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Nanomedicines for antimicrobial interventions

Published:September 30, 2014DOI:https://doi.org/10.1016/j.jhin.2014.09.009

      Summary

      The development of new antimicrobial therapeutic tools addresses the emergence of multidrug-resistant micro-organisms or clones and the need for more effective antimicrobial strategies. Overcoming the hurdles in providing early diagnosis and intervention on hard-to-reach and/or resting bacteria (i.e. biofilm-embedded cells) represents a challenging task. In this review, we identify a set of organic, inorganic, and hybrid materials that might be used for prevention and control of healthcare-associated infections. We report the current knowledge on nano- and microparticle-based antimicrobial agents and describe the possible mode of their action.

      Keywords

      Introduction

      Micro/nanomedicine is nowadays a well-established branch of science that deals with design of micro/nanodevices, i.e. micro/nanoparticles, possessing unique therapeutic and diagnostic properties. A schematic illustration of nano/microsystems currently used for the delivery of therapeutic agents is shown in Figure 1. The biological and therapeutic properties of micro/nanoparticles (MPs, NPs) are correlated to their structural and functional characteristics. A large number of studies aimed at understanding the interactions between MPs/NPs and cells as a function of their size, shape, and surface chemistry have been published. Indeed particle surface and bulk properties (size, charge, shape, elasticity, and functional groups) have a significant impact on their cellular association and internalization. For instance, a significant diminution of particle association with cells was observed when the particles had a negative surface charge versus particles showing a positive surface charge.
      • Gratton S.E.A.
      • Ropp P.A.
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      The effect of particle design on cellular internalization pathways.
      Rigidity and elastic modulus of MPs/NPs have also been found to greatly affect cellular internalization, trafficking, in-vivo circulation lifetime, and biodistribution.
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      • Giovia A.
      • Follo C.
      • Caputo G.
      • Isidoro C.
      Biocompatibility, endocytosis, and intracellular trafficking of mesoporous silica and polystyrene nanoparticles in ovarian cancer cells: effects of size and surface charge groups.
      Plasticity and versatility of nanomaterials are such that almost any platform can be adapted for a specific use: in this way, when a specific particle or material is deemed suitable for its antimicrobial properties, it can then be structured for either prophylactic or therapeutic purposes.
      Figure thumbnail gr1
      Figure 1Schematic illustration of nano/microsystems: (a) antimicrobial polymers; (b) polymer chains, (c) inorganic nanoparticles, (d) liposomes, (e) polymeric nanoparticles, (f) solid lipid nanoparticles loaded with antimicrobial drug; (g) microbubbles loaded with nanoparticles.
      This review assesses current knowledge on nano- and microparticle-based antimicrobial agents. In addition, the possible modes of their action are described. Understanding of structure–function relationship in nano- and microparticle-based antimicrobial agents is crucial for the design of new devices.

      Micro/nanosystems

      Among antimicrobial micro/nanosystems, a set of organic, inorganic, and hybrid materials can be identified. The antimicrobial activity exhibited by these systems depends on their different physical, chemical, and functional properties.

