Journal of Controlled Release 156 (2011) 128–145Contents lists available at ScienceDirect Journal of Controlled Release j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n r e l Review “Nanoantibiotics”: A new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant era Ae Jung Huh a, b, Young Jik Kwon a, c, d,⁎ a Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, United States Division of Infectious Disease, Department of Internal Medicine, National Health Insurance Corporation Ilsan Hospital, 1232 Baekseok-dong, Ilsandong-gu, Goyang-si, Gyeonggi-do 411-719, Republic of Korea c Department of Chemical Engineering and Materials Science, University of California, Irvine, CA 92697, United States d Department of Biomedical Engineering, University of California, Irvine, CA 92697, United States b a r t i c l e i n f o a b s t r a c t Despite the fact that we live in an era of advanced and innovative technologies for elucidating underlying mechanisms of diseases and molecularly designing new drugs, infectious diseases continue to be one of the greatest health challenges worldwide. The main drawbacks for conventional antimicrobial agents are the development of multiple drug resistance and adverse side effects. Drug resistance enforces high dose administration of antibiotics, often generating intolerable toxicity, development of new antibiotics, and requests for significant economic, labor, and time investments. Recently, nontraditional antibiotic agents have been of tremendous interest in overcoming resistance that is developed by several pathogenic microorganisms against most of the commonly used antibiotics. Especially, several classes of antimicrobial nanoparticles (NPs) and nanosized carriers for antibiotics delivery have proven their effectiveness for treating infectious diseases, including antibiotics resistant ones, in vitro as well as in animal models. This review summarizes emerging efforts in combating against infectious diseases, particularly using antimicrobial NPs and antibiotics delivery systems as new tools to tackle the current challenges in treating infectious diseases. © 2011 Elsevier B.V. All rights reserved. Article history: Received 3 January 2011 Accepted 29 June 2011 Available online 6 July 2011 Keywords: Infectious disease Antibiotics resistance Nanoparticles Antimicrobial drug delivery Nanoantibiotics Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Challenges and use of nanotechnology in treating infectious diseases . . . . . . . . . . . 2.1. Resistant ‘superbugs’ create needs for breakthrough . . . . . . . . . . . . . . . . 2.2. Potential impact of nanomedicine on the control of infectious diseases . . . . . . . 2.2.1. Nanotechnology-assisted detection of antimicrobial infection and resistance 2.2.2. Emerging roles of nanotechnology in antimicrobial actions and treatment of 2.2.3. Nanotechnology for vaccination and prevention of infectious diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . infectious . . . . . . . . . . . . . . . . . . . . . . . . . diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 129 129 130 130 131 131 Abbreviations: Ag, silver; Al, aluminum; Al2O3, aluminum oxide; AMs, alveolar macrophages; Apt, aptamers; Au, gold; AUC, area under curve; B. anthracis, Bacillus anthracis; BBB, blood brain barriers; B. subtilis, Bacillus subtilis; C. albicans, Candida albicans; CdS, cadmium sulfide; Chol, cholesterol; CNS, central nervous system; CNTs, carbon nanotubes; C. pneumoniae, Chlamydia pneumoniae; Cu, copper; CuO, copper oxide; DC-Chol, dimethylammonium ethane carbamoyl cholesterol; DCP, diacetylphosphate; DPPC, 1,2-dipalmitoylphosphatidylcholine; DSPG, distearoyl phosphatidylglycerol; E. coli, Escherichia coli; E. faecium, Enterococcus faecium; EPC, egg PC; FWS, Fullerene water suspensions; GB, glyceryl behenate; gp, glycoproteins; GPAA, glycosylated polyacrylate; GPS, Glycerol palmitostearate; GSH, glutathione; H. influenzae, Hemophilus influenzae; HSPC, hydrogenated soybean phosphatidylcholine; LDH, lactic dehydrogenase. L. monocytogenes, Listeria monocytogenes; L. pneumophila, Legionella pneumophila; MAP, Mycobacterium avium spp. paratuberculosis; MgF2, magnesium fluoride; MIC, minimum inhibitory concentration; MPS, mononuclear phagocytic system; MRSA, methicillin-resistant Staphylococcus aureus; M. tuberculosis, Mycobacterium tuberculosis; MWNTs, multi-walled tubes; NGF, nerve growth factor; N. gonorrheae, Neisseria gonorrheae; NIR, near-infrared; NPs, nanoparticles; NO, nitric oxide; O/W, oil-in-water; PAA, polyacrylate; P. aeruginosa, Pseudomonas aeruginosa; PAMAM, polyamidoamine; PC, phosphatidyl choline; PCA, poly(cyanoacrylate); PCL, poly(ε-carprolactone); PECA, polyethylcyanoacrylate; PEG, polyethylene glycol; PEG-DSPE, 1-2-disteroyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol-2000); PG, phosphatidyl glycerol; PGA, poly(glycolic acid); PHEPC, partially hydrogenated egg phosphatidyl choline; PIHCA, polyisohexylcyanoacrylate; PLA, poly(lactic acid); PLCP, pegylated lysine based copolymeric dendrimers; PLGA, poly(lactide-co-glycolide); PTMC, poly(trimethylene carbonate); PVA, polyvinyl alcohol; PVP, polyvinylpyrrolidone; QDs, quantum dots; RES, reticuloendothelial system; RNS, reactive nitrogen species; ROS, reactive oxygen species; SA, stearic acid; S. aureus, Staphylococcus aureus; SDBS, sodium dodecyl benzene sulfate; SDC, sodium deoxycholate; S. epidermidis, Staphylococcus epidermidis; SLNPs, solid lipid nanoparticles; SMZ, sulfamethoxazole; SPC, soybean phosphatidyl choline; S. pneumoniae, Streptococcus pneumoniae; STC, sodium taurocholate; SWNTs, single-walled nanotubes; TBGC, teicoplanin-loaded borate bioactive glass and chitosan; TEM, transmission electron microscopy; THF, tetrahydrofuran; TiO2, titanium dioxide; VRE, vancomycin-resistant Enterococcus; VRSA, vancomycin-resistant Staphylococcus aureus; W/O, water-in-oil; ZnO, zinc oxide. ⁎ Corresponding author at: Sprague Hall Room 132, Irvine, CA 92697-3905, United States. Tel.: + 1 949 824 8714; fax: + 1 949 824 4023. E-mail address:
[email protected] (Y.J. Kwon). 0168-3659/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2011.07.002 . . . . . . when compared to conventional antibiotics [10. Antimicrobial peptides and chitosan . . . . . . Kwon / Journal of Controlled Release 156 (2011) 128–145 129 Nanoantibiotics: Nanomaterials for infection control .1. . . . and the continued evolution of antimicrobial resistance threatens human health by seriously compromising our ability to treat serious infections [5]. . . . .5. Disadvantages of nanoantibiotics. . . . . . . . . . . . . . resistance to antibiotics has been reaching a critical level. . . . . . 3. . . . . . . . . . . . . . . . . . . . . . . . . .1. .2. . . . 3. . . . a capability of acquiring resistance to all currently available antibiotics [2]. . . . aureus (VRSA) strains is a global and daunting medical challenge for the twenty-first century because vancomycin is . . and lowering cost. . . . . . . . . . . . Zinc oxide (ZnO) NPs . . . . . . 4. . . . . . . .1. . . . . . 3. . 3. . . . . . . . . . . . . .2. . . . . . . which could be beneficial for achieving sustained therapeutic effects. . . . . . . . . . . . . . . . . . . . . . 1) [13].2. . . . . . . Unfortunately. . . . . . . . . . . . . . . . . . . . . . . . . . . .4. Challenges and use of nanotechnology in treating infectious diseases 2. . . . . . 3. . . . . . . 3. . . . . . . . . . . . . . 3. . . . . . . . . . A combination of increased pressure of antibiotic selections and a decline in the development of new antibiotics has raised the specter that once treatable infections become untreatable [1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. . . . . . . . and novel nanosized platforms for efficient antibiotics delivery. . . . . . . . especially in overcoming antimicrobial drug resistance. . Polymeric NPs .2. . . . . . . . . . . . . . . . . . . . . . . 2. . . . . . . . .8. . Development of antimicrobial drugs gives a low return on investment. . . . . . Treating vancomycin-resistant S. . . . . . . . . . . . . . . . . Silver (Ag) NPs . . . . . . . . . . . Liposomes for antimicrobial drug delivery . . . . . . . . . . . . . 3. In the ongoing race of the development of antimicrobial agents. . . . . . . . . . . . . . . and the pipeline for new drugs is verging on empty (Fig. . . . . . . . . . . . . .J. . .2. . . . . . . . . . . . . invalidating major antimicrobial drugs that are currently used in the clinic [2. . . . . . . . . .5. . Y. . . . . . . . . . . . . . . . . . . . . . . . which is utilized in controlling infectious diseases [7–9]. . . . . . . . . . . . . .9. . . . . . 2). . . . . . . . . . . . . . . . . . . . . . . . . .7.1. . . . . . . . . . . . . 3. . . . Huh. . . . . . .1. . . . while reducing the adverse effects of antibiotics. . . . . . . . . . . . . . . . . . . . . . . . The bacterial resistance to antimicrobial drugs has been attempted to be resolved by discovering new antibiotics and chemically modifying existing antimicrobial drugs. . . . . . . . . . . . . . . . . . . . .3. . the safety profiles of NPs and nanosized antibiotics drug carriers. . . . . . Treatment of drug-resistant microorganisms and biofilms . . . . Introduction At the beginning of the 20th century. . . . . . . . . . . . . . . . . . . For example. . Nitric oxide (NO)-releasing NPs . . . Surfactant-based nanoemulsions . . . . . . . . . . . . . . . . . . . . . . Despite extensive efforts in research and enormous investment of resources. . . . . 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1. . . . . . . . . . . . . . . . . Concluding remarks . . . . . could be an overriding safety factor and must be considered with therapeutic effects [12]. . . . Antimicrobial nanoparticles (NPs) offer many distinctive advantages in reducing acute toxicity. . . . . . . . . This challenging and dynamic pattern of infectious diseases and the emergence of bacterial strains resistant to many currently used antibiotics demand for longer-term solutions to this ever-growing and foreseeable problem [6]. Solid lipid (SL) NPs . . . . . . . . NPs for efficient antimicrobial drug delivery . . . .10. . The first serious clinical threat in treating infectious diseases using antibiotics was the emergence of vancomycinresistant Enterococcus (VRE). .6. . . . . . . . . . . . . aureus. . . . . . . . . 3. . . . . . . . For example. . . . . . . which has intrinsic resistance to several commonly used antibiotics and. . . . . . . . . . . . . . . . . . . . . . . . . it has been suggested in recent studies that some metal nanoconstructs are known to possess antimicrobial activities. overcoming resistance.1. . . . . . . . . . . .4. MRSA) [1] and some of them were found to be resistant to vancomycin. . . . . . . . 4. in the context of research and clinical prospectives of this novel and promising strategy. . The decreases in morbidity and mortality from infectious diseases over the last century were attributed mainly to an introduction of antimicrobial agents. . . . . . . . . . One of the recent efforts in addressing this challenge lies in exploring antimicrobial nanomaterials. . . . . . . . . . . . Acknowledgment . . . . 3. . . 3. . . . . . perhaps more importantly. . drugresistant infections in hospitals and in the communities caused by both Gram-positive and Gram-negative bacterial pathogens are growing [4]. . . . . . . . . .3]. . . . . . . . . . . . . . . . however. . . particularly upon long-term exposure. . . . . . . . . . . . . 3. . . . . . . . . . . . . and to the development of antimicrobial resistance. . . . . . Dendrimers . .4. . . to which microbial pathogens may not be able to develop resistance. . Nowadays.1. . . . . . . . . Translation of nanoantibiotics from bench to bedside . . . . . . . . . . . . . . . . . . . . microbes appear to be the winner. . . . . . . . . . . . . . . . . . . . however. . . . . . . . . . . . . . . . . . . and evolving microorganisms themselves are cooperatively contributing to the escalation of emerging and re-emerging infectious diseases. . . References . Advantages of nanoantibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gold (Au) NPs . . 4. . . . . . . . . . . .1. . . . . . . . 3. . . . Changes in societal activities. . . resulting in mortality due to failure in infection control and high health care costs [14].1.1. . . . the pace of drug development has not kept up with the development of resistance (Fig. . . . . . there is no assurance that the development of new antimicrobial drugs can catch up to the microbial pathogen's fast and frequent development of resistance in a timely manner. . . . . progress of technology. . . . . . . . . . . . . . . . . . Titanium dioxide (TiO2) NPs . . . . . . . . .3. . . . . . Local administration . infectious diseases were the leading cause of death worldwide [1]. . . 3. . . . . . . . . . . . . . . . . . . . . . Fullerenes (C60) and fullerene-derivatives . . . . . . . . . .2. . . . . . . . Theoretically. . . . . . . . . . Carbon nanotubes (CNTs) . . . . . . . 131 131 132 132 132 133 133 133 134 134 134 134 135 135 135 136 137 137 137 138 138 139 139 140 140 140 1. . . . Aluminum (Al) and copper (Cu) NPs . .A. . . . . . . . .1. .3. . . . . . . . . . . . . . . . . . This review introduces employing nanotechnology as a new paradigm in controlling infectious diseases. . . . . . . . . . . including nanotoxicology 4.2. . . . NPs are retained much longer in the body than small molecule antibiotics. . . . . . . . . . . . . Targeted therapy for infections using NPs . . 4. .1. . . . On the other hand. . . . . . . . . . .2. . . . . . . . .1. . . . . . . 4. . . . . . . . . . . Resistant ‘superbugs’ create needs for breakthrough Use of antibiotics began with commercial production of penicillin in the late 1940s and claimed to be a great success until the 1970–1980s when newer and even stronger antibiotics were additionally developed. 3. . More than 40% of Staphylococcus aureus strains collected from hospitals were resistant to methicillin (methicillin-resistant S. Various nanosized drug carriers are also available to efficiently administer antibiotics by improving pharmacokinetics and accumulation. . . . . . . . . . . .11]. . . . . . . . . . . . . . . . . . . . .1. . . . . . . . . . . . . . . contributing to the current crisis in fighting against drug-resistant pathogens [3]. Antimicrobial nanomaterials . . . . . . . . . .J. . . . . . . . . . . . . . .5]. . . Increasing rates of bacterial resistance also invalidate the utility of even the most potent antibiotics. . . . . . . . . . . . Huh. gonorrheae) and Haemophilus influenzae (H. Kwon / Journal of Controlled Release 156 (2011) 128–145 Fig.2. Treating such conditions necessitates frequent intravenous administrations of high-dose antibiotics. and delivery of antimicrobial drugs with improved efficacy and avoidance of resistance are highly demanded [22]. Therefore. magnetic. 2. and rapid Fig. conventional diagnostic methods for a microbial infection require cumbersome sample preparation and long readout times [27]. convenient. Drug-resistant Neisseria gonorrheae (N. aureus infection [15. design and delivery of antimicrobial drugs. Therefore. and β-lactam antibiotics. coli O157:H7. History of antimicrobial agent development vs. and parasites is a high level alert to find paradigm-shifting approaches for treating microbial infections as a top priority in medicine. pneumoniae) [17]. 2. delivery of antimicrobial agents.29]. and diagnosis and control of cross-infections. the latest generation of antibiotics and is assumed at the moment to be the most effective for S. VRSA. often rendering them multiplication-resistant [2]. Resistance to antimicrobial drugs becomes a threatening problem not only in hospitals but also in communities. using nanotechnology. . The spread of resistance to many currently used antimicrobial agents among fungi. macrolides. MRSA.1. An attractive alternative to using antibiotics is utilizing agents that cause physical damages to antimicrobial resistant strains. influenzae) were already recognized worldwide in the 1970s [18]. Multi-drug resistance has been increasing particularly among nosocomial Gram-negative bacteria that are capable of developing many different mechanisms for antimicrobial resistance. complete eradication of infection under such conditions is hard to achieve because of bacteria's ability to form biofilms [25]. Moreover. This implicates that treating this virulent bacteria with antibiotics is extremely difficult [19–21]. Antibody-conjugated NPs amplify the signals for bioanalysis and enumeration of highly pathogenic bacteria such as E. This section introduces various challenges in controlling infectious diseases. design.J. encompassing diagnosis of bacterial resistance. luminescent. coli). has been explored as a promising alternative to the current antibiotics-based approaches [6. Recently. and cost-effective diagnosis as well as rapid determination of the susceptibility and resistance of anti-bacterial drugs [28.J. resulting in fewer effective drugs available to control infections by “old” established bacteria such as Streptococcus pneumoniae (S. This also explains the increasing antimicrobial resistance of nosocomial Gram-negative bacteria to extended-spectrum cephalosporin. 1. Another challenge in antimicrobial therapy is the treatment of chronically infected conditions such as cystic fibrosis and other chronic obstructive pulmonary diseases. sensitive. Unique electrical. selective photothermal therapy for in vivo antimicrobial treatment using pulsed laser was reported [24]. resulting in highly selective. FDA approval on new antibiotics [13]. 