Biocompatible hybrid silica nanobiocomposites for the efficient delivery of anti-staphylococcal drugs

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Abstract

This work reports the non-surfactant templated synthesis and characterization of a new tyrosine—silica/antibiotics (TyR-SiO2/ATBs) nanocomposite, as well as both in vitro and in vivo cytotoxicity and antimicrobial activity against the microbial pathogen Staphylococcus aureus. The in vitro microbiological tests proved that the obtained nanobiostructure significantly enhance the antimicrobial activity of three commonly used antibiotics against S. aureus (i.e. erythromycin (ERI), gentamicin (GEN), and cloxacillin (CLO)) as revealed by the increased diameters of the growth inhibition zones and the decreased minimal inhibitory concentration values, as well as by the inhibitory effect of sub-lethal antibiotic concentrations on the ability of the respective pathogenic strains to adhere and colonize different substrata. These results, correlated with the lack of toxicity against mesenchymal stem cells along with an appropriate in vivo biodistribution highlight the promising therapeutic potential of this carrier that allows a decrease of the required active doses while significantly lessening the harmful side effects of the medication on the host organism.

Introduction

Staphylococcus aureus is one of the most commonly encountered pathogenic microorganisms in nosocomial infections (Najm et al., 2015). There is a worldwide increasing concern about the prevalence of multidrug resistant S. aureus strains isolated from patients receiving hospital care. Methicillin resistant S. aureus (MRSA) strains are increasingly prevalent among bacterial isolates obtained from difficult to treat infection, such as those in critical-care patients, burn-related infections, immunocompromised chronic patients, and those with indwelling medical devices (Tong et al., 2015, Ionescu et al., 2015). Along with the high genetic resistance, S. aureus is able to successfully produce multicellular communities, called biofilms, which are resistant to high amounts of any known antimicrobial agent and also to the host defense system (Cristea et al., 2015). Biofilm-related infections represent one of the main cause of mortality and morbidity in patients hospitalized in critical care units and a key factor in device-associated failure in patients with both permanent and transient prosthetic or indwelling devices (Iwase et al., 2010, Cristea et al., 2015, Fufa et al., 2015). Since the current therapeutic approaches, based mainly on antibiotic therapy, are becoming inefficient, the development of more efficient treatments against these commonly encountered Gram-positive bacteria represents an actual challenge (Rasmussen et al., 2011). One of the most accepted approach is based on the development of nanostructured drug delivery systems, efficient in the stabilization and effective potentiation of antimicrobial agents (Liakos et al., 2014, Tarescoa et al., 2015). Moreover, the implementation of nanostructured systems to efficiently deliver antibiotics is boosted by the fact that the therapy including multiple and high amounts of antibiotics is very toxic for the host. Therefore, the design of appropriate nanosystems, highly biocompatible for the host, able to deliver to a precise site active amount of antibiotic, avoiding the spread of high quantities of the drug within the body, represents one of the main aims of the current nanotechnological applications in biomedicine (Gao et al., 2011). Within the last two decades, silica networks have gained much interest due to their unique features since they provide an inert, biocompatible and well organized matrix with tunable porosity and large surface specific area (Xu et al., 2013, Bariana et al., 2013, Chen et al., 2013, Benhamou et al., 2013, Qiang et al., 2013, Roik and Belyakova, 2013, Voicu et al., 2014).

Several silica-based nanoformulations have been recently reported to increase the therapeutic activity of the antimicrobial payloads they carry (Grumezescu et al., 2013, Grumezescu et al., 2014a, Grumezescu et al., 2014b, Holban et al., 2014a, Holban et al., 2014b, Voicu et al., 2013, Mihaiescu et al., 2013, Balaure et al., 2013).