      Metal-based nanoparticles

      Nanoparticles based on metals that express antimicrobial ability are among the most studied. Compared to the ionic form of a metal, NPs exhibit an equivalent or superior antimicrobial activity.
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      • Sharma V.K.
      • Zboril R.
      Silver polymeric nanocomposites as advanced antimicrobial agents: classification, synthetic paths, applications, and perspectives.
      • Park H.
      • Park S.
      • Roh J.
      • et al.
      Biofilm-inactivating activity of silver nanoparticles: a comparison with silver ions.
      • Nie M.
      • Sun K.
      • Meng D.D.
      Formation of metal nanoparticles by short-distance sputter deposition in a reactive ion etching chamber.
      Size, shape, and surface properties (ζ-potential) are crucial features determining the antimicrobial efficacy of NPs. In particular, the huge increase in the surface area determines a higher interaction of NPs with the surrounding materials. In this context, the real added value of the nanotechnology is the capability to tune the particle properties by selecting different methods of synthesis for NPs. Physical methods used to produce metallic NPs include sputtering, evaporation, laser ablation, ion ejection, photolithography and electron-beam lithography. Chemical approaches to obtain NPs require the reduction of the metallic ions to form a well-dispersed colloidal solution. In particular, chemical reduction of metallic ions is widely performed with citrate, ascorbate, and sodium borohydride as reducing agents.
      • Chen M.
      • Wang L.Y.
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      • Zhang J.Y.
      • Li Z.Y.
      • Qian D.J.
      Preparation and study of polyacrylamide-stabilized silver nanoparticles through a one-pot process.
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      • Yuan C.
      • Archer L.A.
      An unusual example of hyperbranched metal nanocrystals and their shape evolution.
      • Kuo P.L.
      • Chen W.F.
      Formation of silver nanoparticles under structured amino groups in pseudo-dendritic poly(allylamine) derivatives.
      The toxicity of the reagents and the agglomeration and precipitation of NPs are disadvantages of these methods. In order to prevent NPs coalescing during synthesis, NPs can be trapped inside a carbon matrix or stabilized by water-soluble polymers such as polyvinyl sulphonate or polysaccharides.
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      • Elechiguerra J.L.
      • Camacho A.
      • et al.
      The bactericidal effect of silver nanoparticles.
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      • Goreham R.V.
      • Ndi C.
      • Short R.D.
      • Griesser H.J.
      Antibacterial surfaces by adsorptive binding of polyvinyl-sulphonate-stabilized silver nanoparticles.
      • Mohanty S.
      • Mishra S.
      • Jena P.
      • Jacob B.
      • Sarkar B.
      • Sonawane A.
      An investigation on the antibacterial, cytotoxic, and antibiofilm efficacy of starch-stabilized silver nanoparticles.
      • Seo S.Y.
      • Lee G.H.
      • Lee S.G.
      • Jung S.Y.
      • Lim J.O.
      • Choi J.H.
      Alginate-based composite sponge containing silver nanoparticles synthesized in situ.
      • Potara M.M.
      • Jakab E.
      • Damert A.
      • Popescu O.
      • Canpean V.
      • Astilean S.
      Synergistic antibacterial activity of chitosan–silver nanocomposites on Staphylococcus aureus.
      • Jena P.
      • Mohanty S.
      • Mallick R.
      • Jacob B.
      • Sonawane A.
      Toxicity and antibacterial assessment of chitosan coated silver nanoparticles on human pathogens and macrophage cells.
      When the stabilizer possesses antimicrobial activity, i.e. chitosan, the hybrid system chitosan–NPs may exhibit a synergistic effect.
      • Potara M.M.
      • Jakab E.
      • Damert A.
      • Popescu O.
      • Canpean V.
      • Astilean S.
      Synergistic antibacterial activity of chitosan–silver nanocomposites on Staphylococcus aureus.
      • Li Q.
      • Mahendra S.
      • Lyon D.Y.
      • et al.
      Antimicrobial nanomaterials for water disinfection and microbial control: potential applications and implications.
      • Rabea E.I.
      • Badawy M.E.T.
      • Stevens C.V.
      • Smagghe G.
      • Steurbaut W.
      Chitosan as antimicrobial agent: applications and mode of action.
      Nanocomposites are produced by using metallic NPs supported by polymer matrices to form hybrid sponges, electron-spun nanofibres, membranes, and nanowires. These nanocomposite materials are used to coat medical devices and for production of antimicrobial cotton textiles that have been demonstrated to reduce postoperative infections.
      • Seo S.Y.
      • Lee G.H.
      • Lee S.G.
      • Jung S.Y.
      • Lim J.O.
      • Choi J.H.
      Alginate-based composite sponge containing silver nanoparticles synthesized in situ.
      • Foudaa M.M.G.
      • El-Aassarc M.R.
      • Al-Deyaba S.S.
      Antimicrobial activity of carboxymethyl chitosan/polyethylene oxide nanofibers embedded silver nanoparticles.
      • Liu S.
      • Zhao J.
      • Ruan H.
      • et al.
      Antibacterial and anti-adhesion effects of the silver nanoparticles-loaded poly(l-lactide) fibrous membrane.
      • Hebeish A.A.
      • Abdelhady M.M.
      • Youssef A.M.
      TiO2 nanowire and TiO2 nanowire doped Ag-PVP nanocomposite for antimicrobial and self-cleaning cotton textile.
      Inorganic NPs can also be produced by environmentally friendly technology (bionanotechnology) that uses plants and micro-organisms (bacteria, yeasts, fungi, and actinomycetes) as nanofactories for fabrication of inorganic NPs.
      • Li X.
      • Xu H.
      • Chen Z.
      • Chen G.
      Biosynthesis of nanoparticles by microorganisms and their applications.
      Micro-organisms possess significant ability to reduce a wide range of metal oxides, the synthesis of which can occur intra- and/or extracellularly. In the intracellular pathway, ions are transported into the microbial cell where the synthesis of NPs is mediated by enzymes. In the extracellular process, ions are trapped on the cells' surface and reduced in the presence of enzymes.
      • Vahabi K.
      • Mansoori G.A.
      • Karimi S.
      Biosynthesis of silver nanoparticles by fungus Trichoderma reesei (a route for large-scale production of AgNPs).
      Unfortunately, micro-organism-mediated NP preparations may yield metallic NP suspensions that are not well dispersed. Moreover, when the bacterial biomass method is used, the biological hazard should be taken into account.

      Synthetic antimicrobial polymers

      Synthetic antimicrobial polymers represent a huge class of molecules with great potential for effective antimicrobial therapy. Compared to low molecular weight antimicrobial agents, synthetic polymers possess an improved and prolonged antimicrobial activity due to the capability to destroy the bacterial membrane. Table I shows a list, which is not exhaustive, of synthetic antimicrobial polymers, together with their principal features. The possibility of building an effective polymeric architecture by chemical modification allows fine tuning of the biocidal and biocompatibility behaviour of synthetic polymers.
      • Muňoz-Bonilla A.
      • Fernandez-Garcia M.
      Polymeric materials with antimicrobial activity.
      Indeed, biocompatibility is an important feature of any new synthetic polymers and NP. The goal is to minimize non-specific cytotoxic effects to healthy tissues while maximizing drug efficacy at the target tissue or against invasive pathogens. A biocompatibility assay is essential before any nanomaterial can be used in a clinical setting.
      • Alkilany A.M.
      • Murphy C.J.
      Toxicity and cellular uptake of gold nanoparticles: what we have learned so far?.
      Evaluation of synthetic polymer NPs on safety grounds, however, can be quite challenging given the great variety of physicochemical properties that contribute to the biological/toxicological profile of NPs. Several in-vitro methods that take into account cell proliferation rates and cell and DNA damage may be used for toxicological evaluation.
      • Alkilany A.M.
      • Murphy C.J.
      Toxicity and cellular uptake of gold nanoparticles: what we have learned so far?.
      In addition, cell viability can be obtained by direct light and/or electron microscopy. Both transmission (TEM) or scanning (SEM) electron microscopy can produce images at high magnification and great resolving power. When equipped with micro-analytical devices, TEM and SEM provide information on the elemental composition of the structure under observation.
      Table ISynthetic antimicrobial polymers
      PolymersCharacteristics and antimicrobial effect
      Polymers with quaternary nitrogen atoms