2. leading to a number of fatal cases. Even with aggressive antibiotic treatment.2. which cause serious adverse effects from a high concentration of antibiotics in serum. more than 1500 people in Germany have been infected by a new virulent strains of Escherichia coli (E. subsequent acquaintance of resistance by microorganisms. bioinformatics analysis revealed that this deadly bacterial strain carries several antibiotic resistance genes. which was not previously known to be involved in any outbreaks but turned out to be highly infectious and toxic. a class of the newest and most powerful antibiotics [4]. a new antimicrobial therapy employing a cuttingedge technology that is more effective and safer than the currently available ones is desperately desired [26]. in particular in overcoming antibiotics-resistant pathogens. Y. Potential impact of nanomedicine on the control of infectious diseases Use of nanotechnology in immunization. including resistance to aminoglycosides. and vaccination. and other multidrug-resistant microorganisms [23]. and catalytic properties of nanomaterials enable fast. Nanotechnology-assisted detection of antimicrobial infection and resistance Despite their high sensitivity and reproducibility.12].16].130 A. viruses. discovery. There have been considerable efforts in searching for new natural product-derived antibiotics to control infections by VRE. The persistent infection also leads to the rise of bacterial strains that possess elevated tolerance to current antibiotics. For example. specific site-targeted delivery. although potential toxicity upon long-term exposure is questionable. are called “nanoantibiotics” and their capability of controlling infections in vitro and in vivo has been explored and demonstrated. and . recent studies using nanotechnology have demonstrated the feasibility of achieving fast and reliable pharmaceutical assays for microbial infections in opaque media (e. Huh. naturally occurring antibacterial substances. coli antibodies [31]. and can facilitate double or even triple immunostaining of bacterial cells (e.41–43. especially in liquid environment [24]. 2) compromising the bacterial cell wall/membrane. The size. can be achieved by employing appropriate nanocarriers [12]. The broad absorption spectra (i. These NPs were able to assess the microbial metabolic activity and determine antimicrobial susceptibility in blood. nanosized silver. For example.. In particular. 2) improved solubility. A new photothermal approach to antimicrobial nanotherapy and pathogen detection at a single bacterium level has also been developed using carbon nanotubes (CNTs) [47]. intracellular or extracellular synthesis of metallic NPs (cadmium sulfide [CdS]. and immune presentation of antigens [50.g. including improved solubility. and highly efficient converter of optical energy into thermal energy.37]. high affinity and clustering agents for bacteria.11. 3) interruption of energy transduction. charge. Emerging roles of nanotechnology in antimicrobial actions and treatment of infectious diseases Metal and metal oxide NPs produce reactive oxygen species (ROS) under UV light and find their increasing uses in antimicrobial formulations and dressings [12].A.41]. A great deal of efforts have been invested in developing affordable. 4) improved patient-compliance.and nanoparticles are approximately the sizes of bacteria and viruses that the immune system recognizes.48. such as high temperature sterilization.2. and 6) enhanced cellular internalization [56–58]. and they are quite stable enough for long-term storage with a prolonged shelf-life [11].g. Antibiotics delivery using nanomaterials offer multiple advantages: 1) controllable and relatively uniform distribution in the target tissue. and silver [Ag]) using microbial cells or enzymes has also been explored as novel biological and environment-friendly NP preparation [60–64]. chemical composition. In in vivo studies. under which conventional antibiotics are inactivated. Table 1 also summarizes nanomaterials with their antimicrobial mechanisms.2. Key pharmacokinetic characteristics of antibiotics. coli strains [45]. controlled release. This type of vaccine does not require cold storage and can be administered via mucosal routes.54]. compared with nonpolymerized forms of penicillin and N-methylthio β-lactams [22. gold [Au].55]. and their compounds have been reported to be effective in inactivating various microorganisms [40. antibiotics formulated in polymeric NPs have demonstrated enhanced antimicrobial activities and anti-MRSA activities. Vancomycincapped gold (Au) NPs has also exhibited enhanced antimicrobial activities against VRE strains and E. These characters suggest that QDs are a promising modality for the analysis of complex samples for histology. recombinant Bacillus anthracis [B.2. In addition. 5) minimized side effects. without any sample preparations [38. It was shown that NPs with specific Raman spectroscopic fingerprints can distinguish antibioticresistant bacteria. 3) and many concurrent mutations would have to occur in order to develop resistance against NPs' antimicrobial activities. Antimicrobial mechanisms of nanomaterials include: 1) photocatalytic production of reactive oxygen species (ROS) that damage cellular and viral components.44]. The use of magnetic NPs also could be a very sensitive and rapid strategy to detect microbial infection. paratuberculosis (MAP) as well as the quick quantification of MAP in milk and blood with high sensitivity [34]. robust. Nanoantibiotics: Nanomaterials for infection control Nanomaterials.g. antimicrobial NPs may not pose direct and acute adverse effects.. Listeria monocytogenes [L. some NPs can withstand harsh conditions.1. Furthermore. amphipathically coated NPs efficiently deliver antigens to dendritic cells (DCs) that concomitantly orchestrate cellular and humoral immunity [51.55. A recent study also demonstrated that naturally occurring bacteria do not develop antimicrobial resistance to metal NPs [40].52]. compared with antibiotics synthesis. 2. or carried via encapsulation [48]. Recently. and surfactant-based nanoemulsions [43]. whole blood and milk). influenza A virus) or proteins (e. Supermagnetic iron oxide nanoprobes greatly assisted the identification of Mycobacterium avium spp. Preparation of antimicrobial NPs could be cost-effective. and surface properties of particulate vaccine carriers can also be tuned for enhanced uptake by mononuclear phagocytic system (MPS). Y.. 3. High surface area to volume ratios and unique chemico-physical properties of various nanomaterials are believed to contribute to effective antimicrobial activities [11].59] (Fig. This technology leads to effective and irreparable damage to the bacterium bound with Au NPs of different sizes conjugated with antiprotein A antibodies. monocytogenes]) [36]. and 4) inhibition of enzyme activity and DNA synthesis [10. and reproducible nanodiagnostic assays to be globally accessible and applicable even in rural areas of developing countries [27. and potential clinical and industrial uses. which would be particularly desirable for vaccination in developing countries [12]. carbon-based nanomaterials. This study revealed CNTs' threefold roles: high near-infrared (NIR) contrast agents. mixtures of nanoemulsions with either whole viruses (e. For example. such as MRSA from non-resistant strains. Particulate systems provide several benefits for vaccine delivery [49] in such that micro. antimicrobial NPs tackle multiple biological pathways found in broad species of microbes (Fig. 2. 3).J.39]. Most importantly.J.51]. The high reactivity of titanium and zinc dioxide has been extensively utilized in the bactericidal substances that are used in filters and coatings on catheters [41–43]. Many types of lipophilic and water-soluble antibiotics can be conjugated inside or on the surface of NPs. Recently.g. dextrancoated supermagnetic iron oxide NPs were clustered by Con-A treatment. by rapidly quantifying polysaccharides. A quick method for detecting infections in the urinary tract have also been developed using gold nano wire arrays (GNWA) in conjunction with a linker arm attached to specific E. A wide range of antimicrobial agents can be effectively administered using various NPs.e. 3. pathology and cytology.3. Nanotechnology for vaccination and prevention of infectious diseases Use of NPs as novel adjuvants and colloidal vaccine carriers for immunization has been explored [12]. or equipped with Con A-conjugated nanosensors [33].. stimulation of antigen presenting cells (APs). Antimicrobial nanomaterials Antibacterial NPs consist of metals and metal oxides. 3) sustained and controlled release. The studies illustrated facile one-step preparations of antibiotics-conjugated polyacrylate network in aqueous media and incorporation of water-insoluble drugs directly onto the polymeric network without post-synthesis modifications of the NPs. by detecting single-nucleotide polymorphisms in microarray-based systems [32]. which either show antimicrobial activity by themselves [43] or elevate the effectiveness and safety of antibiotics administration [7. Kwon / Journal of Controlled Release 156 (2011) 128–145 131 detection of single bacterium within 20 min [30]. excitation at a wide range of wavelengths) of quantum dots (QDs) can be exploited to simultaneously excite QDs emitting different colors using a single wavelength [35].. Selective killing of target bacteria by irradiating Au NP-attached bacterial surface with a laser has been recently demonstrated [46]. zinc. anthracis] protective antigens) have been explored as potential vaccines [53. Unlike many antimicrobial agents currently being used in the clinic. cellular internalization. in the forms of metallic silver.J. enhancing activity of infiltrating neutrophil Cell membrane damage by ROS. aureus [92]. DNA damage Intracellular accumulation of NPs. and UV-blocking properties [91]. 3. ZnO NPs have advantages over Ag NPs.1. Nanomaterial Ag NPs ZnO NPs TiO2 NPs Au NPs Chitosan Fullerenes CNTs NO-releasing NPs Nanoemulsion Antimicrobial mechanism Release of Ag ions. Zinc oxide (ZnO) NPs Some NPs made of metal oxides are stable under harsh processing conditions and have selective toxicity to bacteria but also exhibit a minimal effect on human and animal cells [85–87].g. and other eukaryotic microorganisms [67–70].90]. ZnO NPs were found to have antibacterial activity against important food borne pathogens. . chelation of trace metals. In addition.92] [42. such as a low production cost. ZnO NPs. resulting in a leakage of intracellular contents and eventually the death of bacterial cells [41. 3. Ag NPs have proven to be the most effective against bacteria.71–73] [41. irritation (e. Diverse applications of Ag NPs include wound dressings. biofouling-resistant membranes.. surface coating of medical device.254] Abbreviations Ag NPs.149] [154] [168. air purifiers. A great amount of information accumulated over the last 20 years [95] demonstrated the strong bactericidal Fig.g.43. therefore. nitric oxide. while concomitantly releasing silver ions that enhance bactericidal activity [71]. ZnO NPs are believed to destruct lipids and proteins of the bacterial cell membrane. catheters. carbon nanotubes. Prolonged exposure to soluble silver-containing compounds may produce an irreversible pigmentation in the skin (argyria) and the eyes (argyrosis). erythromycin. viruses. mouthwash Antibacterial agent. antifungal agent Antibacterial creams. and bacterial infection control. microbiocide in biomedical products Potential disinfection applications Antibacterial agent. titanium oxide nanoparticles. a white appearance. which are nontoxic and biocompatible. wound dressings) [13].73] and shape [10].84].. and vancomycin. enzyme inactivation Destruction of cell membrane integrity.59. antibacterial agent. impregnated textile fabrics. Silver (Ag) NPs The antibacterial property of silver has been noticed since ancient times. The antimicrobial activity of Ag NPs is inversely dependent on size [72. 3. Kwon / Journal of Controlled Release 156 (2011) 128–145 medical devices and surgical masks. Various antimicrobial mechanisms of nanomaterials.1. coli [67. cosmetics ingredients. Au NPs. respiratory. aureus) [7. Recently. metallic silver appears to pose a minimal risk to health and Ag NPs are suggested to be non-toxic in some studies [81.98] [68. anti-biofilm agent. cell membrane and wall damage Interaction with cell membranes. lotions and ointment. resulted in enhanced and synergistic antimicrobial effects against Gram-positive and Gram-negative bacteria (e.3. antifungal agent Drinking water disinfectants. These studies suggested that the application of ZnO NPs may be effective for preserving agricultural products and food. coatings for medical devices. NO.81] [43. coating for Table 1 Antimicrobial nanomaterials.J. Huh. food sterilizing agent.91. Silver has been used for burn wound treatment. and medical filling materials [88. The nano-ZnO multilayer deposited on cotton fabrics showed excellent antibacterial activity against S.1. vaccine delivery agents References [10.74. Among the many different types of metallic and metal oxide NPs.89]. and intestinal tract). silver nanoparticles. and silver sulfadiazine [65]. E. dental work.g. and intracellular structural change of polyvinyl alcohol (PVA)-coated ZnO NPs were also reported [41]. Using silver to treat bacterial infections became unpopular after penicillin was introduced in the 1940s [66]. release of Zn2+ ions Production of ROS. silver nitrate. oxidation of cell membrane proteins and lipids NO release and production of ROS Membrane disruption. ZnO NPs. adjuvant treatment after serious infections antibacterial agent. H2O2 production. requires clear and full elucidations of their potential toxicity. portable water filters.113] [124–128] [146. Increased membrane permeability. generation of hydrogen peroxide and Zn+ 2 ions were suggested to be key antibacterial mechanisms of ZnO NPs [93]. have been utilized as drug carriers. water filter. strong electrostatic attraction Increased permeability and rupture of membrane. For example. disruption of the spore coat + Clinical and industrial applications Dressing for surgical wound and diabetic foot. On the contrary. and changes in blood cell counts [80]. Ag NPs attack the respiratory chain and cell division that finally lead to cell death. 3.82].75]. water treatment systems Photothermal therapy with near infrared light. The advent of Ag NPs as promising antimicrobial nanomaterials..1. bacteria immobilizer. such as E. gold nanoparticles. Y. including organ damages (e. disruption of cell membrane and electron transport.85.148. but some studies reported concentration-dependent adverse effects of Ag NPs on the mitochondrial activity [83. Combined use of Ag NPs with antibiotics. Titanium dioxide (TiO2) NPs TiO2 is a commonly used semiconductor photocatalyst and TiO2 NPs are the most studied for photocatalytic antimicrobial activity among various NPs [94]. surface-coating Infected wound and diabetic foot treatment Antimicrobial inhaler. nanogels. nasal application. eyes. zinc oxide nanoparticles.g. skin.132 A. cell membrane damage. liver and kidney). and nanolotions [76–79]. The recent emergence of antibiotics-resistant bacteria and the limited effectiveness of antibiotics revived the clinical use of silver (e.96. CNT.2.95. TiO2 NPs. such as penicillin G. coli and S.67]. amoxicillin. coli O157:H7 and enterotoxigenic E. in addition to other toxic effects.. sponges. and screws [98]. Chitosan's antimicrobial mechanisms have been explained by various theories. For example. aeruginosa [97]. TiO2 is particularly suitable for water treatment because it is stable in water. 3. subtilis spores. which was also supported by the observation that cationic particles were found to be moderately toxic while anionic particles were not [8].1. dental implants. Au NPs conjugated with antimicrobial agents and antibodies have been explored to obtain selective antimicrobial effects [103]. a broad spectrum of activity. aureus in a recent study [106]. The clinical potential for such combinatory uses of chitosan in overcoming untreatable resistant infections could be immense.1. For example. such as pit and fissure sealants. Chitosan was found to be more effective for controlling fungal and viral infections than bacterial ones [59]. and fungi [59. 3. was demonstrated [40].104]. The required concentration for killing bacteria varies in the range of 100–1000 ppm. which eventually induces a leakage of intracellular components [113].. and a low toxicity on mammalian cells [59].A. The photocatalytic activity by UV-A and the potential activation by visible light. coliN P. it was shown that Cu NPs have greater affinity to amines and carboxyl groups at a high density on the surface of Bacillus subtilis than that of Ag NPs. Y. albicans.1. 