Various sacrificial templates or structure-directing agents (SDAs) that are eventually removed through calcination or extraction have been employed in the synthesis of uniform porous materials. Templating by small organic molecules gives rise to microporous materials, micelles, and liquid crystals, block-copolymers lead to mesoporous materials when used as templates, while microemulsions or latex particles generate macroporous materials (Pagliaro, 2009, Guillemot et al., 2013). The traditional method in the synthesis of mesoporous materials uses surfactants as templates (Kresge et al., 1992), even though the widely used surfactant templated synthesis of mesoporous materials has also a series of important drawbacks. For instance, surfactants are toxic and the harsh conditions of calcination may reduce the hydrophilic character of silica, but also the number of surface silanol groups available for further functionalization (Yagűe et al., 2008). Furthermore, the procedures required for removal of the surfactant template may also remove or alter sensible cargos such as drugs (Baù et al., 2009). Therefore, the use of non-surfactant templates is preferred whenever possible. Several types of non-surfactant organic molecules fulfill the structural requirements to direct the further construction of the mesophase. We mention here some of these non-surfactant organic compounds acting as templates: d-glucose, d-maltose, dibenzoyl-l-tartaric acid, and some p-dodecanoyl-aminophenyl-β-d-aldopyranosides (Wei et al., 1998; Jung et all. 2004); hydroxyacetic acid derivatives (Zheng et al., 2000); a mixture of β-cyclodextrin and urea (Zheng 2002); siloxane oligomers with long alkyl chains as self-template (Shimojima and Kuroda, 2003); cholesterol derivatives (Ono et al., 1998); bis-urea compounds (van Esch and Feringa 2000);polyamino acids (Patwardhan et al., 2006); amphiphilic peptides (Cui et al., 2010, Dehsorkhi and Hamley, 2014); fibrous proteins (Hassan et al., 2012, Alvarez et al., 2014).

The novelty of the present study is the utilization of the amphiphilic naturally occurring amino acid l-tyrosine as template for the sol-gel polymerization of sodium metasilicate in the presence of an acid catalyst. We decided to choose l-tyrosine due to its proved capacity to self-assemble in water into fiber-like aggregates formed by π-π interactions between the aromatic rings of neighboring molecules (Yang et al., 2004, Perween et al., 2013) and to its biocompatibility.

In the present work we aimed to synthesize a new effective and biocompatible nanocarrier based on porous silica networks capable to enhance the antimicrobial activity of some antibiotics currently used in the treatment of infections caused by S. aureus. We have chosen three main anti-staphylococcal antibiotics, each one belonging to a different class: erythromycin (ERI) – a macrolide antibiotic, gentamicin (GEN) – an aminoglycoside antibiotic and cloxacillin (CLO) – a β-lactam antibiotic. Silica was chosen to build up the polymeric network of the nanocarrier due to its high loading capacity (up to 40% of its dry mass) and to its known ability to effectively release the active compound to a target site (Wang et al., 2014).

Section snippets

Materials and methods

All chemicals were of analytical purity and used with no further purification. Na2SiO3, tyrosine, H2SO4, cloramphenicol, gentamycin and erythromycin were purchased from Sigma–Aldrich ChemieGmbh (Munich, Germany).

SEM

The morphology of the silica network was studied by Scanning Electron Microscopy. In Fig. 1 are presented only the results for Tyr3G-SiO2. The other two prepared materials (Tyr1G-SiO2 and Tyr5G-SiO2) showed a grains morphology (not presented). By analyzing the presented SEM images it can be concluded that the Tyr3G-SiO2 showed a rod-shaped silica morphology. The length of rods are  5 μm, while the diameter is  500 nm.

XRD

The XRD patterns of the Tyr1/3/5G-SiO2 and tyrosine samples have been obtained and

Conclusions

This work reports the template synthesis and characterization of a new Tyr-SiO2/ATBs nanocomposite which is intended to be utilized as an alternative and efficient antimicrobial agent. Our in vitro microbiological tests proved that the obtained nanobiostructure exhibited a significantly improved activity against S. aureus, as revealed by the increased diameters of the growth inhibition zones and the decreased minimal inhibitory concentration values, as well as by the inhibitory effect of

Acknowledgement

This work was supported by a grant of the Romanian National Authority for Scientific Research and Innovation, CNCS—UEFISCDI, project number PN-II-RU-TE-2014-4-2269.

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