      Polymers containing aromatic or heterocyclic structures

      Cationic conjugated polyelectrolytes
      Direct binding to bacteria, diffusion through the cell wall, disruption of the cytoplasmic membrane, and cell death.

      Light-activated biocides. The light activity is attributed to the ability of these polymers to generate singlet O2 after exposure to UV–visible light.
      Polymers mimic natural peptides

      Synthetic peptides
      Amphiphilic and positively charged peptides pass through the lipid-rich membranes.
      Fluorine-containing polymers

      Chlorine-containing phenyl methacrylate polymers
      Principal features of fluorine-containing polymers: water and oil repellency due to the low polarizability and strong electronegativity of the fluorine. The antimicrobial activity is associated with their surface activity and their high hydrophobic character.
      Polymers containing phospho and sulpho derivativesThe action mechanism is similar to that for polymers containing quaternary ammonium, killing bacteria by damaging the membrane and cell wall.
      Phenol and benzoic acid derivative polymersThe interaction with the surface of the cell causes cell death through disintegration of the cell membrane and release of intracellular constituents. Phenols also cause intracellular coagulation of cytoplasmic constituents, leading to cell death or inhibition of cell growth.
      Organometallic polymersOrganometallic polymers contain metals either in the backbone chain or in the pendant group. The organotin derivatives attached to the chain through O–Sn and N–Sn bonds have been considered as potential biocides.

      Lipid based micro-nanodevices

      Liposomes are spherical vesicles composed of a lipid bilayer structure, mostly used for drug delivery as they can carry both lipophilic and hydrophilic drugs.
      • Samad A.
      • Sultana Y.
      • Aqil M.
      Liposomal drug delivery systems: an update review.
      Lipid-based nanoparticles are ideal for topical application for prevention or treatment of superficial infections because the lipid carrier can increase the penetration of antimicrobial or antifungal agents as well as sustain their delivery over time.
      • Üner M.
      • Yener G.
      Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives.
      Drugs can be accommodated on the surface, within the surface, or inside the core of the carrier. A variety of methods to load the drug into the micro/nanodevice is available, i.e. by physical encapsulation, adsorption, and chemical conjugation. Coupling of antimicrobial agents with solid lipid nanoparticles has been shown to increase minimum inhibitory concentration (MIC) up to eight times that of the drug alone.
      • Raza K.
      • Singh B.
      • Singla S.
      • et al.
      Nanocolloidal carriers of isotretinoin: antimicrobial activity against Propionibacterium acnes and dermatokinetic modeling.
      • Aboutaleb E.
      • Noori M.
      • Gandomi N.
      • et al.
      Improved antimycobacterial activity of rifampin using solid lipid nanoparticles.
      An example of liposomal antimicrobial system, effective against Candida albicans and Aspergillus spp. biofilms, is represented by AmBisome, a US Food and Drug Administration-approved liposomal formulation. In AmBisome, amphotericin B is intercalated into the phospholipid bilayer of liposomes. When compared to free amphotericin B, AmBisome has shown prolonged systemic circulation half-life, reduced plasma clearance rate, decreased renal toxicity and enhanced therapeutic efficacy.
      • Walsh T.J.
      • Yeldandi V.
      • McEvoy M.
      Safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients.
      • Walsh T.J.
      • Goodman J.L.
      • Pappas P.
      Safety, tolerance, and pharmacokinetics of high-dose liposomal Amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study.
      Greater permeability after topical administration was demonstrated for daptomycin-loaded liposomes, possibly due to the liposomes' flexibility in adapting to the environment, diffusing through the skin and underlying tissues, and interacting with natural biomembranes.
      • Walsh T.J.
      • Goodman J.L.
      • Pappas P.
      Safety, tolerance, and pharmacokinetics of high-dose liposomal Amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study.
      Such formulation was shown to be more active than the free drug against Staphylococcus aureus biofilm, with improved penetration through both the dermal layers and within the biofilm.
      • Li C.
      • Zhang X.
      • Huang X.
      • Wang X.
      • Liao G.
      • Chen Z.
      Preparation and characterization of flexible nanoliposomes loaded with daptomycin, a novel antibiotic, for topical skin therapy.

      Mechanisms of action of antimicrobial micro/nanosystems

      The efficacy of micro- and nanosystems in killing micro-organisms depends on both the platform (organic, inorganic, etc.) and, where present, on the specific antimicrobial loaded into, or associated with, the chosen system. The best feature of such systems can be identified in their versatility, i.e. the possibility of tailoring the chosen platform to fit the required application. Whereas a majority of studies are still directed at the evaluation of the antimicrobial activity of dispersed particles, the same materials can be assembled in platforms suitable for therapeutic purposes as well as in the form of various devices (bandages, catheter or implant coatings, etc.) for prevention and control of infection in hospital settings.