3. aureus. Irradiationindependent bacterial death also indicates other unknown nonphotocatalytic antimicrobial activity of TiO2 NPs [99]. aeruginosa and S. Utilizing chitosan is a promising. coli and B. Au NPs are promising adjuvants for antibiotics therapy in treating serious bacterial infections at a reduced antibiotics dosage with minimal adverse effects. gentamicin.6. Therefore.100].g. by Au/drug nanocomposites (e. a high microbe-killing efficiency. . Ag/(C. It was also proposed that chitosan liberated from the fungal wall by host hydrolytic enzymes penetrates to the nucleus of fungi and inhibits RNA and protein syntheses [59]. and cost-effective. Although antibacterial activity of Ag NPs is well established and proven to be most effective in general among the metallic NPs [55. aeruginosa when used with sulfamethoxazole [118]. which target the bacterial surface. According to recent studies. and nanocages have been employed to treat bacterial infections via irradiation with focused laser pulses of suitable wavelengths [69. by exploiting the combined bactericidal activity of Ag and TiO2 together [101]. potent antimicrobial activities of oleoyl-chitosan NPs against both bacteria were observed [121]. compared with that of free ampicillin [68].112. superior antibacterial activity [109. and technologically affordable disinfection method that is particularly useful in developing countries. Hydroxyl radicals generated by photocatalytic TiO2 are very potent oxidants with a broad reactivity.116]. Antibacterial effects of TiO2 on Lactobacillus acidophilus would also be used in orthodontic appliances. Huh. A study also showed chitosan's synergistic antimicrobial activity against drug resistant P. depending on the thickness of microbial surface structure [96]. chitosan-capped Au NPs coupled with ampicillin showed a 2-fold increase in antimicrobial activity.100]. The antimicrobial activity of Au NPs seems to be initially mediated by strong electrostatic attractions to the negatively charged bilayer of the cell membrane [68. chitosan chelates trace metals and thereby inhibits enzyme activities and the microbial growth [119]. Ag/TiO2) improved the light absorbance of TiO2 and increased its photocatalytic inactivation of bacteria and viruses [95. faeciumN C. A different study reported a strong antibacterial activity of oleoylchitosan NPs with enhanced dispersion in the culture medium and reduced pH effects on solubility [121]. Many studies have reported strong antimicrobial effects against Gram-positive and Gram-negative bacteria. including antibiotic-resistant strains [69. cost-effective. toothbrushes. Growth inhibition of Enterobacter cloacae by UVA-irradiated TiO2 NPs was less effective than that of E.108]. such as a high antibacterial activity. Copper oxide (CuO) is cheaper than silver. An attractive feature of disinfection by TiO2 is its potential for activation by visible light (e.5. and neomycin). make TiO2-mediated disinfection especially useful in developing countries where electricity is not available for sterilization [43]. Water-soluble derivatives of chitosan showed a higher antimicrobial activity. nanoshells. non-toxic by ingestion. the antibacterial activity of NPs vary depending on the microbial species [109]. Copper is a structural constituent of many enzymes in many living microorganisms. The antimicrobial effect of chitosan is strongly dependent on the molecular weight of chitosan and intrinsic differences in target bacterial wall structure: chitosan of a low molecular weight generated high antimicrobial effects on Gramnegative bacteria while the reverse is observed with chitosan of a high molecular weight on Gram-positive bacteria [117]. which makes TiO2 a promising agent for improving process hygiene and product safety in food industry and cosmetics [95. In addition. It is only recently when these materials have been engineered into a form of NPs. One of them is the binding to the negatively charged bacterial surface to cause agglutination.S)-TiO2 NPs were shown to have strong light-independent antimicrobial activities against both E. Antimicrobial peptides and chitosan Chitosan is a partially deacetylated chitin (a long biopolymer chain of N-acetylglucosamine) and it has a wide-spectrum of antibacterial activity [112]. coli and S. Damaged membrane structure impairs many crucial biological functions. by disrupting the outer and inner membranes of bacteria. that the nano-scale chitosan as well as its derivatives exhibit antimicrobial effects against bacteria. increasing the permeability of the microbial wall. aureus by Au NPs conjugated with anti-protein A antibodies. Nano-scale chitosan could be used to disinfect microbes in membranes. aeruginosa N S..113]. aureusN E. hence.81].4.J. According to another proposed mechanism.J. However.g. sunlight). and oxidative phosphorylation reactions [42].g. Very interestingly. respiration. Even with distinctively different internalization pathways in E. easily miscible with polymers. A further elucidated tendency has been shown by recent studies [115.. Au NPs coated with antibiotics such as streptomycin. Kwon / Journal of Controlled Release 156 (2011) 128–145 133 activity of TiO2 upon receiving irradiation with near-UV light and UVA.114]. coli and P. selective killing of S. It was found that strong laser-induced hyperthermic effects accompanied by bubble-formation around clustered Au NPs effectively damaged bacteria [40]. and relatively stable chemically and physically [111]. nanorods. in direct contact with or close to a microbe.110].70. metal doping (e. It was also reported that the photocatalytic antimicrobial efficiency of TiO2 NPs was in the order of virusN bacterial wall N bacterial spore.102]. A new study reported the TiO2 NPs' antibacterial efficiency in the order of E. or surface coatings of water storage tanks [113]. The limited solubility only in acidic media and precipitation in the culture medium prevent from correctly investigating the antibacterial activity and its mechanisms [112]. Gold (Au) NPs Near-infrared (NIR) light-absorbing Au NPs. The photocatalytic antibacterial activity of TiO2 is attributed to the production of ROS such as free hydroxyl radicals and peroxide [98]. when doped with novel metals. depending on the TiO2 NP size as well as the intensity and wavelength of the light source [42]. such as semipermeability. Aluminum (Al) and copper (Cu) NPs Aluminum oxide (Al2O3) NPs are known to exhibit mild inhibitory effects on microbial growth via cell wall disruption but only at very high concentrations [105] while Ag/meso-Al2O3 NPs showed broad inhibitory effects on P. In a recent study. TiO2 also inactivates various microorganisms that are highly resistant to desiccation and UV radiation. than native chitosan [120]. viruses. and the microbial surface is the primary target of the initial oxidative attack by irradiated TiO2 NPs. It has several advantages over other disinfectants. and the antimicrobial activity of chitosan has previously been considered greater for Gram-positive bacteria than Gram-negative ones [113. is seemingly determined by the complexity and the density of the cell membrane/wall [96]. free ionic Cu 2+ at a high concentration can generate toxic effects by generating ROS that disrupts the amino acid synthesis and DNA [107]. 147] via combination of membrane and oxidative stress.152]. Surfactant-based nanoemulsions Nanoemulsions.g. Gram-negative (P. the degree of aggregation. tetrahydrofuran [THF] or its oxidative by-products) that were used or generated during C60 preparation [43. and using polyvinylpyrrolidone (PVP/C60) as a solubilizing agent exhibited strong antibacterial activity [139]. FWS prepared by using THF as a solvent (THF/nC60).g. Y. For example. membrane perturbation. numerous techniques for creating stable colloidal C60 aggregates (nC60) in water are noted for their potent and broad antibacterial activity [43. The latest work proposed detailed antimicrobial mechanisms of SWNTs in three-steps: initial SWNTbacteria contact. aqueous nanoemulsions of soybean oil. were documented [167. sonicating C60 dissolved in toluene with water (son/nC60). Kwon / Journal of Controlled Release 156 (2011) 128–145 3. Unfortunately.129]. Biofilm formation and subsequent biofouling of surfaces (e. The antimicrobial activity of carboxyfullerene is mediated by insertion into the cell wall.151]. Aggregated form of C60 in water (fullerene water suspensions [FWS]) has unique physicochemical properties. stirring C60 powder in water (aq/nC60). epidermidis) bacteria as well as fungi (Candida albicans) within established biofilms were effectively killed by NO-releasing silica NPs that were found to be nontoxic to mammalian cells [159. PVP. it was demonstrated that the aqueous dispersity of CNTs can be greatly improved after being stabilized by surfactants or polymers (e.162]. Polyhydroxylated fullerenes [C60(OH)n]. new observations suggest that the observed toxicity of nC60 in both human cells and microorganisms may be due to solvent contaminants (e. Utilizing CNTs for water purification. Early studies indicate profound cytotoxicity of CNTs in alveolar macrophage.167–170]. aureus and S.147.171].9. the antimicrobial efficacy of independent NO donors were not well-documented.131].150]..g. exhibited a strong antimicrobial activity over a wide-range of microorganisms with lower toxicity than that of nC60 [134].1. A transient inflammation and lung injury after SWNTs instillation in vivo was also reported [144. SWNTs exhibit the strongest antimicrobial activity [141. aeruginosa [170]. and death) [156.145]. Single-walled nanotubes (SWNTs) are a single pipe with a diameter in the range of 1–5 nm. whereas NO donor molecules were reported to be effective in healing wounds in diabetic mice [157]. aeruginosa [169] as well as biofilms of P. effective inactivation of E. Recently. These microemulsions were found to be effective in killing S.1. followed by spontaneous bacterial adsorption to the clusters and selective destruction of drug-resistance microorganisms upon near infrared irradiation [21. The debatable antibacterial mechanism for nC60 includes photocatalytic ROS production in eukaryotic cells [125–127]. While NO has been reported to effectively act in combination with other agents [155]. coli) and Gram-positive (S. aeruginosa and E. Although it was suggested that SWNTs have antimicrobial properties [146]. which is comparable to the antimicrobial effects of vancomycin [133]. which were found to be thermodynamically stable and either transparent or translucent. some O/W micro. semiconducting)-dependent manner [149].10. bicontinuous.160]. 3. Recently. and their unique optical. have been found to be susceptible to gaseous NO and small molecule NO donors [156]. Among various carbon-based nanomaterials. Bactericidal properties of soybean oil-based nanoemulsion against Gram-positive.. and size) are easily tunable in comparison with small molecular NO donors [161]. and NO-releasing NPs can be a promising antimicrobial alternative [153]. determined by water to oil ratios) via high-stress mechanical extrusion. metallic vs. rope-like CNT agglomerates are more cytotoxic than well-dispersed CNTs at the same concentrations [142]. and water-in-oil [W/O] emulsions.7.143]. have been investigated for their antimicrobial activity [164–166]. NOreleasing silane hydrogen-based NPs showed antimicrobial activity against MRSA in vitro as well as in abscesses that frequently lead to serious complications (e. known as fullerols. including antimicrobial activity different from those of bulk solid C60 [43.. NO-releasing NPs can be used to treat infected wounds [154. 3.130.8.. Stable and antimicrobial O/W microemulsions with various compositions of Tween 80. followed by disruption of the cell membrane structure [122].148].1. showed antimicrobial properties [165. Although the acute toxicity of fullerols is low.146. mechanical.. In addition. and membrane oxidation in an electronic structure (i. and the bioavailability of CNTs must be considered [140].. Huh. and ethyl oleate [169. sepsis. Carbon nanotubes (CNTs) CNTs are cylindrical nanostructures made of pure carbon atoms covalently bonded in hexagonal arrays [140]. electrical. both Gram-negative and positive bacteria.e. coli and poliovirus. spontaneous NO release under aqueous conditions at physiological temperature and pH was demonstrated using various NPbased scaffolds that are capable of storing large NO payloads [159–161]. nC60 prepared without using any polar organic solvent resulted in no acute or subacute toxicity in rodents. In particular. NO and its derivatives known as ‘reactive nitrogen species (RNS)’ generate broad antibacterial activity [154].g.134 A. Lacking protein oxidation as well as light. The suspension of nC60 prepared via THFindependent methods was demonstrated to be nontoxic. BCTP. a diatomic free radical.1.g. possibly in a synergic way [146. particularly after γ-irradiation [123.J. Fullerol can also be used as a drug carrier that bypasses the blood ocular barriers [135]. while multi-walled tubes (MWNTs) have several nested tubes with lengths varying from 100 nm up to several tens of micrometers [43]. which are cytotoxic in general.139]. [A large quantity of NO can be reversibly constrained within the lattice structure of zeolites [158].N-dimethylpyrrolidinium iodide) derivatives affect the respiratory chain and effectively inhibit bacteria growth. in the order of SWNTs N MWNTs N quartz N C60 [142. the poor aqueous dispersion of pure CNTs undermined the promise as an antibacterial and antiviral agent [43].170] were also obtained. Unlike conventional filters.150]. water filtration membranes) may be sufficiently prevented by SWNTs [43. Moreover.and oxygen-independent antibacterial properties of nC60 indicate the ROS-independent toxicity mechanism [127]. long retention in the body raises concerns about chronic toxic effects [136–138]. but not against enteric Gram-negative species. For example. and Triton-X) [140]. Alkylated C60-bis(N. Although native fullerenes are nearly aqueous-insoluble. CNT filters can be cleaned repeatedly to regain their full filtering efficiency [150. is a molecular modulator for immune responses to infection. High chemical stability and ease of functionalization make SWNTs additionally attractive antimicrobial biomaterials [148]. hydrophilicity/hydrophobicity. In recent years.J. Treating cutaneous infections using acidified nitrite was reported to be effective but also caused inflammation [157]. surface charge. and removal of MS2 bacteriophage has been increasingly explored [24. the lack of suitable vehicles for NO storage and delivery has been a limiting factor for utilizing NO as an antibacterial agent. including MRSA. and thermal properties have been of great interest [141].and nanoemulsions. aureus and resistant P. Fullerenes (C60) and fullerene-derivatives Fullerenes' antimicrobial properties are of very recent findings based on limited knowledge [122].128]. The physico-chemical properties of NO-releasing NPs (e. CNTs can also be used for antimicrobial photothermal therapy by delivering CNT nanoclusters to an infected area.163]. Some studies assert that antibacterial activity of nC60 to prokaryotic cells is mediated via lipid peroxidation in the cell membrane [124. they can be dispersed in water by the several recently developed methods [123]. pentanol. and also protected the livers from damages by free-radicals in a dose-dependent manner [132]. Recently. Triton . Nitric oxide (NO)-releasing NPs Nitric oxide (NO). sodium dodecyl benzene sulfate [SDBS]. In order to exploit fully effective antimicrobial properties. 3.123.124]. Recently. tissue damage. the stabilization effects by natural organic matter. mixed water-immiscible and aqueous phases (oil-in-water [O/W]. NPs for efficient antimicrobial drug delivery Despite the well-established efficacy of antimicrobial drugs. Huh. peptides and small molecule) [173.175]. aptamers. In addition. and reproducibility and feasibility for large-scale production should be considered in utilizing liposomes for antimicrobial drug delivery [173]. which was confirmed by transmission electron microscopy (TEM). Encapsulation of vancomycin and teicoplanin in liposomes resulted in significantly improved elimination of intracellular MRSA infection [193]. and resistance-overcoming effects via co-delivery of multiple antimicrobial drugs can be achieved using NP carriers [173. econazole. increased transdermal diffusion of water-insoluble azole antifungal drugs (e. ultrasmall and controllable size.175]. prolonged drug half-life and systemic circulation time. Altered distribution in tissue and significantly extended half-life (blood 24. which was proposed to be overcome by tobramycin-loaded SLNPs [197]. incorporation of certain glycolipids (e. and sustained and stimuli-responsive drug release. soybean oil. aeruginosa. aeruginosa. safe. high interactions with microorganisms and host cells..J.5 h. drugs to be loaded. Kwon / Journal of Controlled Release 156 (2011) 128–145 135 X-100. Novel nanomaterials.g. flow cytometry. via parenteral. long-circulation) but also enabled targeted delivery of antimicrobial drugs after tethered with various targeting ligands (e. monosialoganglioside and phosphatidylinositol) in the liposomes resulted in prolonged circulation time and reduced uptake by the MPS in the liver and the spleen [180–182]. The advantages of NP-based antimicrobial drug delivery include improved solubility of poorly water-soluble drugs. The nasal administration of O/W nanoemulsion-based anthrax and hepatitis B vaccines were found to be well tolerated and did not induce inflammation in mice [171. NPs in particular. For example. Since Doxil (doxorubicinencapsulating PEGylated liposomes) became the first liposomal drug approved by the Food and Drug Administration (FDA) in 1995 [176].J. SLNPs in various formulations for oral administration (e. liposomes are rapidly cleared from the blood by mononuclear phagocytic system (MPS) [57] so various strategies to extend circulation were developed in the 1980s [178. Conjugating “stealth” material (e. and pulmonary administration routes [197–199].2.g.170]. which suggests that liposomal ciprofloxacin can be an effective therapy for systemic salmonella infection [189]. 