the development of materials with specific applications, such as wound dressings or food packaging. These nanoparticles can be utilized in scenarios where burst delivery is desired or when prolonged antibacterial activity is sought.

Project description:BackgroundCancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin.Methodology/principal findingsApotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano) have diameters of 25-50 etam, which increase to 60-80 etam upon direct loading of drug (direct-nano), and showed further increase in dimension (75-95 etam) in conjugated nanoparticles (conj-nano). The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a) localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus) (b) pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c) the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in regression of hepatocellular carcinoma with negligible toxicity to kidney and liver.ConclusionsThe present study thus demonstrates that the direct-nano is highly efficacious in delivery of drug in a target specific manner with lower toxicity to heart, liver and kidney.

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Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy.

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Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy.

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