      Inorganic systems

      Currently, a large majority of information on the application of nanotechnology in the infectious disease field regards the use of silver (Ag) and gold (Au) nanoparticles. It is known that silver salts have potent antimicrobial activity against a broad range of micro-organisms. Silver ions have been used as antiseptic and silver-containing agents are present in clinical wound dressings and in the coating of biomedical materials (endotracheal tubes, urinary catheters, grafts).
      • Kwakye-Awuah B.
      • Williams C.
      • Kenward M.A.
      • Radecka I.
      Antimicrobial action and efficiency of silver-loaded zeolite X.
      • Zheng Z.
      • Yin W.
      • Zara J.N.
      • et al.
      The use of BMP-2 coupled–Nanosilver-PLGA composite grafts to induce bone repair in grossly infected segmental defects.
      In recent years, an increasing number of papers reporting on a new generation of antimicrobial metallic nanoparticles has been published. In particular, the antimicrobial effectiveness of silver nanoparticles (AgNPs) has been demonstrated against bacteria, viruses, and other eukaryotic micro-organisms.
      • Pinto R.J.B.
      • Marques P.A.A.P.
      • Neto C.P.
      • Trindade T.
      • Daina S.
      • Sadocco P.
      Antibacterial activity of nanocomposites of silver and bacterial or vegetable cellulosic fibers.
      Silver nanoparticles have been shown to be effective against meticillin-resistant Staphylococcus aureus (MRSA).
      • Panacek A.
      • Kvítek L.
      • Prucek R.
      • et al.
      Silver colloid nanoparticles: synthesis, characterization, and their antibacterial activity.
      In addition, the antimicrobial activity of silver nanoparticles was assessed against Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa. Gold nanoparticles (AuNPs) have attracted attention as bactericidal agents due to their lack of toxicity for mammalian cells, high colloidal stability, easy conjugation to biomolecules, and unique optical properties conferred by their localized surface plasmon.
      • Rosi N.L.
      • Giljohann D.A.
      • Thaxton C.S.
      • Lytton-Jean A.K.
      • Han M.S.
      • Mirkin C.A.
      Oligonucleotide-modified gold nanoparticles for intracellular gene regulation.
      High efficiency against multidrug-resistant bacteria has been reported for drug-modified AuNPs
      • Hyland R.M.
      • Beck P.
      • Mulvey G.L.
      • Kitov P.I.
      • Armstrong G.D.
      N-Acetyllactosamine conjugated to gold nanoparticles inhibits enteropathogenic Escherichia coli colonization of the epithelium in human intestinal biopsy specimens.
      • Zhao Y.
      • Tian Y.
      • Cui Y.
      • Liu W.
      • Ma W.
      • Jiang X.
      Small molecule-capped gold nanoparticles as potent antibacterial agents that target gram-negative bacteria.
      However, in some cases AgNPs have shown higher antibacterial efficacy than AuNPs, because of the higher concentration of reactive oxygen species (ROS) generated by the former.
      • Huda S.
      • Smoukov S.K.
      • Nakanishi H.
      • Kowalczyk B.
      • Bishop K.
      • Grzybowski B.A.
      Antibacterial nanoparticle monolayers prepared on chemically inert surfaces by cooperative electrostatic adsorption (CELA).
      Recently, derivatives of other metals have been studied for antimicrobial applications. In particular, the antibacterial effects of zerovalent bismuth NPs and uncoated Au, Ni, and Si NPs were reported.
      • Hernandez-Delgadillo R.
      • Velasco-Arias D.
      • Diaz D.
      • et al.
      Zerovalent bismuth nanoparticles inhibit Streptococcus mutans growth and formation of biofilm.
      • Zhang W.
      • Li Y.
      • Niu J.
      • Chen Y.
      Photogeneration of reactive oxygen species on uncoated silver, gold, nickel, and silicon nanoparticles and their antibacterial effects.
      It has been shown that zinc oxide in bulk form is bacteriostatic, whereas ZnO nanoparticles have a bactericidal effect.
      • Seil J.T.
      • Webster T.J.
      Antimicrobial applications of nanotechnology: methods and literature.
      It is now known that the bactericidal action of silver (Ag+ ions or Ag clusters) is due to its strong interaction with thiol groups present in the enzymes involved in bacterial cell metabolism, thus leading to cell death.
      • Kwakye-Awuah B.
      • Williams C.
      • Kenward M.A.
      • Radecka I.
      Antimicrobial action and efficiency of silver-loaded zeolite X.
      As for AgNPs, a proposed mechanism is that AgNPs in contact with the bacterial cell membrane can be oxidized, leading to the formation of silver ions, which inhibit the action of the enzymes responsible for cell metabolism.
      • Panacek A.
      • Kvítek L.
      • Prucek R.
      • et al.
      Silver colloid nanoparticles: synthesis, characterization, and their antibacterial activity.
      • Liau S.Y.
      • Read D.C.
      • Pugh W.J.
      • Furr J.R.
      • Russell D.
      Interaction of silver nitrate with readily identifiable groups: relationship to the antibacterial action of silver ions.
      Cell membrane proteins and nucleic acids should be preferred sites for the binding of AgNP silver ions. Silver ions are weak acids that can easily react with weak bases such as thiolates (of the cell membranes) or phosphates (in DNA).
      • Morones J.R.
      • Elechiguerra J.L.
      • Camacho A.
      • et al.
      The bactericidal effect of silver nanoparticles.
      • Atiyeh B.S.
      • Costagliola M.
      • Hayek S.N.
      • Dibo S.A.
      Effect of silver on burn wound infection control and healing: review of the literature.
      Changes in the morphology of the bacterial membranes when in contact with AgNPs, and possible DNA damage caused by the NPs, would affect the bacterial metabolic processes ultimately causing cell death.
      • Morones J.R.
      • Elechiguerra J.L.
      • Camacho A.
      • et al.
      The bactericidal effect of silver nanoparticles.