3.g..195]. clotrimazole. Y. tissue 63–465 h) were obtained with liposomal amikacin [190]. Liposomal gentamicin and ceftazidime showed prolonged blood circulation and enhanced localization at the infection site [192]. and drugs for treating many different diseases [177]. is a fast-working antimicrobial agent against bacteria that are planktonically grown. ototoxicity. and high concentrations in the lungs was achieved after intravenous administration of tobramycin-encapsulating SLNPs. High area under curve (AUC).. minimized systemic side effects via targeted delivery of antimicrobial drugs as well as combined. In addition. in aqueous core and in the phospholipids bilayer. intracellular infections and acquired resistance of infectious microbes are also key challenges for many antimicrobial drugs [174]. Moreover..201–203]. while improving its antimicrobial activity [184]. and structural/functional versatility) and are a promising platform to overcome those limitations [173. When applied onto the skin. glycerol monooleate. refined soya sterols. capsules. PEG) on the surface of liposomes not only resulted in enhanced in vivo stability (i. Solid lipid (SL) NPs SLNPs offer combined advantages of traditional solid NPs and liposomes. has been limited due to its toxic side effects (e.g. an ATP-dependent efflux pump on the brush border of small intestine actively export the drugs. respectively [58. polyethylene glycol. Improved bioavailability and targeted delivery of antimicrobial drug using SLNPs have been investigated [196]. Ciprofloxacin in liposomal formulation was found to be rapidly cleared from the blood but the drug persisted in the liver and the spleen at least 48 h after the last administration. ocular. a mixture of BCTP and P10 liposomes (Tween 60. A high dosage of antimicrobial agents is immediately dumped into the bacteria when a liposome fuses with the cell membrane. Upon administration.. SLNPs are also a promising means for . disrupt the membranes of enveloped viruses and bacteria. Systemic administration of polymyxin B. and inactivate the spores of different Bacillus species [168]. A preliminary study showed that multiple daily inhaled doses of undiluted NB-401 were well tolerated in mice with no apparent pulmonary inflammation and toxic injury identified upon postmortem pathologic examination [164]. and neuromuscular blockade) [183]. while avoiding some of their disadvantages [194. Imaging infectious and inflammatory foci using radioactively labeled PEGylated liposomes was also demonstrated [180].. or in the sputum [164. in comparison with free drugs [187]. liposomes have been popularly studied as promising clinically acceptable delivery carriers of enzymes. which also markedly improved capability of crossing blood–brain barriers [197]. as a biofilm. low amounts trapped in the kidneys.to micro-sized vesicles comprising of a phospholipid bilayer with an aqueous core. lipid mixing assay. and the cationic cetylpyridinium chloride).2.183]. have unique physicochemical properties (e.g.172]. without chemical modifications. particle size and polydispersity.. P-glycoproteins (P-gp). and tri-n-butyl phosphate [65]. and effective formulation for treating acne vulgaris and other Propionibacterium acnes-associated diseases [186. and pellets) can also be used for antimicrobial drug delivery [204]. resulting in poor intestinal absorption of tobramycin [199]. and ticonazole) was reported by encapsulating them in SLNPs [173.g. oxiconazole. A number of parameters such as the physico-chemical properties of lipids. Liposomes are also the most widely used antimicrobial drug delivery vehicles [48. Aminoglycosides-loaded liposomes interact with the outer membrane of multidrug resistant P. nephrotoxicity. and immunocytochemistry [185]. topical. Liposomal carriers for antimicrobial drug delivery are summarized in Table 2. Formulation of polymyxin B in liposomes dramatically diminished side effects of the drug.2.178].179]. oral.179]..2. 3.1. Completely inhibited growth of S. miconazole. Liposomes for antimicrobial drug delivery Liposomes are nano.A. leading to the membrane deformation. aureus strain by benzyl penicillin-encapsulating cationic liposomes was reported at lower drug concentrations for shorter exposure times than when free drugs were used [188]. both hydrophilic and hydrophobic antimicrobial drugs can be encapsulated and retained. Tobramycinencapsulating SLNPs provided significantly higher bioavailability in the aqueous humor than standard eye drops [199] and may replace the advantages of subconjunctival injections for pseudomonal keratitis and preoperative prophylaxis. which eventually lowers administration frequency and dose [57.174.183]. Successful treatment of Mycobacterium aviuminfected mice by liposomal streptomycin was also demonstrated [191].175]. 3. large surface area to mass ratio. antibody segments. SLNPs tend to adhere to the surface and form a dense hydrophobic film [200] that is occlusive and affords a long residence time on the stratum corneum [201]. In addition. stability in storage (shelf-life). potentially outriding the efflux pumps and suppressing the drug resistance of microbes [173. proteins.g. a suboptimized therapeutic index and local/systemic adverse reactions need to be addressed in order to obtain maximized therapeutic effects [173]. tablets.58] because their lipid bilayer structure mimics the cell membrane and can readily fuse with infectious microbes [173]. which is effective in controlling infections by P. antibody. synergistic. Lauric acids loaded in liposomes can be an innate. NB-401. The drug stability and antimicrobial activity against Micrococcus luteus were shown to be greatly enhanced when ampicillin was loaded in liposomes.e. surface charge (zeta-potential). glyceryl behenate.g. prolonged ciprofloxacin release. Glycerol palmitostearate. Apt) are conjugated on the termini of PEG (e. high encapsulation efficiency. 1. EPC.J. SPC. enhanced drug penetration through stratum corneum Prolonged drug release Ref.g. Unlike liposomes and polymeric NPs. DSPG.J. hydrogenated soybean phosphatidyl choline. Intravenously injected colloidal drug carriers are undesirably taken up by the MPS.206]. Majority of polymeric NPs prepared with linear polymers are either nanocapsules or solid nanospheres [58]. Often targeting ligands (e. SLNPs are assumed to be phagocyted by alveolar macrophages in the lungs. stearic acid. SDC. PG. 1-2-disteroyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol-2000). soybean phosphatidyl choline. STC. have a high drug incorporation capability. and STC GB. ampicillin . surfactants. In polymeric nanocapsules. and poly(cyanoacrylate)(PCA). isoniazid. Table 2 summarizes SLNPs investigated for antimicrobial drug delivery. albumin and peptide hormones using poly[ethylene vinyl acetate] polymer) was demonstrated in 1976 [207–209].2-dipalmitoylphosphatidylcholine. partially hydrogenated egg phosphatidyl choline. and DC-Chol SA. poly(lactide-co-glycolide)(PLGA). SPC. Chol. GPS. and Chol SPC and Chol HS PC. aptamers. Chol. SA. diacetylphosphate. PHEPC. drugs are homogeneously distributed in the polymeric matrices of variable porosities in solid nanospheres [212. For example. These results propose a cost-effective and patient-friendly approach to obtain a high chemotherapeutic potential for tuberculosis treatment using antimicrobial drug-loaded SLNPs. and subsequently transported to the lymphoid tissues [196–198]. Two major types of polymeric NPs have been explored for antimicrobial drug delivery: linear polymers (e. size. DPPC.3. polyalkyl acrylates and polymethyl methacrylate) and amphiphilic block copolymers.g. sodium deoxycholate. high physical stability Increased drug bioavailability and residence time. It was demonstrated that lectin-conjugated gliadin NPs selectively adhered to the carbohydrate receptors on the surface of microbes.. such as Helicobacter pylori.2. targeted delivery to the site of bacterial multiplication Decreased mortality of animals.173]. decreased administration frequency Controlled drug release profile. and pyrazinamide-encapsulating SLNPs were nebulized to infected guinea pigs every 7 days. zeta-potentials. egg PC. inhalable SLNPs are stable.g. distearoyl phosphatidylglycerol. For example. isoniazid. and DSPG PHEPC. reduced renal clearance and excretion Increased survival rate of animal models. improving drug targeting and accumulation necessitates an alternative administration route such as pulmonary drug delivery [198]. cholesterol. increased bioavailability Lower drug concentrations and shorter time of exposure Increased drug bioavailability Prolonged drug release. pyrazinamide Econazole nitrate Staphylococcus aureus Pseudomonas aeruginosa fungi Mycobacterium tuberculosis Fungi [188] [199] [279] [196] [203] SA. enhanced intracellular antimicrobial effect Increased stability. Huh. PC. Y. and Chol Encapsulated antibiotics Streptomycin Target microorganism Mycobacterium avium Mechanism for improved therapeutic effects Increased antimicrobial activity by drug encapsulation.g. DCP. controlled drug release using biocompatible and biodegradable polymers further emerged in the 1980s and has been extensively investigated in the clinic for enhanced intracellular drug delivery and reduced rapid clearance by reticuloendothelial system (RES) [210]. PC. Gram-positive bacteria. no tubercle bacilli were detected in the lungs and spleens after rifampicin. poly(glycolic acid)(PGA). sodium taurocholate. Nanocarrier type Liposomes Composition PG. and released antimicrobial agents into the bacteria [211].. In contrast. including poly(lactic acid) (PLA).. and 3) facile and versatile surface functionalization for conjugating drugs and targeting ligands [57]. Polymeric NPs Shortly after the first polymer-based delivery of macromolecules (e. Kwon / Journal of Controlled Release 156 (2011) 128–145 Table 2 Lipid-based nanocarriers for antimicrobial drug delivery.. Antimicrobial drug delivery using polymeric NPs offers several advantages: 1) structural stability in biological fluids and under harsh and various conditions for preparation (e. and SDC SA GPS Benzyl penicillin Tobramycin Ketoconazole Rifampicin. activity against extracellular bacterial colonies Prolonged drug residence in tissue and plasma.215]. has been used as hydrophobic segments (forming drug-encapsulating core for controlled drug release) of the amphilphilic copolymers. Chol. PEGDSPE. whereas PEG has been most commonly used as a hydrophilic segment [173].g. HSPC. Amphiphilic block copolymers spontaneously self-assemble micellar NPs with the drugencapsulating hydrophobic core and the hydrophilic corona shielding the core from opsonization and degradation [214. A library of biodegradable polymers. [191] DPPC and Chol EPC. spray drying and ultra- fine milling) and storage. GB.136 A. a polymeric membrane that controls the release rate surrounds the drugs that are solubilized in aqueous or oily solvents.213]. 2) precisely tunable properties (e. and PEG-DSPE DPPC and Chol Ciprofloxacin Vancomycin or Teicoplanin Ampicillin Amikacin Gentamicin Polymyxin B Salmonella dubli MRSA Micrococcus luteus and Salmonella typhimurium Gram-negative bacteria Klebsiella pneumoniae Pseudomonas aeruginosa [189] [193] [187] [190] [278] [183] Solid lipid NPs DPPC. and drug release profiles) by manipulating polymer lengths. DC-Chol. and mycoplasma [205] Abbreviations Chol. PLGA-b-PEGb-Apt) for selective delivery [216. whereas daily oral administrations of the free drugs for the same period were required in order to obtain equivalent therapeutic effects [196. DCP. Polymeric NPs have been explored to deliver various antimicrobial agents and greatly enhanced therapeutic efficacy in treating many types of infectious diseases has been reported. and STC Ciprofloxacin hydrochloride Gram-negative bacteria. dimethylammonium ethane carbamoyl cholesterol. poly(ε-carprolactone) (PCL). and offer a significantly reduced risk of retaining residual organic solvents [195]. phosphatidyl glycerol.. and organic solvents used for NP preparation [48. decreased lung injury caused by bacteria. therefore. particularly in ocular and skin infections via local delivery [205]. 3. distribution of liposomes to all areas of infection Enhanced drug uptake by macrophages.217]. SPC. increased therapeutic efficacy Decreased bacterial colony count in lung. phosphatidyl choline.. Solubilization and controlled delivery of a hydrophobic antimalarial drug. Sulfamethoxazole (SMZ)-encapsulating PAMAM dendrimers led to sustained release of the drug in vitro and 4–8 folds increased antibacterial activity against E. poly(ε-carprolactone).or hydroxyl-terminated PAMAM dendrimers. which are synthesized in a layer-bylayer fashion around a core unit. was able to retain its full antimicrobial activity against MRSA even in the presence of β-lactamase at high concentrations [19. Meanwhile. [218] [219] [280] [223] [22] GPAA Dendrimers PAMAM PLCP PAMAM N-sec-butylthio β-lactam. generating not only excellent solubility but also similar or increased antibacterial activity [228]. monocytogenes infection in mouse peritoneal macrophages was reported by using ampicillin-encapsulating NPs [219]. which are unstable or inadequately absorbed in the gastrointestinal tract. Directly destroying the cell membrane of microorganisms or disrupting multivalent binding interactions between microorganism and host cell are the primary mechanisms of antimicrobial action of dendrimer biocides [229]. Carboxylic. which is known as antimicrobials. Many other antimicrobial drugs have been successfully incorporated into dendrimer NPs for improved solubility and. Translation of nanoantibiotics from bench to bedside 4. glycosylated polyacrylate. branching points (drug conjugation capability). GPAA. enhanced anti-MRSA activity by PAA NPs' anti-MRSA activity Improved antibacterial properties against MSSA and MRSA by the protection of the drug from enzymatic degradation and enhanced delivery of the PAA-bound antibiotics to the bacteria Improved bioavailability.4.2. . N-thiolated β-lactam antibiotics covalently conjugated onto the polymer network of polyacrylate NPs demonstrated potent antibacterial properties against MRSA with improved bioactivity relative to the free drug [223]. Pseudomonas aeruginosa. Ultrasonic autography confirmed that the NPs readily diffused through the membrane of a human cell and acted on the cell wall of intracellular bacterial parasites [220]. compared to free SMZ [230]. prolonged circulation half -life Ref. therapeutic efficacy (Table 3). 3. In addition. The highlybranched nature of dendrimers provides enormous surface area to size ratios that generate great reactivity to microorganisms in vivo [173]. higher therapeutic efficacy by the antibiotics-conjugated with GPAA High payload. Penicillin incorporated in the polyacrylate NPs.229]. There have been efforts to overcome the limited oral administration of the drugs. coli. Y. Huh. hence. increased cellular drug uptake by macrophages.. and surface functionality [225]. PAA. using polyethylcyanoacrylate (PECA) NPs [221]. Antimicrobial Table 3 Polymer-based nanocarriers for antimicrobial drug delivery. PLCP. Nanocarrier type Solid NPs Polymer Encapsulated antibiotics PIHCA PIHCA PCL PAA PAA Ampicillin Ampicillin Amphotericin B N-methylthiolated β-lactams Penicillin Target microorganism Salmonella typhimurium Listeria monocytogenes Leishmania donovani MRSA MSSA and MRSA Mechanism for improved therapeutic effects Increased drug concentration in liver and spleen.A. enhanced solubility. which prevents their liquid formulations and restricts their use in topical application [225]. Kwon / Journal of Controlled Release 156 (2011) 128–145 137 encapsulated in poly(isohexyl cyanoacrylate) (PIHCA) NPs resulted in 120-fold enhanced efficacy in treating Salmonella typhimurium infections in mice [218]. The highly dense surface of functional groups allows the synthesis of dendrimers with specific and high binding affinities to a wide variety of viral and bacterial receptors [227]. polyamidoamine. polyisohexylcyanoacrylate. Cyanoacrylate NPs and their antimicrobial therapeutic potentials with a variety of antibiotics are well-documented [212]. and rendered mucoadhesivei capabilities [222]. ergosterol) Enhanced activity for water-insoluble drug conjugated with PAA. Both hydrophobic and hydrophilic drugs can be loaded/conjugated/adsorbed inside empty internal cavities in the core and on the multivalent surfaces of dendrimers. respectively [228]. which were prepared by free radical emulsion polymerization in water. 4. Staphylococcus aureus and Bacillus Ciprofloxacin anthracis Silver salts Staphylococcus aureus. PAMAM. efficiently controlled intracellular L. can be easily conjugated with antimicrobial agents via abundant functional groups [58. on the surface at a high density displayed greater antibacterial activity than free antibiotics [173. and Escherichia coli Artemether Plasmodium falciparum Sulfamethoxazole Escherichia coli [213] [239] PAMAM Nadifloxacin and Prulifloxacin Escherichia coli Increased drug stability. which appear to be more biocompatible and less toxic than unmodified ones. PAMAM dendrimer is a promising drug delivery carrier but its cytotoxicity because of amine-terminated nature has been a limiting factor for clinical use [58]. pegylated lysine based copolymeric dendrimer.227].J. Advantages of nanoantibiotics The use of NPs as delivery vehicles for antimicrobial agents suggests a new and promising paradigm in the design of effective therapeutics against many pathogenic bacteria [13]. the dendrimers functionalized with quaternary ammonium. Polyamidoamine (PAMAM) is the initial and most commonly studied dendrimer and also a variety of dendritic building blocks have become exponentially available [226]. were also achieved using PEGylated lysine-based dendrimers [231]. were loaded in PAMAM dendrimers. the cationic and hydrophilic gentamicin entrapped in the PLA/PLGA NPs showed good antimicrobial activity against intracellular Brucella infection due to their suitable size for phagocytosis [224].e. In addition. assisted by surface amine groups at a high density Improved water solubility with strong antimicrobial activity via [228] enhanced penetration of antibiotics through the bacterial membrane Abbreviations PIHCA. prolonged drug [231] circulation half-life Sustained drug release.1.48]. decreased mortality in animal model Increased activity of antibiotics inside phagocytes by efficient intracellular release of antibiotics Greater therapeutic efficacy by improved availability of the drug interacting with target membrane molecules (i. Aqueous insoluble quinolones.J. Similarly. dramatically increased the half-life in serum. artemether. PCL. PEGylation of PECA NPs reduced phagocytosis. Polymeric NPs for antimicrobial drug delivery are summarized in Table 3. polyacrylate. resulting in a high level control of size. increased antibacterial activity via enhanced [230] penetration of antibiotics through the bacterial membrane. Dendrimers Dendrimers are hyperbranched polymers with precise nanoarchitecture and low polydispersity. For example. some classes of NPs can affect the circulatory system by altering heart rate [245] as well as reproductive system by increased detachment of seminiferous epithelium [246] and possible spermatotoxicity [240. Fourth. blood.239]. The toxic effects of antimicrobial NPs on central nervous system (CNS) are still unknown.2. and overexpression of efflux pumps [174. vancomycin-capped Au NPs (Au@Van NPs) exhibited 64-fold improved efficacy against VRE strains and Gram-negative bacteria such as E.g. Mn2O3 30 nm. Inhaled NPs also can enter the systemic circulation and reach lung. tissues.. and glycolysis. 80. These include thoroughly evaluating the in- teractions of nanoantibiotics with cells. NPs exhibit size-specific properties that limit the use of currently available in vitro assays in a universal way. contributing to hepatotoxicity and nephrotoxicity [244]. Potential toxicity of nanoantibiotics to human health is not known much at the moment although it likely shares the nanotoxicity of various non-antibiotic nanomaterials [240. heart. and concurrent delivery of multiple agents for synergistic antimicrobial therapy [173. Antimicrobial NPs Advantage Targeted drug delivery via specific accumulation Lowered side effects of chemical antimicrobials Low antimicrobial resistance Extended therapeutic lifetime due to slow elimination Controlled drug release Broad therapeutic index Improved solubility Low immunosuppression Low cost Accumulation of intravenously injected nanomaterials in tissues and organs High systemic exposure to locally administrated drugs Nanotoxicity (lung. etc. Various metabolic changes suggest mitochondrial failure. there are foreseeable challenges in translating this exciting technology for clinical use. Disadvantages of nanoantibiotics. liver.J.3. germ cell. antimicrobial NPs can be prepared and administered in convenient and cost-effective ways via various routes with lowered administration frequency [11]. genetic polymorphisms. For example.g. Table 5 presents potential multiorgan nanotoxicity that has been implicated to be generated by therapeutically used antimicrobial NPs. enhancing the overall pharmacokinetics [173]. lung. Generally.. administration of antimicrobial agents using NPs can improve therapeutic index. In addition. This means that there is a high demand to develop new characterization techniques that are not affected by NP properties as well as biological media [243]. 4. and brain [240.232]. and enhanced ketogenesis.J.g. BBB) [235].138 A.e. number. For another example. 155 nm. bone marrow. and inside organs) [241. amoxicillin was freeze-dried in formulation with chitosan and polyvinyl pyrrolidone for acid-responsive release of antibiotics [234]. Kwon / Journal of Controlled Release 156 (2011) 128–145 NPs propose several clinical advantages. Thus.. liver. 13 C NPs 36 nm) were capable of efficiently targeting infectious diseases by overcoming anatomic barriers (e. heat. fatty acid βoxidation.175]. which consequently recalibrates doses and identifies proper administration routs to obtain desired therapeutic effects [232. coli K12 [238]. Y. Huh. and pH) for targeted delivery as well as biological sensors [232. However. and there is no standardized definition for NP dose in mass. brain.247].. which is particularly facilitated for small size NPs because of efficient cellular uptake and transcytosis across epithelial and endothelial cells into blood and lymph circulation [59]. and lymphatics [241]. chemical. This system could be particularly useful for treating abscess which is frequently acidic and reduces the potency of conventional antimicrobial therapy. Profound knowledge about the potential toxicity of nanoantibiotics is also required to warrant successful clinical translation [240].242]. nanocarriers can be engineered to be activated by stimuli (e.. including nanotoxicology Although nanoantibiotics promises significant benefits and advances in addressing the key hurdles in treating infectious disease. proteomics and metabonomics). and biological specimens (e.. spleen. kidney. metabolic.. in particular the decreased susceptibility by halted division. One alternative antimicrobial drug delivery Table 4 Advantages and disadvantages of antimicrobial NPs over free antimicrobial agents. a tight barrier to protect the brain from the penetration of xenobiotics. prolong drug circulation (i. extended half-life). NP-based antimicrobial drug delivery is promising in overcoming resistance to traditional antibiotics developed by many pathogenic bacteria [13]. Besides. It has been shown that intravenously injected NPs can be accumulated in colon. Nanocarriers seem to be able to reduce the side effects by improving the solubility and stability of antimicrobial agents [173. liver. Fe2O3 280 nm. and ototoxicity and nephrotoxicity of aminoglycosides) [236]. mesoporous silica NPs were used as controlled release ionic liquids with proven bactericidal efficacy against E. magnetic field.237]. urine.248]. and the interactions of NPs with the cells and tissues in CNS are poorly understood [235]. coli over vancomycin alone [45].244]. and organs. hepatotoxicity of cephalosporins. Treatment of drug-resistant microorganisms and biofilms Antimicrobial resistance to classical antibiotics is attributed to the altered bacterial growth phase. spleen. coupled with other emerging technologies (e. TiO2 25. and achieve controlled drug release. Many recent studies suggest the possibility of multi-organ nanotoxicity that therapeutically administered antimicrobial NPs may generate. antimicrobial NPs are of great interest as they provide a number of benefits over free antimicrobial agents (Table 4). could reveal the mechanisms of NPs' toxic action at a molecular and genomic level [242].233]. Toxicogenomics.242]. NP-based antimicrobial drug delivery can achieve improved solubility and suspension of drugs. surface area. First. free radical-mediated oxidative stress generated by the interaction of antimicrobial NPs with cells may result in hepatotoxicity and pulmonary toxicity [243.g. Third. NPs can be molecularly tailored for versatile physico-chemical properties in order to minimize side effects generated upon systemic administration of traditional antimicrobial agents (e.g.) Lack of characterization techniques that are not affected by NPs' properties Free antimicrobial agents Disadvantage No specific accumulation High side effects of chemical antimicrobials High antimicrobial resistance Short half life due to fast elimination Usual pharmacokinetics of free drugs Narrow therapeutic index Sometimes poor solubility Immunosuppression High cost Absence of nanomaterials in the whole body Low systemic exposure to locally administrated drugs Absence of nanotoxicity Well-established characterization techniques Disadvantage Advantage . most molecules poorly cross the blood brain barriers (BBB). For example. Many studies demonstrated greater efficacy of antimicrobial NPs than their constituent antibiotics alone [236]. it was also reported that antimicrobial NPs made of certain materials and at varying particle sizes (e.g. 4. Second. monocytogenes [254]. Alternatively.A. C. pneumoniae. NGF nerve growth factor. while minimizing systemic adverse effects [258. intracellulary survive or multiply. mitochondrial failure.and nanoemulsions with antimicrobial properties might be effective anti-biofilm agents. Some micro. A folic acidtagged chitosan NPs loaded with vancomycin were found to be an effective drug delivery carrier for VRSA treatment [15]. including drastically reduced mitochondrial function. E. diminished ability to form neuritis in response to NGF.J. if feasible. parital vacuolation of seminiferous tubules and cellular adhesion of seminiferous epithelium.258]. and multidrug-resistant P. However. Huh. Tween 80. oxidative stress Renal glomerulus swelling. Ag NPs) is also a promising approach to improve antimicrobial activity and potentially overcome resistance to the current antibiotics.263]. a common cause of recurring infections. local antibiotics delivery to the lung via inhalation can avoid drug loss and alteration by metabolism and enzymes in the gut and liver. especially intracellular infections. typhimurium. granuloma formation.5. Assessing the respiratory toxicity of inhaled pharmaceuticals is greatly affected by 4. Toxicity type Pulmonary toxicity Renal toxicity Hepatotoxicity Neurotoxicity Spermatotoxicity NP-protein interactions Mechanism for toxicity Acute inflammatory change. aeruginosa or L. local administrations. strategy to overcome antibiotics-resistance is to incorporate more than one antimicrobial agent in the same NPs for concurrent delivery [173]. Recently. A similar result has been reported for ciprofloxacin-coated Au NPs [251]. Y. also showed anti-biofilm activities against food pathogens such as E. are the ideal mode of antimicrobial drug administration. For example. L. mild cognitive impairment. using NPs is an exciting prospect in treating infectious diseases [38. monocytogenes [256] A study reported that BCTP has higher activity against the biofilms of S. In addition. spleen. such . followed by releasing the payloads to eliminate intracellular microbes [174. and L. and ampicillin against Gram-positive and Gramnegative bacteria were increased in the presence of Ag NPs [249]. fatty acid beta-oxidation. various NPs displaying preferential accumulation in the lung and other organs have been attempted [210. LDH leakage Reduced neuro viabilities. and optimized low-density microstructure for delivery to the peripheral lung [58. both low.and teicoplanin-encapsulating liposomes.223]. tuberculosis. Recently. aeruginosa [254] which are common nosocomial pathogens and very difficult to eliminate. GSH depletion. upon long-term exposure [240]. as M. It is highly foreseeable that the use of NP-based drug delivery systems will continue to improve treating bacterial infections. In contrast. increased membrane leakage. and central nervous system. kanamycin..g. encapsulated in a micellar nonionic surfactant solution. bone. especially when forming biofilms [255]. and S. Antibioticsloaded NPs can enter host cells through endocytosis. Intracellular microorganisms. Vancomycin-capped gold NPs (Au@Van) were demonstrated to enhance antibacterial activity against VRE in vitro [45].213. and are resistant to the antimicrobial agents [257]. NPs may have adverse effects on respiratory mucosa. VRE. coli O157:H7. Combining antibiotics and antimicrobial NPs (e. VRSA. It was reported that intratracheally administered antibioticsloaded NPs were able to penetrate through the alveolar-capillary barrier into the systemic circulation and accumulate in extrapulmonary organs including liver.263]. Benzyl penicillin-encapsulating cationic liposomes and NO-releasing silica NPs showed antimicrobial and antibiofilm activities [156. are not responsive to antimicrobial drugs [188]. It was shown that vancomycin-encapsulating cationic liposomes have strong affinity to biofilms and efficiently penetrated into the skin layers [253].281] [244] [244] [235. coli O157:H7 and L. the antibacterial activities of chloramphenicol.240] Others [240. 139 [243. two essential oil compounds. In addition to vancomycin. lactic dehydrogenase. Local administration Antibiotics are generally administered via oral or intravenous routes in order to treat infections. ciprofloxacin-loaded.188]. Bacterial biofilms. magnesium fluoride (MgF2) NPs prepared by microwave-assisted MgF2 coating on the glass surfaces prevented the formation of bacterial biofilms [252]. NPs can be formulated for enhanced suspension of waterinsoluble drugs.193]. erythromycin. exacerbation of cytoskeletal and blood-brain barrier (BBB) disruption. necrosis/apoptosis induction.193. Delivery of antimicrobial agents to the lung via systemic NP administration is invasive and potentially harmful upon systemic exposure to the drugs [39]. n-pentanol) were highly effective in eradicating biofilms of MRSA and P.262].4. mitochondrial dysfunction. are taken up by alveolar macrophages (AMs). aeruginosa. Kwon / Journal of Controlled Release 156 (2011) 128–145 Table 5 Potential toxicity of therapeutically used NPs. proximal tubular necrosis. 4. antibioticsconjugated polyacrylate and carbohydrate NPs showed potent antibacterial properties against MRSA [22. raising protein potential for autoimmune effects Embryo neurotoxicity. the low endocytic capacity of non-MPS cells interferes with targeted antimicrobial drug delivery to the cells that are intracellulary infected [174]. better control of the drug morphology than in a dry powder form. For example. monocytogenes. aureus than those P. Targeted therapy for infections using NPs Targeted antimicrobial drug delivery to the site of infection. it was found that BCTP and TEOP (O/W microemulsion of ethyl oleate. the toxicity caused by high local drug concentration should be evaluated. LDH. The delivery to infected non-MPS tissue was improved with MPS-avoiding liposomes or stealth liposomes [176]. metabolic alkalosis Ref. For example. It was also reported that the antibacterial activity of cefoperazone against MRSA was enhanced when it was used with colloidal silver [250]. enhanced ketogenesis.246] Abbreviations GSH. edema formation Sperm fragmentation. Therefore. and glycolysis ROS generation. Further enhanced targeted antimicrobial drug delivery to AMs has been explored by tethering the surface of NPs to bind to mannose receptors which are highly expressed in AMs [260]. suppressed proliferation of Leydig cell Abnormal protein functions generated by structural and conformational changes upon adsorption to NPs.and high-molecular weight drugs can be selectively delivered to nasal epithelia and the lung using NP delivery platforms [264]. cardiovascular system. especially by MRSA. embryo death. Other in vivo studies reported substantially higher AM-targeted antimicrobial drug delivery than alveolar epithelial type II cells using mannose-coated liposomes [261.J.173]. pneumophila. glutathione. and inflammation in the lung. Carvacrol and eugenol.247] [237. and kidney [259]. often resulting in undesired systemic side effects by nonspecific drug distributions in many different tissues and organs. mannose-conjugated liposomes led to efficient drug targeting to AMs by pulmonary administration [257].240] [246. J. and immune response needs to be fully elucidated in order to achieve efficient and safe treatment of pulmonary infections. S. A.. Pramanik. Lancet 377 (2011) 9782. Concluding remarks For more than a half century antibiotics have been saving an enormous number of lives from many infectious diseases. “nanoantibiotics” strategies to develop efficient. D. including PLA and/or PGA and their variants [268.. Appl. Med. using NPs as antibiotics carriers seems to hold highest promise. 