      Alternatively, direct damage to membranes caused by ROS such as superoxide anions, hydrogen peroxide, and hydroxyl radicals may be responsible for the potent bactericidal activity of AgNPs.
      • Kim J.S.
      • Kuk E.
      • Yu K.N.
      • et al.
      Antimicrobial effects of silver nanoparticles.
      As already mentioned, the bactericidal activity of NPs is dependent on parameters such as size, concentration, shape, and stability in the growth medium.
      • Morones J.R.
      • Elechiguerra J.L.
      • Camacho A.
      • et al.
      The bactericidal effect of silver nanoparticles.
      • Shrivastava S.
      • Bera T.
      • Roy A.
      • Singh G.
      • Ramachandrarao P.
      • Dash D.
      Characterization of enhanced antibacterial effects of novel silver nanoparticles.
      Size was found to be important also for zinc oxide NPs against S. aureus, where the killing effect was possibly attained through both the production of ROS and the accumulation of NPs in the cytoplasm or on the outer bacterial membranes.
      • Raghupathi K.R.
      • Koodali R.T.
      • Manna A.C.
      Size-dependent bacterial growth inhibition and mechanism of antibacterial activity of zinc oxide nanoparticles.
      The ROS species produced depend on the NPs' electronic structure, redox potential, or surface plasmon resonance, with AgNPs being the most effective due to their ability to produce superoxide and hydroxyl radicals as well as singlet oxygen.
      Dispersed metallic NPs often tend to aggregate and separate from solutions, resulting in a decrease in their antimicrobial efficiency. With the aim of improving the antibacterial properties of nanoparticles, functionalization of NPs has been attempted with surfactants, polymers, or antibiotics resulting in more stable, less aggregated NP suspension and innovative synergistic antibacterial agents. For instance, silver nanoparticles stabilized by polymers (polyvinylpyrrolidone) and surfactants (sodium dodecyl sulphate and Tween 80) exhibit enhanced antibacterial activities.
      • Huynh K.A.
      • Chen K.L.
      Aggregation kinetics of citrate and polyvinylpyrrolidone-coated silver nanoparticles in monovalent and divalent electrolyte solutions.
      NPs can act as drug-carriers able to pass through cell membranes.
      • Rosi N.L.
      • Giljohann D.A.
      • Thaxton C.S.
      • Lytton-Jean A.K.
      • Han M.S.
      • Mirkin C.A.
      Oligonucleotide-modified gold nanoparticles for intracellular gene regulation.
      • Balland O.
      • Pinto-Alphandary H.
      • Viron A.
      • Puvion E.
      • Andremont A.
      • Couvreur P.
      Intracellular distribution of ampicillin in murine macrophages infected with Salmonella Typhimurium and treated with (3H)ampicillin-loaded nanoparticles.
      • Rosemary M.J.
      • MacLaren I.
      • Pradeep T.
      Investigations of the antibacterial properties of [email protected]
      • Thomas M.
      • Klibanov A.M.
      Conjugation to gold nanoparticles enhances polyethylenimine's transfer of plasmid DNA into mammalian cells.
      • Cho E.C.
      • Au L.
      • Zhang Q.
      • Xia Y.
      The effects of size, shape, and surface functional group of gold nanostructures on their adsorption and internalization by cells.
      Widely used antibiotics such as vancomycin or ciprofloxacin may benefit from the association with NPs, and conjugation may result in an antibacterial effect also against micro-organisms resistant to the same molecule in the naturally occurring form.
      • Balland O.
      • Pinto-Alphandary H.
      • Viron A.
      • Puvion E.
      • Andremont A.
      • Couvreur P.
      Intracellular distribution of ampicillin in murine macrophages infected with Salmonella Typhimurium and treated with (3H)ampicillin-loaded nanoparticles.
      • Rosemary M.J.
      • MacLaren I.
      • Pradeep T.
      Investigations of the antibacterial properties of [email protected]
      When the antimicrobial agents are covalently linked to, or contained within, NPs, a higher drug concentration is attained in the area of interest, resulting in better efficacy at comparable doses and/or in slower release over time that may be exploited for preventing bacterial colonization.
      • Kitov P.I.
      • Mulvey G.L.
      • Griener T.P.
      • et al.
      In vivo supramolecular templating enhances the activity of multivalent ligands: a potential therapeutic against the Escherichia coli O157 AB5 toxins.
      • Yavuz M.S.
      • Cheng Y.
      • Chen J.
      • et al.
      Gold nanocages covered by smart polymers for controlled release with near-infrared light.
      Moreover, specific biological sites can be attacked after modification of NPs with target molecules.
      • Lin C.C.
      • Yeh Y.C.
      • Yang C.Y.
      • et al.
      Selective binding of mannose-encapsulated gold nanoparticles to type 1 pili in Escherichia coli.
      • Nair L.S.
      • Laurencin C.T.
      Silver nanoparticles: synthesis and therapeutic applications.
      As the NPs themselves may have antibacterial properties, the combination of NPs and loaded drugs exerts a synergistic action. Zhao et al. capped gold NPs with amino-substituted pyrimidines, which are not antibacterial per se, to inhibit growth of E. coli and P. aeruginosa, thus providing interesting new antimicrobial devices for prevention of nosocomial infections.
      • Zhao Y.
      • Tian Y.
      • Cui Y.
      • Liu W.
      • Ma W.
      • Jiang X.
      Small molecule-capped gold nanoparticles as potent antibacterial agents that target gram-negative bacteria.
      • Kumar A.
      • Vemula P.K.
      • Ajayan P.M.
      • John G.
      Silver-nanoparticle-embedded antimicrobial paints based on vegetable oil.
      • Loher S.
      • Schneider O.D.
      • Maienfisch T.
      • Bokorny S.
      • Stark W.J.
      Micro-organism-triggered release of silver nanoparticles from biodegradable oxide carriers allows preparation of self-sterilizing polymer surfaces.
      • Tang H.
      • Zhang P.
      • Kieft T.L.
      • et al.
      Antibacterial action of a novel functionalized chitosan-arginine against Gram-negative bacteria.