335 (1996) 1445–1453.W. Adv. such as NPbased dressings. there are very little data on the clinical applications and toxicity of NPs as antibiotics themselves and carriers of antimicrobial drugs. T. Antibiotics encapsulated in SLNPs produced significantly lower ocular irritation than most antimicrobial drugs are known to cause [174]. South. no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. [10] S. S. including silicate-based bioactive glass and calcium phosphate-based materials (e. [3] C. H. Boucher. synthetic hydroxyapatite and tricalcium phosphate). coli outbreak. [15] S. J. J. Germany reels in the wake of E. which is 100 times higher than the minimum inhibitory concentration (MIC) of pefloxacin for MRSA. mucociliary clearance. C. Agents Chemother. Rice. Molecular mechanisms that confer antibacterial drug resistance. Soc. Y. Bioconjug. L. 15 (2004) 897–900. bronchoalveolar lavage. D. compared to cancer. which has been attempted by pharmaceutical companies. R. Yilmaz.H. Microbiol. toxicology.140 A. For example. Kwon / Journal of Controlled Release 156 (2011) 128–145 the nature of the administered materials [265]. Périchon. Antimicrobial-drug resistance. reaching the drug concentration peak. coli outbreak. using several FDA-approved biodegradable polymers. Various NPs have been investigated as efficient antibiotics delivery vehicles which also protect antimicrobial drugs from a resistant mechanism in a target microbe (e. BMJ 14 (2011) 342.K. and high drug encapsulation efficiency [275. Nature 406 (2000) 775–781.C. Silver nanoparticles as a new generation of antimicrobials. Nanoconjugated vancomycin: new opportunities for the development of anti-VRSA agents. Environ. J.P. [14] R. At the moment. Prolonged and controlled release of antibiotics can be achieved. Microbiol.K. Ren. Luzio. and nanolotions. pharmacology. Talyor.M. and nanotechnology. pathology. Temperature-responsive polymers are attractive for the injectable antimicrobial drug delivery because of the minimally invasive administration. Goodman.M. P. Biodegradable carriers have also recently been introduced in orthopedic surgery for prophylaxis of postoperative osteomyelitis and treatment of chronic osteomyelitis [268]. Bean sprouts are identified as cause of E. Pal. A.J. nanogels. declining sensitivities. [21] R. and targeted therapy for infectious diseases in antibiotics resistant era require interdisciplinary knowledge and tools of microbiology.B. Spellberg. N. sputum cytology. McCusker. G. [18] F.276]. The field of nanomaterial-based or assisted antibiotics (“nanoantibiotics”) is barely in its infancy. Acknowledgment The authors thank Kellie Komoda (UC Irvine) for proofreading the manuscript. Dis. easy preparation without using harmful organic solvents.265].J. safe. Walsh. Rotello. and enzyme and mediators). and evaluations on pulmonary function.D. Clinical impact of antibiotic-resistant gram-positive pathogens. it was demonstrated that teicoplanin-loaded borate bioactive glass and chitosan (TBGC) implants treated chronic osteomyelitis in rabbit. Science 321 (2008) 356–361. Bodewaldt. [7] M. Taubes. Microbiol. V. Respir. It becomes clear that overcoming antibiotic resistance by developing more powerful antibiotics. NPs themselves have been employed as potent antimicrobial agents for a variety of medical applications. aeruginosa reduced bacterial counts more significantly and for a longer period than the free antibiotics [267].M. Bartlett. can lead to an only limited and temporary success and eventually contribute to developing greater resistance. F. Lode. [8] C. Scheld. Physiol. Trop. for treatment of ‘resistant’ pseudomonal keratitis.K. mucociliary clearance. Trans. while simultaneously playing roles in bone regeneration [274].S. Stapleton. Most importantly. not only locally deliver antibiotics but also contribute to the bone regeneration process. Analyst 133 (2008) 835–845.205]. Toxicity of gold nanoparticles functionalized with cationic and anionic side chains. Opin. Chakraborty.. Bal. As briefly introduced in this review. Biotechnol. Antimicrob. Hamm. Korting. providing sustained and high antibiotics release rates [273].201. 53 (11) (2009) 4580–4587. [19] Eurosurveillance editorial team. was demonstrated in the rat skinabscess. and completely eradicated the bacteria in the MRSA osteomyelitis in rabbits [269]. Rice. 16 (23) (2011) 19886. Engl. High local therapeutic efficacy by septacin. NP-coated medical devices. Infect.P. a gentamicin sulfatecontaining polyanhydride implant.L-dilactide achieved sustained drug release of pefloxacin.266]. Of many different approaches to overcome antimicrobial resistance. Gade.S. Clin. . Emerging gram-negative antibiotic resistance: daunting challenges. Today 7 (21) (2002) 1086–1091. J. Regan. B. [12] R. Lawlor. 88 (8) (1995) 797–804.g. Berkowitz. M. Antibiotic resistance in bacteria. [11] E. and infections in human prosthetic hip and knee joint [272].W. Nature 406 (2000) 762–767. 27 (6) (2007) 1712–1720. 17 (2004) 31–36. Infect. In contrast to PLA/PGA. 27 (2009) 76–83. in order to enhance antimicrobial activity and overcome resistance to antibiotics. R. Chem. Siegel. Tak. Among many currently available methods (e. bronchoalveolar lavage coupled with biochemical analysis is regarded as a proper way of assessment for the respiratory toxicity of NPs [133. Nanotechnology 21 (2010) 1–9. Susmita. Allaker.C. 15 (3) (2009) 212–217. histopathology of lung sections. immunology.E. P. Yadav. immune response. Several types of bioceramics.g. [6] P. 5. Gilbert. Courvalin. P. VanA-type vancomycin-resistant Staphylococcus aureus. Rai.D.L. cost-effective. Bradley. Laude. Hyde. NPs enable combining multiple independent and potentially synergistic approaches on the same platform. Euro Surveill.g. 102 (1) (2008) 1–2. J. [16] B. Care 53 (4) (2008) 471–479.and cardiovascular diseases-targeted nanomedicine. Moellering. Weir. The use of nanoparticles in anti-microbial materials and their characterization. Med. S. Whelan. [9] M. A. Gold. J. Roy.270. The local delivery of tobramycin-encapsulating liposomes to surgical wound infections in soft tissue by P. [17] H. H. References [1] M. Drug Discov.271]. polymers. Clin. horse-joint infections. Song. J.P. Changing patterns of infectious disease. without surgical removal. Antibiotics-loaded SLNPs were explored to treat ocular infections by intravitreously administering antimicrobial drugs for sustained drug release at a high drug concentration [199. nanomaterials are promising antimicrobial agents of a new class. [5] L. Talbot. Huh. Skin Pharmacol. Preliminary clinical studies indicated that intravitreal injection of antibioticsencapsulating liposomes and SLNPs can be more advantageous than using free drugs. Because of high surface area to volume ratio and unique physicochemical properties. M. 48 (2009) 1–12. The clinical consequences of antimicrobial resistance. or for preoperative prophylaxis against endophthalmitis [199. Schaller. S. and dire consequences. Toxicity and antimicrobial activity of a hydrocolloid dressing containing silver particles in an ex vivo model of cutaneous infection. An in vivo study showed treatment of osteomyelitis in rabbits via sustained release of teicoplanin from biodegradable thermosensitive PEG-PLGA hydrogel NPs [277].B. A. Curr. biomaterials. How various antimicrobial NPs and antimicrobial drug carriers affect the respiratory function.. Tuffs. Mahapatra. [2] H. Y. the emergence of resistance to antibiotics acquired by microbial variants is a serious threat in combating against infectious diseases. The bacteria fight back. For example. [13] G. 12 (2009) 476–481. New ways to treat bacterial infections.E.E. degradation by βlactamases). [20] A. poly (trimethylene carbonate) (PTMC) generate non-acidic products after uniform surface erosion by enzymatic degradation. Med. information resources and latest news about the Shiga toxin-producing Escherichia coli (STEC) outbreak in Germany available from ECDC. However. Potential impact of nanotechnology on the control of infectious disease. Cohen. Hyg. [4] H. Sahu. Dose the antibacterial activity of silver nanoparticles depend on the shape of the nanoparticle? A study of the gram-negative bacterium Escherichia coli. Bad bugs. G.M. Edwards Jr. G. E. Venketesan. D. D. Bradford. Basu.J.M. Biomacromolecules 4 (6) (2003) 1457–1465.A. Li. J. [58] A. Leung.L. Myers. Nanostructures in biodiagnostics.A. M. Balaji.F. [25] C. B. R. Polymeric particles in vaccine delivery. Res. Bagwe. Ed Engl. A. Synergism between natural products and antibiotics against infectious diseases.B. R. Y. Proc. R. Minaian. Landers. M. Klasen. W. Panzner.S. Emerging nanotechnology-based strategies for the identification of microbial pathogenesis. Badawy.D. 62 (2010) 560–575. Agents Chemother. Int. Huang. Jain. Colloid Interface Sci. 62 (2006) 58–63. X. A. de la Escosura-Muñiz. Sharma. M. [45] H. Sci. Pugia. Wang.L. Smith. S..P. R. Lett. X.V. Microbiol. Somerfield. Basu. Lin. K. Lee.S. Leaper. Jang. J. D.V. Chen. M. Dzioba. J. D. Rev. Olszewski. Drug Deliv. Antimicrobial effect of surgical masks coated with nanoparticles. Y.S. A. Lim. Sharp. Chen. Biophys. C.R. 54 (2004) 1019–1024. [67] Y. A nanochannel/nanoparticle-based filtering and sensing platform for direct detection of a cancer biomarker in blood. J. J. A. X. [49] L. Ho. Ip. D.H. Sastry. Hemaiswarya. [70] V. Young. [73] I. Turos. H. Ramaraju. Tech. Bandyopadhyay. Rosi. [40] M.L. Doble.Y. Presenting vancomycin on nanoparticles to enhance antimicrobial activities. Tong. Expert Opin. Extracellular synthesis of silver bionanoparticles from Aspergillus clavatus and its antimicrobial activity against MRSA and MRSE. Lefave.L. J. Mosqueira. Sower. Acad. Appl.Y. S. S. Kaittanis. Arenas-Gamboa. D. Nano Lett. nanoparticle-mediated bacterial detection with magnetic relaxation.E. E. [72] F.D.D. B. Zheng. Turos. Y. Ditto. Abeylath. W. Shahverdi. Jin. Infect. Furno. Liga. J.M. P. 68 (2009) 278–283. [43] Q. Chem. Biotechnol. M. Tan. Lim. Application of nanotechnologies for improved immune response against infectious diseases in the developing world. G. Naser.J. Drug Deliv.S. Tascon. V. M. Kaittanis. Blake. J. D. Nanda. [29] N. Historical review of the use of silver in the treatment of burns. Legace.N. D. S. Medvetz. Colloid Interface Sci. J.K. L. Kukowska-Latallo.W. Greenhalgh. Balaji. Small 5 (1) (2009) 51–56. Kötz. Richardson. M. Prabhakar. Biogenic synthesis of silver nanoparticles and their synergistic effect with antibiotics: a study against gram-positive and gram-negative bacteria. J.P. [60] A. [46] V. Angew. Rev. [69] W. Hosp. Kim. Chem. N. 53 (11) (2007) 2002–2007. J.S.G. Natl. Dibrov. C. Wang. Langmuir 24 (8) (2008) 4140–4144. S.C. Biomaterials 30 (2009) 3771–3779. Clement-Major. 5 (9) (2008) 931–949.P. Microbiol. Rev. A. S. Galanzha. Y. Drug delivery approaches to overcome bacterial resistance to β-lactam antibiotics. [65] P. Song. Silver nanoparticles as antimicrobial agent: a case study on E. Abeylath.J. [79] Y. Zharov. Bayston. Y. Hovis. characterization and evaluation of a biopolymeric gold nanocomposite with antimicrobial activity. D.G. [47] V. Hu. Microbiol. Rev. E. Mühling.P. [68] M. Adv.M. Photothermal antimicrobial nanotherapy and nanodiagnostics with self-assembling carbon nanotube clusters. Nanomedicine 5 (4) (2009) 452–456. Alvarez. Y. Med. Wound J. Adv. Q.J. A. Chang. The antimicrobial efficacy of sustained release silver-carbene complex-loaded L-tyrosine polyphosphate nanoparticles: Characterization. J. Baker Jr. Mater. 59 (2007) 587–590. Greenhalgh.A. Maness. J. Suresh Kumar Reddy. [76] F. Bielinska. 75 (8) (2007) 4020–4029. Kumar. Colston. [48] S.P. T. R. P. Nanomedicine 6 (2010) 103–109. Med. Berkland.M. Colloids Surf. Antibacterial activities of zinc oxide nanoparticles against Escherichia coli O157:H7.C. Kalaichelvan. Rhee. Lett. Venkataraman. Silver nanoparticles and polymeric medical devices: a new approach to prevention of infection? J. 101 (1) (2004) 129–134. Huang. E.A. J. Cordna. U. Drug Deliv. R. Y. Janczak. 105 (2005) 1547–1562. Bioorg. G. 12 (5) (2007) 051503. Sci. Yao. Shashkov. J.J. Fayaz. Landers.J. Sturm. Girilal.U. Youngs. 42 (2008) 4591–4602. Kuk.U.R. Fahmy. Chiappetta. The increasing use of silver-based products as antimicrobial agents: a useful development or a cause for concern? J. Opin. Kruthiventi. Antibiotic-conjugated polyacrylate nanoparticles: new opportunities for development of anti-MRSA agents. Yu. Burns 26 (2000) 117–130. Nanomedicine 3 (2007) 95–101. Development of immune response that protects mice from viral pneumonitis after a single intranasal immunization with influenza A virus and nanoemulsion. Environ. S. M. Kim. J. Chemother. Phytomedicine 15 (2008) 639–652. [42] P.V. Deshpande.S. Macromol. S. Santos-Magalhães. Y. Nanoparticles in energy technology: examples from electrochemistry and catalysis. A.H. [44] E. 40 (1996) 665–669. Glycoconj. Drug Deliv. [56] H.Q. P. 13 (1) (2010) 106–112. [37] C. W. [35] Y. Yan. Miller. Jin.K. 44 (2005) 2190–2209. Holmes. A. Mucosal immunization with a novel nanoemulsion-based recombinant anthrax protective vaccine protects against Bacillus anthracis spore challenge. Dickey. Appl. 62 (2010) 547–559. Hu. B Biointerfaces 77 (2010) 214–218. D. J. [75] A.S. P. pathogens. Leonard. Alper.J. Mirkin. 62 (4–5) (2010) 408–423. Rabea.R. Synthesis and effect of silver nanoparticles on the antibacterial activity of different antibiotics against Staphylococcus aureus and Escherichia coli. 39 (2007) 622–634. 65 (9) (1999) 4094–4098. Mustapha. Antimycobacterial immunity induced by a single injection of M. C.C. Brown. K. 275 (2004) 177–182. [63] J. Antimicrobial effects of silver nanoparticles. 46 (8) (2002) 2668–2670.D. A. X. S. M. [64] M. M. Mercer. Silver dressings: their role in wound management. S. M. New old challenges in tuberculosis: potentially effective nanotechnologies in drug delivery. J..K. [39] E.D. Rajasab. Int.M. Peek. Immun. Santra. Silver nanoparticles: green synthesis and their antimicrobial activities. C. L.R. Shahverdi. Li. H. Jiang. J.M.D. Zhao. Look. Chamundeeswari. Steurbaut.S. Shashkov.A. B Biointerfaces 68 (2009) 88–92. [54] A. [41] Z. Yao. Smeltzer. Liu. D. Sosnik. Environ.H.S. Rroc. [55] J. T. B. Li. B. Wang. [61] D. Henshaw. H.E. Hamouda. Seggerson. P. [50] M.J. Hindi. E. Lasers Surg. Natl.S. S. Antimicrob.C. M. 21 (2004) 487–496. [38] H. D. 7 (2) (2007) 380–383. A. M. J. P. [36] C. Kim. Antimicrobial nanomaterials for water disinfection and microbial control: potential applications and implications. G. Middaugh. Lowrie. Dickey. A. Galitovskaya. Mar. R. Jeong. B. Chem. 145 (1–2) (2008) 83–96. Reid. 3 (4) (2006) 282–294. Boyle. Science 297 (2002) 1536–1540.S. K. Wu. A.L. Wokaun. Fakhimi. A. Opt. Handy.B. P. Rice-Ficht. P. Kang. T. Häse. Colloids Surf. Y.J. Adv. Arnold. Kim. Rapid nanoparticle-mediated monitoring of bacterial metabolic activity and assessment of antimicrobial susceptibility in blood with magnetic relaxation. Cannon. Kim. Jacoby. [31] A. [59] E.A. [34] M. E. Saravanan.M. Grossman. Zharov. Zharov.A.K. J. Bertozzi. Huang. Nanotechnology applied to the treatment of malaria. 101 (42) (2004) 15027–15032. Water Res. Raynaud. Yngard.A. Perez. [32] M. Hwang. K. Antimicrob. L. V. Mansour. [62] S. Nanoparticles and microparticles as vaccine-delivery systems. J.J.C. S. 141 [51] A. Yun. Cao. Yadav. Energy-dispersive X-ray analysis of the extracellular cadmium sulfide crystallites of Klebsiella aerogenes. Chemiosmotic mechanism of antimicrobial activity of Ag+ in Vibrio cholera. K. [30] M.K. Carcaboso. Preparation. Photothermal nanotherapeutics and nanodiagnostics for selective killing of bacterial targeted with gold nanoparticles. D. Beaulac.R. Biomed. Nanotechnology in vaccine delivery. 62 (4–5) (2010) 378–393.E. Lung. A. Immunol. Z. Toxicological effect of ZnO nanoparticles based on bacteria. Chem.J. Acad. Applications of nanobiotechnology in clinical diagnostics. A rapid bioassay for single bacterial cell quantitation using bioconjugated nanoparticles. Lee.I. Appl.J.K. Poon. L. Xu. S.L. Li.H.K. Med.C. P. Chemother. G. Hilliard. R. Nanda. Clarke.A. C.V. Kwon / Journal of Controlled Release 156 (2011) 128–145 [22] E. Blum. M. C. S.A. Newton. Park. Chem. 90 (2) (2006) 619–627. Scherer. Makidon.M. Vreeland. [53] A. Venkataraman. J. M.A. [33] X. [27] C. Grabinski. Biochem. Park. Morley. A. Clin.C. Myc. Agents Chemother. Janczak. Stevens. Moretton. Shim. S.H.R. W. in vitro and in vivo studies. Wolfrum. Lui. P. 163 (2) (1995) 143–147. Bielinska. Gu.W.R. Sodeau. Mechery. Turos. Ficht. He. S.J. Mahendra.J.C. A. P. Penicillin-bound polyacrylate nanoparticles: restoring the activity of βlactam antibiotics against MRSA. R.J. N.B. Park. Evans-Gowing. [71] H.J. Hilliard. Li. Nanomedicine in pulmonary delivery. Burd. Sobhana. Myc. 3 (2003) 1261–1263. S.J. Lyon. A. Basavaraja.J. A. Glisoni. Salopek-Sondi.H. Tsai. Med. J. [24] J. Kaittanis. Mirkin.V. C.E. 17 (2007) 3468–3472. P. Gosink.J. leprae Hsp65encoding plasmid DNA in biodegradable microparticles.K. M. J. Brunet. Reddy. C.V. Tuchin. I. R. Hao. 43 (2008) 1164–1170. [57] N. Nath. Adv. [78] D. A. P. L. B.G. R. B.R. 107 (2009) 1193–1201. S. Sondi. L. K. Han. Biol. V. Adv. O'Kennedy. Small 7 (5) (2011) 675–682. Raimondi. Int. Mandal. Arch. [28] K. Antimicrob. Lett. Expert Rev.V. 39 (1–3) (2006) 127–134. J.S.E. Vaccines 6 (5) (2007) 797–808. [26] K. K. T. Bioorg.L. Russell. Galanzha. Early uses. [66] I. Extracellular biosynthesis of functionalized silver nanoparticles by strains of Cladosporium cladosporioides fungus. M. Mahesh. G. Nanomedicine 3 (2) (2007) 168–171. 81 (18) (2009) 7724–7731.K. using quantum dot-labelled antibodies for the detection of Listeria monocytogenes cell surface proteins. Extracellular biosynthesis of silver nanoparticles using the fungus Fusarium semitectum. [52] P.S. C.J.P.R. Chakrapani. C. Basavaraja. Balaji. J. Y.B. Nano Lett. [74] A. Baker Jr.M. coli as a model for gram-negative bacteria. K. P. K.P. Z.R. Jacob. E.T. E. Chem. Nano-biosensor development for bacterial detection during human kidney infection: use of glycoconjugate-specific antibody-bound gold nanowire arrays (GNWA). T. A.H. H. 55 (2010) 29–35. 55 (2006) 59–63. Huh. R. J. J.C. PLoS One 3 (9) (2008) e3253. C.J. Y.Y. Photoacoustic flow cytometry: principle and application for real-time detection of circulating single nanoparticles. R. Microbiol. I.P. Devi. Howdle. Vaccine 21 (25–26) (2003) 3801–3814. Res.R. Adv.W.J.W. Y. Liu. One-step.I. S. Rev. J. Y. Smagghe. M. Multifunctional Fe3O4@Au nanoeggs as photothermal agents for selective killing of nosocomial and antibiotic-resistant bacteria. Nanoparticles with Raman spectroscopic fingerprints for DNA and RNA detection. S. [77] M. . Kahl-McDonagh. Smolinski. Int. K. Taylor. A. 60 (8) (2008) 915–928. Bactericidal activity of photocatalytic TiO2 reaction: toward an understanding of its killing mechanism. Perez. E. S. The development of rapid fluorescence-based immunoassays. 