      Organic systems

      Among nanoparticle platforms, polymer nanoparticles are the most suitable system that can be used for antimicrobial drug delivery. In fact, particle properties such as size, ζ-potentials, and drug release profiles can be precisely tuned by selecting different polymer lengths, surfactants, and organic solvents during the preparation process. Hydrophobic or hydrophilic moieties (or targeting ligands) can be conjugated to the polymer backbone. Chitosan-based NPs are particularly interesting as the broad spectrum of antibacterial activity of chitosan is well known and documented.
      • Goy R.C.
      • de Britto D.
      • Assis O.B.G.
      A review of the antimicrobial activity of chitosan.
      Hence, chitosan can accomplish the dual purpose of being both carrier and active molecule.
      However, the specific mechanism of chitosan's action is still not fully understood. A key feature of chitosan is the cationic structure that is expected to interact with the negative residues, probably by competing with Ca2+ for the electronegative components on the membrane surface. Binding of the polycation molecules promotes a permeabilizing effect, that can be ascribed to an internal osmotic imbalance of the membrane and to hydrolysis of peptidoglycans in microbial cell walls. Another proposed mechanism is inhibition of mRNA and protein synthesis due to the binding of chitosan with microbial DNA. In this case, chitosan molecules are assumed to be able to pass through the bacterial cell wall. The third hypothesized mechanism ascribes the antimicrobial activity of chitosan to its excellent metal-binding capacities.
      • Kong M.
      • Che X.G.
      • Xing K.
      • Park H.J.
      Antimicrobial properties of chitosan and mode of action: a state of the art review.
      • Tikhonov V.E.
      • Stepnova E.A.
      • Babak V.G.
      • et al.
      Bactericidal and antifungal activities of a low molecular weight chitosan and its N-/2(3)-(dodec-2-enyl)succinoyl/-derivatives.
      Ambiguous results concerning the effective bactericidal activity of high (HMW) and low (LMW) molecular weight chitosans have been reported. The effectiveness of LMW chitosan was argued with an extended conformation due to higher mobility and easier interaction of small chains, thus allowing stronger binding of LMW chains to the membrane surface.
      • Chávez de Paz M.L.E.
      • Resin A.
      • Howard K.A.
      • Sutherland D.S.
      • Wejse P.L.
      Antimicrobial effect of chitosan nanoparticles on Streptococcus mutans biofilms.
      Further, in the case of chitosan nanocomplexes, LMW chitosan nanoparticles possess a reduced number of crosslinks, thus allowing a higher availability of the molecular chains for interaction with the membrane.
      • Chávez de Paz M.L.E.
      • Resin A.
      • Howard K.A.
      • Sutherland D.S.
      • Wejse P.L.
      Antimicrobial effect of chitosan nanoparticles on Streptococcus mutans biofilms.
      Moreover, the ability of chitosan to potentiate the photodynamic inactivation (PDI) effect of photosensitizers has been demonstrated. Chitosan nanoparticles loaded with erythrosine, a photosensitizing cyclic compound that can be used for PDI therapy, were prepared by an ionic gelation method and tested for their PDI efficacy on planktonic cells and biofilms of Streptococcus mutans, P. aeruginosa, and C. albicans.
      • Chen C.P.
      • Chen C.T.
      • Tsai T.
      Chitosan nanoparticles for antimicrobial photodynamic inactivation: characterization and in vitro investigation.
      The authors demonstrated that the antimicrobial activity was significantly higher than erythrosine in free form. Efficacy was enhanced by increasing the incubation time and reducing the size of loaded nanoparticles, thus confirming that surface-to-surface ratio between particles and cells is one of the main factors driving the biocidal activity.