17 (1) (2007) 53–56. J. J. P. Bull. Bruehl.W. Biosynthesis of silver nanoparticles from Staphylococcus aureus and its antimicrobial activity against MRSA and MRSE. S. Lafashetty. Infect. Zhang.M. Liao. Saravanan. E. D.N. R. J.M. D. V. Khlebtsov. Hearty. [23] S. Detection of bacteria in suspension by using a superconducting quantum interference device. Nanomedicine 4 (2009) 299–319. Drug Deliv. J. Curr. Extractive electrospray ionization mass spectrometry toward in situ analysis without sample pretreatment. V.M. M. Yang. S.A. R. Tully. and contrast dyes in vivo. P. Hawari. J.J. Antimicrob. Microbiol. R. An investigation into the effects of silver nanoparticles on antibiotic resistance of naturally occurring bacteria in an estuarine sediment. 90 (2–3) (2003) 81–85. M. Li. Perez. Peterson.W. Huang. D. Antimicrobial activities of silver dressings: an in vitro comparison. S. Drug Deliv. Anal. Kim. Yin. Ktagiri. C.I. Chitosan as antimicrobial agent: applications and mode of action. Cao. Readman. Chen. Wong. Johansen. Rev. O'Hagan. W. H. Cho. Winship. Chora. Merkoçi. Singh. Eradication of mucoid Pseudomonas aeruginosa with fluid liposome-encapsulated tobramycin in an animal model of chronic pulmonary infection. Antibacterial activity of fullerene water suspensions: effect of preparation method and particle size. Boyes. Sci. O.L. Ramos. Z. A. Adv. [118] S.N. Tin. V.Y. Phototoxicity and cytotoxicity of fullerol in human retinal pigment epithelial cells. Colloids Surf. Chem.Y. Babic-Stojic. K. Fernandes. A 297 (2007) 63–70. Yamori. E.M. Esteban-Tejeda. Hughe. Environ. 25 (2008) 922–928. Wilson.Y. Aktaş. 40 (19) (2006) 3527–3532. A. [89] J. Alvarez. I. Osuji. [103] D. [100] P. M. Xavier Malcata.) 14 (34) (2008) 4013–4015. 49 (2002) 641–649. K. Sci. Selective toxicity of zinc oxide nanoparticles to prokaryotic and eukaryotic systems. Park. 40 (2006) 3274–3280. C.142 A. Biol. C. V. and ZnO water suspensions. Braydich-Stolle.Y. [93] J.K. 24 (11) (2005) 2757–2762. Jiang. J. M. Pandian. H. S.K. Massholder.M. Gómez. Pape. Ferarri-Iliou.L. Toxicol. Contini. Oberdörster. Chang. 4 (2008) 707–716. Antimicrob. Nikolic. B. 133 (12) (2003) 4077–4082. [94] S. B. L. Valenzuela. Hydroxyapatite-supported Ag-TiO2 as Escherichia coli disinfection photocatalyst. Biotechnol. Ito. Gelover. S. Cheng. Kühn. Klabunde. Lyon. Hoon Byeon. Reddy. P. C. Fortner.D.Y. Wielgus.M. X. 228 (1) (2007) 49–58. J. Labille. Lei. Functionalised gold nanoparticles for controlling pathogenic bacteria. upon Staphylococcus aureus and Escherichia coli. Gearhart.Y. Riviere. Uçar.J. Inorganic nanomedicine—part 2.R. Gai.R. Misirkic. Hu. Sci. J. N. Harhaji. Occup.W. K. F. Toxicol.C. J. J.E.J. Chung. J. Choy. Chou. Reip. Antibacterial efficacy of aminoglycosidic antibiotics protected gold nanoparticles—a brief study. J. H.F. J. F. Hu.M. Anatase TiO2 nanocomposites for antimicrobial coatings. Raicevic. Lett. Zou. Todorovic-Markovic. Lett. G. Trajkovic. A review of the in vivo and in vitro toxicity of silver and gold particulates: particle attributes and biological mechanisms responsible for the observed toxicity.K. Mashino. J. [131] G. J. Technol.B. 41 (2007) 379–386. D. Zhao. Hinkal. Antimicrobial sensitivity of Escherichia coli to alumina nanoparticles. Preparation and antibacterial activity of chitosan nanoparticles. L. J. Evaluation of the anti-microbial properties of an activated carbon fibre supporting silver using a dynamic method. Microbiol. Z. Wang. K. Geiss. J. 88 (2005) 412–419.B. V. Kamboj. [126] Z. Roberts. Disinfection of surfaces by photocatalytic oxidation with titanium dioxide and UVA light. C. J. 20 (2) (2010) 311–318. Cortie. 132 (2009) 127–133. Yamana. J. [117] J. [109] J. G. Fortner.K. Wang. Agents 33 (6) (2009) 587–590. H. Oleoyl-chitosan nanoparticles inhibits Escherichia coli and Staphylococcus aureus by damaging the cell membrane and putative binding to extracellular or intracellular targets. Sci. A. [129] X. Adv. 373 (2–3) (2007) 572–575. Finamore. Natural organic matter stabilizes carbon nanotubes in the aqueous phase. Hussain. . X. Photobiol. P.R. Meyers. Falkner. X.J.B. J. Lyon.M. Feris. Janjetovic. Nano Lett. Res.J. Nano-C60 cytotoxicity is due to lipid peroxidation.L. D. Malcata. Z. Ikenberry. Reyes. [124] D. Erden. P. Duttagupta. Christensen. Carbon 40 (2002) 2947–2954. L. Uğur. Chem. 40 (2006) 4360–4366. M.S. J. J. H. [119] R. S. Marchin. V. Mengheri. M. 41 (7) (2007) 2636–2642. M.K. Dissolving behavior and stability of ZnO wires in biofluids: a study on biodegradability and biocompatibility of ZnO nanostructures. Dill. Olivi. D.R. Ausman. Wilson. Isakovic. W. Maftah. M.P.J. [95] M.Y. Pharmacol. [84] S. In vitro action of carboxyfullerene.G. Appl. Xu. A. Hazelwood. Nutr. Luh. Activity of chitosans in combination with antibiotics in Pseudomonas aeruginosa. K.Y. J. 91 (1) (2006) 173–183.L. Harhaji.S. Rev.H. Sekhon. Nanomedicine 6 (5) (2010) 612–618.M. Characterizing the impact of preparation method on fullerene cluster structure and chemistry. Chemosphere 53 (2003) 71–77. S. Nikolic. C.A. Don. Health Perspect. Raicevic. [132] N. N.T.T. Xu. Alvarez. F. [133] T. Phys. Z. Lyon. Seki. Todorovic-Markovic. [140] H. Stickler. L. Susceptibility constants of Escherichia coli and Bacillus subtilis to silver and copper nanoparticles. [80] P. Chitosan derivatives killed bacteria by disrupting the outer and inner membrane. M. C. Funct. L.A. Park. Environ. M.E. Brayner. [121] K. Int. Fonseca. K. Vranjes-Djuric.N. Chem. J.A. Phototoxicity and cytotoxicity of fullerol in human lens epithelial cells. Hamal. [134] H.K. Biocontrol Sci.C. Antimicrobial efficiency of titanium dioxide-coated surfaces. D. I. Agric. [88] P. Mater. M. C. Zhou. Quantitative evaluation of antibacterial activities of metallic oxide powders (ZnO. Haggstrom. Chignell. Zinc oxide protects cultured enterocytes from the damage induced by Escherichia coli. Liu. J. F. B Appl. 8 (5) (2008) 1539–1543. Toxicol. Water Res. Wang.J. Vargas-Reus. 40 (4) (2010) 328–346. D. N. M.A. Ann. Todorovic-Markovic.S. H. Wiesner.B. Tavaria.Q. S. T. Brant.J. Sadiq.C.C. [81] H. Markovic. G. Preparation and antibacterial test of chitosan/PAA/PEGDA bi-layer composite membranes. Z. J. J. C. [123] J. [96] K. Langmuir 26 (4) (2010) 2805–2810.L. J. Nanomedicine 5 (2009) 282–286. N. Hadchouel. 80 (2) (2007) 353–359. Hierarchical shelled ZnO structures made of bunched nanowire arrays. Trends Biotechnol. Ramos. [127] D. Hwang. L. Dramicanin. Roselli. Nishikawa. [128] J. C.K. 54 (18) (2006) 6629–6633. Mirkovic. Mater.P. Alvarez. Mukherji. Markovic. N. 6 (2006) 866–870. [101] D. J. Weisner. Washington. K. Colvin.S. J.Y. F.R. K. A. 28 (4) (2010) 207–213. J. Chen. Total Environ. Park. [104] A. Effect of a fullerene water suspension on bacterial phospholipids and membrane phase behavior. (Camb. Sun. Garaguso. Schlager. Harhaji. T. Photochem. [120] J. 5 (2) (2009) 153–160. Shirakawa. Lyon. A review on the application of inorganic nanostructured materials in the modification of textiles: focus on anti-microbial properties. Hughes. Xie. D. Chemother.T. M. S. Toxicol. Adams.K. Technol. Cortie. B Biointerfaces 79 (1) (2010) 5–18. Tsao. A. [113] L. M. Clark.P.P. S. B 62 (2001) 158–165. S. Res. Lin. Chignell. Int. A. K. Mendez. L. In Vitro 19 (2005) 975–983.W. Pierce. M. S. [139] D.A. [111] G. Sci.J.L. Pecharromán. Punnoose. Cheng. Food Chem.J. K. Int. Toxicological impact studies based on Escherichia coli bacteria in ultrafine ZnO nanoparticles colloidal medium. E. Je. J.J. J. T.C. G. Biomaterials 28 (2007) 5437–5448. Harbo. Oppezzo. [82] G.S. Nanopart. A multifunctional biocide/sporocide and photocatalyst based on Titanium dioxide (TiO2) codoped with silver.L. Hohn. Fiévet.L. Toxicol. Vengopal. Johnston. 90 (2007) 2139021–2139023 (213902). K. C. Biomaterials 27 (29) (2006) 5049–5058.D. Lim. Y. M. Sci.H. Isakovic. O. Technol. Biomater. Andley. Benz. Toxicol.S.J. Djediat. Lee. Leal. K. [98] J. Yoon. Sci. Hussainn. Adams. Microbiol. Nikolic. Xia. Sci. D.J. Hu. Antibacterial activity of fullerene water suspensions (nC60) is not due to ROS-medicated damage. Malpartida. Lee. Sci. A. Intrinsic biological property of colloidal fullerene nanoparticles (nC60): lack of lethality after high dose exposure to human epidermal and bacterial cells. S.D. Li. Benedetti. [102] B. [87] G. Bottero. Sakharkar. Appl. Colloids Surf.T. Hankin. V.L. Muranyi. Mater. [114] T.F. Sublethal effects of ultraviolet A radiation on Enterobacter cloacae. J. J. M. Kleut. B 109 (2005) 8889–8898. Baker. Pintado. 5 (12) (2005) 2578–2585. 41 (1) (2007) 179–184.P. Antimicrobial effects of chitosans and chitooligosacharides.S. Fernandes. Nano Lett. H. Markovic. K. Sonntag. In vitro toxicity of nanoparticles in BRL 3A rat liver cells. Toxicol. C. Nano Lett.A. aiming at potential uses in functional textiles. and sulfur. Nanotechnology 20 (50) (2009) 505701. Chowdhury. Hyg. Food Microbiol. Gharbi. No. Drake. Y. Ren. In vitro screening for anti-microbial activity of chitosans and chitooligosaccharides. Wang. T. Dastjerdi. Moussa. Hutchison. Med. [90] M.N. Huh. Sawai. 16 (12) (2005) 1503–1519. Effect of abiotic factors on the antibacterial activity of chitosan against waterborne pathogens. J. S. Pissuwan.R. Aoshima. A practical demonstration of water disinfection using TiO2 films and sunlight. Monteiro-Riviere. C. Wielgus.L. B. C. Microbiol. Antimicrob. M. M. 13 (1991) 441–444. Hyung. Polym. Nikolic. [115] H. Lett. Chen. Grace. Nanoscale Res. M. 14 (2) (2009) 69–72.W. Antibacterial and antifungal activity of a soda-lime glass containing copper nanoparticles. M. [110] K.C.L. N. Food Microbiol. Leprat. Sayes. J. Staska.S. 5 (2010) 1204–1210. Wu. Antibacterial activity of chitosans and chitosan oligomers with different molecular weights.S. [125] C. R.F. Allaker. N. Pharmacol. N. Wang. 242 (1) (2010) 79–90. Lee. Vucicevic. Choi. S.R. N. J. Water Res. Cheung. Characterisation of copper oxide nanoparticles for antimicrobial applications.J. F. Schraml. J. [99] L.Y. Water Res. Biomaterials 26 (2005) 7587–7595. Brunet. Buckley.J. Soares. Vranjes-Djuric. Lett. M. N. 13 (24) (2003) 4395–4397. L. Kim. S. Bioorg. The mechanism of cell-damaging reactive oxygen generation by colloidal fullerenes.Y. Ji. Sarıışık. J. M. Methods 54 (2) (2003) 177–182. Environ. Szwarc. Lett. João Monteiro. Mukherjee. Int. Kim.L. Oberdörster. [116] J. [60] fullerene is a powerful antioxidant in vivo with no acute or subacute toxicity. N. Bioresour. Chem. M.C. S. Bacterial cell association and antimicrobial activity of a C60 water suspension.G..C. 18 (2006) 2432–2435. Zhou. Antibacterial and antiproliferative activity of cationic fullerene derivatives. C. 17 (2007) 1303–1310. 88 (2003) 179–184. B. Kim. Wingett. [86] K. Comparative eco-toxicity of nanoscale TiO2. P. H.J. J. H. R. Esteban-Cubillo.F. Cahberny. M. West. Sakharkar. Peters. Colvin. K. T. Takahashi.A. 113 (7) (2005) 823–939. N. Kwon / Journal of Controlled Release 156 (2011) 128–145 [112] Y. Romcevic.F. [137] J. Moya. B. [122] N. [130] A.L. S. Z. Erdinger. carbon. Wiesner.S.R. K. Xie. P. K. Usui. Biomater.S. Sayes. Crit. P. Britti. Devillers. Subrahmanyam. Pizarro. W. [85] R. Kokubo. M. Dramicanin. M.M. V. J. SiO2. Schlager. Reddy. Roberts. 339 (2004) 2693–2700. MgO and CaO) by conductimetric assay. Kim. N-carboxymethylchitosan inhibition of aflatoxin production: role or zinc. A. L. S. P. Gupta. Inactivation of nanocrystalline C60 cytotoxicity by gamma-irradiation. Vary. Gobin.Y. K. Fang. Vranjes-Djuric. [105] I.E. [97] O.Y. Oberdörster. S. Brivois. Q. C. Oshima. Trajkovic.C. [91] R. Xing. Biomed. J. J. Wunderlich. J.H. D.M. Ruparelia. Lyon. Valenzuela. L. Stone.S. [136] A. F.G. In vitro cytotoxicity of nanoparticles in mammalian germline stem cells. 101 (1) (2008) 122–131. 49 (7) (2005) 575–585. D. [138] A. Endo. Y. S. Wang. E. Qi.H. Trajkovic. 74 (1) (2002) 65–72. Tavaria. Hofmann. A. Cureo. Oh. A. M.M. Technol. Montazer. [135] Z.Y. F. [107] L. Mochizuki. Biodistribution and tumor uptake of C60(OH)x in mice. P. [108] H. Acta Biomater. Cha. B. M.A. Exposure-related health effects of silver and silver compounds: a review. Appl. Environ. A. Serena. Phys. A. Distinct cytotoxic mechanisms of pristine versus hydroxylated fullerene.K. Environ. [106] J. Liu. Modifying of cotton fabric surface with nano-ZnO multilayer films by layer-by-layer deposition method. S. Strain specificity in antimicrobial activity of silver and copper nanoparticles. Langmuir 22 (2006) 3878–3885.L.H. Res. Fu. Hess. Pintado. Biotechnol.E. Chandrasekaran.M. 197 (2) (2010) 128–134.P. 108 (6) (2010) 1966–1973. R. B. [83] L.R. Photocatalytic antibacterial effect of TiO2 film formed on Ti and TiAg exposed to Lactobacillus acidophilus.F. in food model systems. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles.X. [92] S. K. Chatterijee.T.M. Liu. K. V. Toxicol. C. Bell. Hanley. U. Carbohydr. 8 (2006) 53–63. J. Pressac.R. Food Microbiol.M. Inhalation toxicity and lung toxicokinetics of C60 fullerene nanoparticles and microparticles. A. Chen. F. M. Silver carbonate nanoparticles stabilized over alumina nanoneedles exhibiting potent antibacterial properties. J. Fang. L.H. E. Vasiljevic-Radovic. C. J. Appl. Antimicrobial activity of fullerenes and their hydroxylated derivatives. M. Toxicol. Dramicanin. Jiang.J. Commun. S. S. Ed.P. Z.C.K. M. Isakovic.E. E. M. J. 77 (1) (2004) 117–125. Agents Chemother. Chem. Chemotherapentic potential of free and liposome encapsulated streptomycin against experimental Mycobacterium avium complex infections in beige mice.M. [154] R. Cao. J. R. Chacko.. P. 39 (5) (2005) 1378–1383. L.S. self-preserving systems.Z. Appl. Zodrow.R. Toxicol. M. Agents 13 (2000) 155–168. Huh. S. J.A. [160] E. Sci. L. Jacobson. Bielinska. Long-circulating sterically stabilized liposomes as carriers of agents for treatment of infection or for imaging infectious foci. A. Vecitis.C. Weller. Kierans. Ormerod. Pandey. M. Beer. G. Videira. Huang. 53 (1) (2009) 249–255. 180 (1999) 1939–1949. A. Stasko.H. M. Microemulsion-based media as novel drug delivery systems. G. C. Zhang. Keoleian. Kang. Guo. J. R. Microemulsions are highly effective anti-biofilm agents. Antimicrob. J. A.J. D. Pharm.D. Wilkinson. J. . Baker Jr. N. Goldstein.M. A. J. Pharm. Webb.H. J. M.L. P. Souto. Van Tassel. T. Technol. Gohla.R. 30 (3) (2008) 157–165. J.M. K. Elimelech. Langmuir 22 (2006) 4357–4362.C. J.R. Dis. M. Immun.R. Huang. de Lima. Wang.J. Khalil. 28 (1991) 425–435. Rice. Schumacher. S. Jones. 89 (2000) 397–403. Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation. [143] G. P. 83 (5) (2008) 761–769. 86 (5) (1997) 635–641. T. P. Y. Alphandary. Makidon. 14 (3–4) (2004) 123–139. J. 90 (6) (2001) 667–680. H.A.S. Barraud. Johnson. Drug Deliv. A. Acad. PLoS One 4 (11) (2009) 1–7 e7804. J. D. E. J. U. Nightingale. M. ACS Nano 2 (2) (2008) 235–246. Appl. R. Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Hetrick. Development of nanoparticles for antimicrobial drug delivery. [159] E.K. Sower. Recent advances with liposomes as pharmaceutical carriers. Solid lipid particle-based inhalable sustained drug delivery system against experimental tuberculosis. Dettlaff-Weglikowska. H. Müller. R. Liposome Res.J. Mihu.D. A. Nitric oxide releasing nanoparticles are therapeutic for Staphylococcus aureus abscesses in a murine model of infection. James. Sci. 17 (2010) 585–594. [146] S.D. Microbiol. Collier. Nigaverkar.C. Srivastava. Agents Chemother. Eur. Hetrick. Debs. N. Zara. Agents Chemother. Invest. Enhanced killing of methicillinresistant Staphylococcus aureus in human macrophages by liposome-entrapped vancomycin and teicoplanin. J. C. Hunter. M. 238 (2002) 241–245. Loebick. Infect. Z. Hassett. Proc. J. K. [152] T. Chan. R.H. Vajtai. Omri. Chetoni. 64 (2002) 1407–1413.B. Moonis. J. fizgfines.S. J. Res. Burgalassi. Pharmacol. Margalit. Roach. Weller. Mechanism of enhanced activity of liposome-entrapped aminoglycosides against resistant strains of Pseudomonas aeruginosa. Sci. Drug Discov. Pharm. L. Z. Nakatsuji.M. Topically applied nitric oxide induces T-lymphocyte infiltration in human skin. P. [162] N.. A single-walled-carbon-nanotube filter for removal of viral and bacterial pathogens. Shin. L.J. Invest. ten Kate. A. L.H. L. M. Effect of elimination of phagocytic cells by liposomal dichloromethylene diphosphonate on aspergillosis virulence and toxicity of liposomal amphotericin B in mice.J. Pharmacol. Ajayan. Fielding. Friedman.M. J. Martinez. Lian. Reed. Stearne-Cullene.A. Kennel. Efficacy of gentamicin or ceftazidime entrapped in liposomes with prolonged blood circulation and enhanced localization in Klebsiella pneumoniae-infected lung tissue. M. S.O.D. Liposome-incorporated ciprofloxacin in treatment of murine salmonellosis. N. L. Sci. L.E. Novel applications of liposomes. Mank. J. Agents 19 (2002) 299–311.P.R. Farokhzad. Tan.A. M. Int. R. Gangadhanun. J. R. Hilliard.C. Friedman.M. Aslan. Maisch. J. Z. 9 (8) (2009) 974–983. Sci. M. 128 (2009) 352–360. and fullerene. [164] J. The delivery of benzyl penicillin to Staphylococcus aureus. Antimicrobial effectiveness of liposomal polymyxin B against resistant gram-negative bacterial strains. Hayes. Carbon nanotube filters.R.N. [153] F. A.F. Collier. Friedman.D. Rutledge. Langmuir 25 (2009) 3003–3012. L. 168 (2007) 121–131. Wright. Mugabe. D. Inactivation of bacterial pathogens by carbon nanotubes in suspensions. Lafrenie. Botelho. Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. [172] A. Biomaterials 30 (14) (2009) 2782–2789.H. Microemulsions are membrane-active. Fundarò.M. Candida and bacterial skin pathogens. C. Morris. McDermott. 