      Antibiofilm systems

      Microbial biofilms are medically important, accounting for >80% of microbial infections (oral tissues, gastrointestinal or urogenital tract, airway/lung tissue) in the body, and are most often found in close association with surfaces and interfaces. Microbial biofilms also play an important role in natural diseases such as cystic fibrosis. The micro-organisms in a biofilm tend to be far more resistant to antimicrobial agents (up to 1000-fold) and to be particularly difficult targets for the host immune system response.
      • Cos P.
      • Toté K.
      • Horemans T.
      • Maes L.
      Biofilms: an extra hurdle for effective antimicrobial therapy.
      Penetration of drugs and elements of the immune system into biofilm is severely hindered by the extracellular polymeric substance matrix, which in some instances also acts as an adsorbent. In addition, due to nutrient and oxygen starvation, bacteria embedded in the deep layers of the biofilm go into altered metabolic states, making them less susceptible to antibiotic drugs which target bacterial metabolism. As a consequence, successful treatment of biofilm infections is rare, even with extensive antibiotic therapy, and this favours the development of drug-resistant microbes. Current therapeutic options are aimed at the prevention of biofilm formation, or at the eradication of mature biofilms, but none of them is generally successful, so that removal of the colonized implant is often the only rescue.
      • Cos P.
      • Toté K.
      • Horemans T.
      • Maes L.
      Biofilms: an extra hurdle for effective antimicrobial therapy.
      It should be clearly stated at this point that, to claim an antibiofilm effect, a substance should either demonstrate the ability to prevent the biofilm formation process or demonstrate a disrupting effect on mature biofilm.
      Silver nanoparticles coated with a polyvinyl sulphonate (PVS) layer have been demonstrated to be effective in preventing early attachment and biofilm formation by Staphylococcus epidermidis.
      • Vasilev K.
      • Sah V.R.
      • Goreham R.V.
      • Ndi C.
      • Short R.D.
      • Griesser H.J.
      Antibacterial surfaces by adsorptive binding of polyvinyl-sulphonate-stabilized silver nanoparticles.
      This steric layer provided excellent colloidal stability, preventing aggregation over periods of months. PVS-coated silver nanoparticles were bound on to amine-containing surfaces, generated by deposition of an allylamine plasma polymer thin film on to various substrates. This method appears promising for the fabrication of a wide range of infection-resistant biomedical devices. Bismuth NPs have also been suggested to have an antibiofilm effect and could be used in conjunction with a colloidal stabilizer.
      • Hernandez-Delgadillo R.
      • Velasco-Arias D.
      • Diaz D.
      • et al.
      Zerovalent bismuth nanoparticles inhibit Streptococcus mutans growth and formation of biofilm.
      • Domenico P.
      • Baldassarri L.
      • Schoch P.E.
      • Kaehler K.
      • Sasatsu M.
      • Cunha B.A.
      Activities of bismuth thiols against staphylococci and staphylococcal biofilms.
      Potara et al. reported that the association of silver NP with chitosan shows a synergistic effect on both MIC and minimum bactericidal concentration (MBC) against S. aureus.
      • Potara M.M.
      • Jakab E.
      • Damert A.
      • Popescu O.
      • Canpean V.
      • Astilean S.
      Synergistic antibacterial activity of chitosan–silver nanocomposites on Staphylococcus aureus.
      Huda et al. observed a long-lasting antibacterial action of AgNPs stabilized with self-assembled monolayers (SAMs) of ω-functionalized alkane thiols.
      • Huda S.
      • Smoukov S.K.
      • Nakanishi H.
      • Kowalczyk B.
      • Bishop K.
      • Grzybowski B.A.
      Antibacterial nanoparticle monolayers prepared on chemically inert surfaces by cooperative electrostatic adsorption (CELA).
      They showed that each Ag nanoparticle ‘leaks’ cations at an almost constant rate. Over a four-month period, only 3% of cations were lost from the coating, indicating the potential for a long-lasting action of such a formulation.
      • Huda S.
      • Smoukov S.K.
      • Nakanishi H.
      • Kowalczyk B.
      • Bishop K.
      • Grzybowski B.A.
      Antibacterial nanoparticle monolayers prepared on chemically inert surfaces by cooperative electrostatic adsorption (CELA).
      Sambhy et al. had previously shown that release of biocidal Ag+ ions could be modulated by controlling the size of the embedded AgBr nanoparticles.
      • Sambhy V.
      • MacBride M.M.
      • Peterson B.R.
      • Sen A.
      Silver bromide nanoparticle/polymer composites: dual action tunable antimicrobial materials.
      Both AgBr NPs and starch-stabilized AgNPs have shown an antibacterial effect on microbial biofilms. The antibacterial properties of nanosized magnesium fluorides is based on their ability to modulate bacterial metabolism through direct binding to different enzymes. Nanosized magnesium fluorides have been used to develop biomaterial coatings to prevent biofilm formation by E. coli and S. aureus.
      • Lellouche J.
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      Antibiofilm activity of nanosized magnesium fluoride.
      • Lellouche J.
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      • Gedanken A.
      • Banin E.
      Antibiofilm surface functionalization of catheters by magnesium fluoride nanoparticles.
      • Lellouche J.
      • Friedman A.
      • Gedanken A.
      • Banin E.
      Antibacterial and antibiofilm properties of yttrium fluoride nanoparticles.
      The authors pointed out that the nanoscale of the fluorides played an important role in the observed antimicrobial activity and that such activity was enhanced by preparing yttrium-fluoride YF(3) NPs.
      • Lellouche J.
      • Friedman A.
      • Gedanken A.
      • Banin E.
      Antibacterial and antibiofilm properties of yttrium fluoride nanoparticles.
      YF(3) NP-modified catheters, prepared by using a one-step synthesis and coating process, were able to significantly reduce bacterial colonization and biofilm formation compared to the uncoated surface.
      • Lellouche J.
      • Friedman A.
      • Lahmi R.
      • Gedanken A.
      • Banin E.
      Antibiofilm surface functionalization of catheters by magnesium fluoride nanoparticles.

      External stimuli-responsive systems

      A further feature of micro/nanosystems that make them potentially useful for several different applications is the possibility of designing the platform so that an external stimulus can be used to prompt the activation of the system where and/or when desired. Photosensitive determinants can be incorporated into the systems to drive the release of the active molecule when necessary. Photosensitizers may also be antimicrobial per se, through the production of highly reactive oxygen species upon activation.
      • Lambrechts S.A.G.
      • Aalders M.C.G.
      • Verbraak F.D.
      • Lagerberg J.W.M.
      • Dankert J.B.
      • Schuitmaker J.J.
      Effect of albumin on the photodynamic inactivation of microorganisms by a cationic porphyrin.
      When light irradiation is not applicable, ultrasound-responsive systems have been found to be effective, particularly the recently developed microbubbles (MBs). These contain a gas core of inert, high molecular weight gases (perfluorocarbons, sulphur hexafluoride), which is generally surrounded by a protein (albumin), lipid, surfactant, or biocompatible polymer shell (Figure 1g). Besides being powerful echogenic systems, extremely useful in imaging applications, ultrasound susceptibility of MBs can be exploited for antimicrobial purposes. The absorption of the acoustic energy by the bubbles upon exposure to ultrasound causes mechanical streaming, thermal effects, and highly reactive free radical production that, coupled with the local release of drugs loaded inside the MBs, greatly potentiate the antimicrobial activity.
      Particularly interesting are the recently designed lysozyme-shelled microbubbles (LSMBs).
      • Zhou M.
      • Cavalieri F.
      • Ashokkumar M.
      Tailoring the properties of ultrasonically synthesised microbubbles.
      LSMBs exhibited significant antimicrobial activity against Micrococcus luteus, even though lysozyme suffers a partial denaturation during LSMB fabrication.
      • Cavalieri F.
      • Micheli L.
      • Kaliappan S.
      • et al.
      Antimicrobial and biosensing ultrasound-responsive lysozyme-shelled microbubbles.
      Gold functionalization did not hamper the antimicrobial activity of MBs but, on the contrary, improved their effectiveness against M. lysodeikticus (Figure 2).
      • Cavalieri F.
      • Micheli L.
      • Kaliappan S.
      • et al.
      Antimicrobial and biosensing ultrasound-responsive lysozyme-shelled microbubbles.
      Figure thumbnail gr2
      Figure 2Antimicrobial activity of lysozyme-shelled microbubbles (LSMBs) (○), lactoferrin-coated LSMBs (□), bovine serum albumin (BSA)–gold nanoparticle (AuNP)-functionalized LSMBs (♢), and polyvinylpyrrolidone (PVP)–AuNP-functionalized LSMBs (✕). The same concentration of LSMBs (0.6mg/mL) was used for all assays. Reproduced with permission from Cavalieri et al.,
      • Cavalieri F.
      • Micheli L.
      • Kaliappan S.
      • et al.
      Antimicrobial and biosensing ultrasound-responsive lysozyme-shelled microbubbles.
      © American Chemical Society (2013).
      LSMBs have also been reported as being able to inhibit biofilm formation by S. aureus clinical isolates, in a dose-dependent manner.
      • Cavalieri F.
      • Zhou M.
      • Tortora M.
      • Baldassarri L.
      • Ashokkumar M.
      Methods of preparation of multifunctional microbubbles and their in vitro/in vivo assessment of stability, functional and structural properties.
      Biofilm formed by P. aeruginosa appeared to be even more susceptible to the presence of LSMBs, indicating a difference in susceptibility between biofilm-embedded Gram-positive vs Gram-negative micro-organisms (i.e. the latter being more susceptible). Lysozyme microbubble technology, again due to the possibility of tailoring, may be applied to the production of coatings for implantable medical devices, the antimicrobial activity of which may be activated on demand.

      Conclusion

      Nanotechnology shows promising openings in several areas of medicine, with oncology being currently the most thoroughly explored. Lately, infectious diseases have also stimulated interest in this area due to the need for alternative prophylactic or therapeutic tools able to counteract the ever-increasing incidence of resistance to antimicrobials. Nanoparticles, used either for their intrinsic antimicrobial properties or as drug-carriers, have the potential for being active at low concentrations towards a large variety of infectious agents, and at the same time unlikely to provoke emergence of resistance. Further studies especially aimed at targeting of nano/micro-platforms would be a major breakthrough in this field, allowing for the use of such devices as diagnostic tools. Promising new approaches include ultrasound-responsive microbubbles, which present a series of attractive features such as easy combination with a large variety of antimicrobials, responsiveness to external stimuli, and low toxicity.

      Conflict of interest statement

      None declared.

      Funding sources

      None.

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