50 (1) (2000) 161–177. D.T. J.R.R. Suntres. Int.E.W. R. Int. Tonda.E. R. Wissing. Antimicrobial effect of acidified nitrite on dermatophyte fungi. Dermatol.B. C. L. T.W. J.S. P. W.W. B. Manser. Small 4 (4) (2008) 481–484.P.O. Maruyama. X. Transmucosal transport of tobramyin incorporated in solid lipid nanoparticles (SLN) after duodenal administration to rats. R. [151] A. [145] C. Sci.A. Cosmet. Biochem. Han. R. Weller. Bactericidal efficacy of nitric oxide-releasing silica nanoparticles. Reynolds. Kalikin. Stark. Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues. L. Gborf. L. J. Part II—tissue distribution. Baker Jr. Scott. Barbosa. I.J. Marangos.R.X. M. Appl. K. Pornpattananangkul.A. Antimicrobial mechanism of action of surfactant lipid preparations in enteric gram-negative bacilli. M. 44 (2010) 3773–3780. Cavalli. J.D. Ther. Impact of solution chemistry on viral removal by a single-walled carbon nanotube filter. S. Trends and developments in liposome drug delivery systems. J.A. Bruinink. Clin. D. Antimicrob. I. O. Webb. Chan.A. Kjelleberg. J. Antimicrobial biomaterials based on carbon nanotubes dispersed in poly(lacticco-glycolic acid). M.M. B. Gialanella. R. Schoenfisch. Souto. Microstructure of microemulsion in MEEKC. 75 (8) (2007) 4020–4029. 3 (2004) 610–614.M. S. Water Res. Ahmad. Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Sheng. Chemother. M. R. Rev. H. Antimicrob. S.R. A novel surfactant nanoemulsion with broad-spectrum sporicidal activity against Bacillus species.D. [163] G. Natl. Landers. Kang.O. Paul. L. J. Elimelech. L. Dijkstra. J. P. Warheit. low-clearance liposomes (MiKasome®).J. 15 (11) (1998) 1775–1781. Bagwe. C. O. The degree and kind of agglomeration affect carbon nanotube cytotoxicity. L.B. [157] R. Hamouda. J. Almeida. A. Rathinavelu. Gasco. H.J. J. B.S. Khuller. Mäder. Kim. J.S. Brisker. P. Bakker-Woudenberg. [166] Y. N. I. K. Tuberculosis 85 (2005) 227–234. S. Appl.C. J. Friedman. [171] P. Al-Adham. Curr. Müller. Nitric oxide-containing nanoparticles as an antimicrobial agents and enhancer of wound healing. S. Mowbray. Cosmetic features and applications of lipid nanoparticles (SLN. J. Jia. Med. Involvement of nitric oxide in biofilm dispersal of Pseudomonas aeruginosa. Int. M.S.K. Lawrencea. R. K.M. M. Brady-Estévez. [158] M. Halwani. S. M. Pre-clinical evaluation of a novel nanoemulsion-based hepatitis B mucosal vaccine. Liposome-encapsulted ampicillin: physicochemical and antibacterial properties. J. A. Lett.J. Price. [144] D. Huang. S.J.. Hu. Electrophoresis 31 (4) (2010) 672–678. Toxicol. 10 (8) (2002) 607–613. 278 (2004) 71–77.P. 87 (1990) 5744–5748.Z.P. Rathinavelu. C. G. Gu. Landers.H. 129 (2009) 2335–2337. P. Pfefferle.F. J.E. 355 (2008) 293–298. Finnen. S. Onyeji.E. but minimal inflammation. N. In vitro activities of a novel nanoemulsion against Burkholderia and other multidrug-resistant cystic fibrosis-associated bacterial species.S. Talapatra. J. 188 (2006) 7344–7353. Antimicrob. A. Targeted delivery of antibiotics using liposomes and nanoparticles: research and applications. C. Yang. LiPuma. [170] I. Cytotoxicity of carbon nanomaterials: single-wall nanotube. Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery. J. Ho. Trends Biotechnol. M.M. [165] M. Fang. Yan.R. Mini Rev. J. Antimicrob. R. [156] L. M. Al-Adham. [155] R. Alipour. Nguyen. C.K.C. J. Saettone.D. A. Hwang. Brady-Estévez. Elimelech.A. Makidon. Pornpattananangkul. T.M. X. Wissing.P.A. Mihu.S. Al-Hmoud. 129 (2009) 2463–2469.N.H. Blanco. O. Bachhawat. Kwon / Journal of Controlled Release 156 (2011) 128–145 [141] L. Schoenfisch. Kang. 50 (6) (2006) 2016–2022. G. Adv. Mucosal immunization with a novel nanoemulsion-based recombinant 143 [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] [197] [198] [199] [200] [201] anthrax protective antigen vaccine protects against Bacillus anthracis spore challenge. 16 (7) (1998) 307–321. Wang.J. Halwani. Martinez. M. Shin. 171 (4) (1995) 938–947. Sci. 37 (11) (1993) 2293–2297. Single-walled carbon nanotubes exhibit strong antimicrobial activity. Dermatol.M. J. Infection 22 (5) (1994) 338–342. C. multi-wall nanotube. Microbiol.L. Environ. A. Limbach. Pinault. Wang. [150] A. Rev. Pharm.J. Han. Zhang. S. Elimelech. Müller. 90 (2001) 648–652. 89 (2000) 32–39. J.M. E. L. T. M. Surface modification of silica nanoparticles to reduce aggregation and nonspecific binding. S.E. Infect. S. A. Holmuhamedov. Lewis. 4 (2) (2005) 145–160. M. Hamouda. McCluskey. M. [147] A. F. S.U.J. P.B. Rev. Pharmacol.J.E. R. G. M.. Baker Jr. Infect.J. W.R.R.A. M.D. Weller.J. X. K. Electronic-structure-dependent bacterial cytotoxicity of single-walled carbon nanotubes. Suntres.A. S.K. Gouveia. A.U.R. N. Foster.A. 43 (5) (2001) 497–502.J. Nitric Oxide 15 (2006) 395–399. D. Arias. Omri. Acta 981 (1) (1989) 27–35. Lymphatic uptake of pulmonary delivered radiolabelled solid lipid nanoparticles. Gutierrez. Langer. D.S. [149] C. Nanoscale 2 (9) (2010) 1789–1794. Cao.H. M. Biopharm.B. Cao. Reesb. Bakker-Woudenberg. Janczak. The antimicrobial activity of liposomal lauric acids against Propionibacterium acnes.R. Pei. Wespe. Antimicrob. M.R. Pharm. V.J. Woodle. Wheatley. T. J. antimicrobial. Magallanes. Srivastava. R. C. U. Pharm.M. Tan. Invest. Nanoparticles in medicine: therapeutic applications and developments. Microbiol. NLC). Shek. J. Zhang. Pharm. R. D. Laurence. Ashtekar. P. Gasco.J.K. Fierer. L. Anti-biofilm efficacy of nitric oxide-releasing silica nanoparticles.F. [161] R. Toxicol. M. Hansen. Santos. K. Bacteriol. R. R. Int. 77 (1) (2004) 126–134. P. L. Nosanchuk. Biochem. N. Int. 36 (2003) 97–100.B. Lipid composition is important for highly efficient target binding and retention of immunoliposomes. Antimicrob. Andremont. Lam.. Azghani. [148] S. Bargoni. Pharm. 2 (2004) 820–832. Nat. J. Carson. Baker Jr. Zhao. M. ACS Nano 4 (9) (2010) 5471–5479. The effects of topical treatment with acidified nitrite on wound healing in normal and diabetic mice. Z. Med. Leifert. Dis. Kierans. Dermatol. Nat. Enhanced activity of liposomal polymyxin B against Pseudomonas aeruginosa in a rat model of lung infection. Mater. Torchilin. Yan. Nat.R. [167] T. Johnson. M. R. Bielinska. Biophys.N. E. Al-Hmoud. Microbiol. Baker Jr. Janczak. Knowlton. R. Solid lipid nanoparticles (SLN) as ocular delivery system for tobramycin. Res. 33 (3) (1994) 571–583. Allen. Lasic.R.H.N. C. Biomaterials 30 (2009) 6035–6040. Krumeich. Altered tissue distribution and elimination of amikacin encapsulated in unilamellar. Microbiol. Wick. Langmuir 23 (2007) 8670–8673.M. E. Chemother.R. Pfefferle.T. D. Antimicrobial and healing efficacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infection. Drug Target. Chem. [168] T. 254 (2003) 65–68. J. 45 (2000) 89–121. A new strategy to destroy antibiotic resistant microorganisms: antimicrobial photodynamic treatment. T. Int.H. Roth. J. I. D. Cavalli.W. Makidon.H.E. Yang. Peterson. Elimelech.D. R. [142] P. Müller. PLoS One 3 (8) (2008) e2954. P. Cosmetic applications for solid lipid nanoparticles (SLN). [169] I. Kang. Omri. Caputo. Benjamin. Lett.J. A. Khalil. Couvreur.J. J. A. Qu. Sips. Dufresne. Sandhiya. Y. Fayaz. M. Pharm. Weiss. J. Drug Deliv. Physiol. [234] M. A. Zhang. Pharm. Lim. Langer. Xu. E. and pharmacokinetics of polymeric nanoparticles. Hetrick. [247] T. Pharm. D. J. Toxicol. Bhonde. Scholten. [213] S. Chemother. 6 (1) (2009) 43–51. [211] R. Wang. 2) (2000) S93–S98. Lung deposition and extrapulmonary translocation of nano-ceria after intratracheal instillation. S. On the toxicity of therapeutically used nanoparticles: an overview. Ranger.E. Oomen. Food Microbiol. W. P. M. [202] A. Pharmacol. Med.A. Chem. J. Turos.S. Expert Opin. Effect of nanoparticle-bound ampicillin on the survival of Listeria monocytogenes in mouse peritoneal macrophages. Occup.Z. Bhadra. Baskaran.M. Food Prot. J. M. F. De Jong. Levy-Nissenbaum. Jain.R.H. El-Ansary. Langer.V. [229] C.144 A. Toxicol. [253] N. The potential advantages of nanoparticle drug delivery systems in chemotherapy of tuberculosis. Pharm.S.S. Dubernet.C. Pinto-Alphandary. Des. Mansueto. Soppimath. Sci. Garrec. J. Wang. R. J. Shin. Potential neurotoxicity of nanoparticles. B. B. Ferreira. Control. M. 42 (2007) 93–98. C. Shi. E. Suryanarayanan. Giunchedi.G. Proc.M. F. J. [240] A. Encapsulation of vancomycin and gentamicin within cationic liposomes for inhibition of growth of Staphylococcus epidermidis. J. A.H. Whitman. Biogenic synthesis of silver nanoparticles and their synergistic effect with antibiotics: a study against gram-positive and gram-negative bacteria. Efficient targeting to alveolar macrophages by intratracheal administration of mannosylated liposomes in rats. Takenaga. E. Couvreur. Z. V. N. Res. lipid. Pinto-Alphandary. Y. [208] R. B Appl. S. Yadav. Livermore. Brown. Adv. B. Poly (alkylcyanoacrylates) as biodegradable materials for biomedical applications. Int. G. C.G. Pharm. [256] D. [260] J. Mol. A. Yoshida. Shim. M. J. Nanotechnology-based drug delivery systems. Eur. Am. J. Polymers for the sustained release of proteins and other macromolecules.J. Mehta. Murray. Ciprofloxacinprotected gold nanoparticles. Chaumard. Leroux. Toxicogenomics to improve comprehension of the mechanisms underlying responses of in vitro and in vivo systems to nanomaterials: a review. H. Cossu. Ma. U. A. Med.J. Natl. Bioorg. A. 307 (2006) 93–102. J. Xu. Utell. H. Pitarresi. Y. 4 (3) (1996) 181–189. D.K.A. Zhang. R. Eur. Emerging trends of nanomedicine—an overview. Surendiran. F. Owens 111. Hahn. Controlled release of microquantities of macromolecules.M. Viron.V.M. Mater. Bhadra. T. V. Langer. K. R. 172 (12) (2005) 1487–1490. [223] E.L. [206] S.L. Drug Discov.C. [239] S.M. [257] S. H. Ma.S. J.A. Gedanken. McLandsborough. Wu. Chem. Sci. Pharm. Johnson. [261] W. Of Pseudomonas. Y.E. D. 2 (2007) 16.K. Fang. Folkman. Dickey. Lei. [221] G. Balland. M. S. Qu. Pérez-Conesa. Luther. H. Gupta. T. Appl. Iseman. Y. Tabata. Venketesan. Fréchet. [258] J. Lin. [241] W. Agents Chemother. Suzuki. Pharmacol. Antimicrobial effects of a microemulsion and a nanoemulsion on enteric and other pathogens and biofilms. T. Chai. Oshio. Pharm. Drug Deliv. H. Sci. Sajja. 8 (3) (2005) 467–482. Sci. Pharmaceut. J.J. Release 127 (2008) 50–58. H. Trewyn. Dickey. 69 (12) (2006) 2947–2954. A. Kubo-Irie. Xu. Irache. Kwon / Journal of Controlled Release 156 (2011) 128–145 [232] S. B. Teply. Frampton. Ichinose. Nanomedine 6 (2010) 103–109. J. Med. Poma. J. Wang. M. Bai. Antimicrob. O. B. S. [231] D. J. I. Cancer Drug Deliv. Hardikar. Controlled release of polypeptides and other macromolecules. [215] S. In vivo and in vitro uptake of surfactant lipids by alveolar type II cells and macrophages. Prior. Lellouche. drug release rate and phagocytic uptake.R. Turos. S. Antimicrob. Crit. Control. B. Van Iwaarden. Pharm. Jain. [225] S. Antimicrob. C. [236] E.N. J. Patton.V. Y. K. Control. Pouton. Acad. Proc. Biomaterials 23 (16) (2002) 3359–3368. Wang. Couvreur. R.H. Greenhalgh. T. Y. Bhat. and chitosan nanoparticles for drug delivery.L. Takano. Preparation. [204] C. A. Ma. Sanderson. J. J. T. A. He. Formulation of functionalized PLGA– PEG nanoparticles for in vivo targeted drug delivery. Banin.K. C.A. Ding. 11 (Suppl.Q. J. 394 (1–2) (2010) 115–121. Biopharm. 1 (1) (1984) 2–10.F.M. Silva. San Biagio. Cheng. Banerjee. P.W. L.S.C. H. Int. Aminabhavi. Morrow. Abeylath. P. [203] V. Lett. Mao. de Jong. 17 (1) (2007) 53–56. Biomed. Nanomedicine: current status and future prospects. Polymeric micelles for drug delivery. 55 (2003) 519–548. D. P. Carlisi. [251] R. Rudzinski. Bioorg. Tomarchio.M. 49 (3) (2007) 217–229. Physiol. Langer. Efficient drug targeting to rat alveolar macrophages by pulmonary administration of ciprofloxacin incorporated into mannosylated liposomes for treatment of respiratory intracellular parasitic infections. Tanino. Elias. Rev. Comparison of ciprofloxacin hydrochloride-loaded protein. P. porins. Kawakami. Sant. Girilal. J. R. H. [227] E.F. S. [252] J. M. Youssef.T. [214] D. [238] B. 91 (2006) 926–929. Y. Chemother. J. D. Z. [210] K. Pharm. Z. J. Morphological control of roomtemperature ionic liquid template mesoporous silica nanoparticles for controlled release of antibacterial agents. E. Igarashi. Teixeira. P.P. J. . Langmuir 20 (5) (2004) 1909–1914. [244] R.A. Yamashita. Y. 12 (2006) 4669–4684. C. H. Biomaterials 19 (1998) 1009–1017. Farokhzad. Rassu. 118 (1) (2007) 15–19. 37 (1996) 105–115. Chem. Biodegradable polymeric nanoparticles as drug delivery devices. J. Int. De Souza. Lachmann. Biopharm. J. [245] D. T. Dendrimers as versatile platform in drug delivery applications. O. Jain. The lungs as a portal of entry for systemic drug delivery. Eur. Eur. Kwon. Kroll.H. Res. Gibbs. Med. Schoenfisch. Chemother. S. Intracellular distribution of ampicillin in murine macrophages infected with Salmonella typhimurium and treated with (3H)ampicillin-loaded nanoparticles. Yang.P. Couvreurr. Leite. 93 (5) (2010) 1695–1699. Sanna. Curr.J. J. Release 70 (2001) 1–20. Opsonization.H. [217] F.H. T. characterization and in vitro antimicrobiral activity of ampicillin-loaded polyethylcyanoacrylate nanoparticles. M. Gentamicin encapsulation in PLA/PLGA microspheres in view of treating Brucella infections. Control. Dkhar. H. P. [250] A. 4 (11) (2004) 2139–2143. Clin.Y.R. Fertil. Svenson. Salman.M. C. What do we (need to) know about the kinetic properties of nanoparticles in the body? Regul. Reddy. M. Schnekenburger. W. Antibiotic-conjugated polyacrylate nanoparticles: New opportunities for development of anti-MRSA agents. D. W. H. Current in vitro methods in nanoparticle risk assessment: limitations and challenges.J.J. Inhibition and inactivation of Listeria monocytogenes and Escherichia coli O157:H7 colony biofilms by micellarencapsulated eugenol and carvacrol. Singh. M. Weers. 277 (2004) 81–90. S.H. Lipid formulations for oral administration of drugs: nonemulsifying. 16 (5) (2008) 2412–2418. J. Chono. Irache. Pharmacol. K. 5 (6) (2008) 703–724. Drug delivery and nanoparticles: applications and hazards. Peppas.M. Nano Lett.A. 196 (2000) 115–125. [218] E. N. 232 (2) (2008) 292–301.W. Q. Curr. Y. Amoxicillinloaded polyethylcyanoacrylate nanoparticles: Influence of PEG coating on the particle size. Andremont. Di Giorgio. 59 (8) (2007) 1057–1064. Antimicrob. [249] A.L.R. Siegel. [242] A. M. N. Receptor mediated targeting of lectin conjugated gliadin nanoparticles in the treatment of Helicobacter pylori. 71 (2009) 445–462. Suri. G. Jones. R.C.B.S. [205] D. Gillies. Lung Cell. Andremont. L. S. Dendrimers and dendritic polymers in drug delivery. Kalaichelvan. Al-Daihan. Xu. T. M. Pharmacol. Cooper. 72 (2009) 370–377. J. Nanotechnology 21 (28) (2010) 285103.L. Yuan.V. V. Cooper. Limb. Health Perspect. Wijagkanalan. A. Pharm. Solid lipid nanoparticles (SLN) as carriers for the topical delivery of econazole nitrate: in-vitro characterization. Hashida.M. L. Evaluation of Polyamidoamine (PAMAM) dendrimers as drug carriers of anti-bacterial drugs using sulfamethoxazole (SMZ) as a model drug. J. Release 68 (1) (2000) 23–30. C. Technol. K. 19 (3) (2005) 311–330. G. Liao. Curr. Radovic-Moreno. M. 23 (3) (2009) 263–269. [228] Y. Huh. Bactericidal efficacy of nitric oxide-releasing silica nanoparticles. N. Balaji.A. Croy. Poelma.C. [207] J. [248] A.C. ex-vivo and in-vivo studies. Effects of fetal exposure to carbon nanoparticles on reproductive function in male offspring. Gao. Zimmermann. G. Thorac. L. Drug Target.H. Soc.M. [235] Y. Farokhzad. Hagens.T. Reddy. V. Environ. Giammona. Komatsu. [219] F. Radovic-Moreno. G.S. Hu. Mycopathologia 166 (2008) 353–367. Cassee. Toxicol.S. Gamazo. Respir. Lu. Gu. Today 10 (1) (2005) 35–43. Nature 263 (1976) 797–800. Domingues. A. Fenniri. Y. R. Gavini. Oberdörster. K. pumps and carbapenems. S. P. Teply. Langer. Forestier. (2009) 754810.W. [226] H. 112 (8) (2004) 879–882. C. Wang. J. self-emulsifying and ‘self-microemulsifying’ drug delivery systems. 30 (1992) 173–179. S. Seki. Drug Target. J. 11 (7) (2003) 415–424. M. 105 (7) (2008) 2586–2591. Cheng. Ultrafine particle deposition in subjects with asthma. L. A. Toxicol. Zhang. 42 (2007) 1032–1038. [224] S. Murray. 47 (2001) 247–250. Shimizu. Nanomedicine 3 (2) (2008) 133–149. [262] D. [243] W. N. B. Licciardi.D. Genomics 9 (2008) 571–585. 33 (9) (1989) 1540–1543. Pharm. Update in antifungal therapy of dermatophytosis. P. Kisich. Polyamidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: an in vitro study. Biomaterials 30 (2009) 5969–5978. E. [216] J. Kahana.G. Sung. G. P. Fang. Ma. [237] S. J. J. The effects of nanoparticles on mouse testis Leydig cells in vitro. C. Nie. [222] G. P. Risbud. E. C. Interactions between dendrimer biocides and bacterial membranes. K. Gu. Fettal. Hiyoshi.X. Int. Eur. Puvion.A. Takeda. Chalupa. Integrated metabolomic analysis of the nano-sized copper particle-induced hepatotoxicity and nephrotoxicity in rats: a rapid in vivo screening method for nanotoxicity. J. E. G. E. Drug Discov. Labarre. [233] M. Yang. H. Zhao. Am. 1 (4) (2004) 338–344. Int. Quero. Couvreur. A. pH-sensitive freeze-dried chitosan-polyvinyl pyrrolidone hydrogels as controlled release system for antibiotic delivery. Moghimi. K. D.G.F. S. Morimoto. Steril. Fontana.E. R. Gelperina.B. Antibiofilm activity of nanosized magnesium fluoride. J. Gamazo. In Vitro 22 (8) (2008) 1825–1831. J.J. Holmuhamedov. M. L. M. Xu.I. J. R. M. K. Development of multifunctional nanoparticles for targeted drug delivery and noninvasive imaging of therapeutic effect. Cheng.K. Mannose-targeted systems for the delivery of therapeutics. ACS Nano 2 (2) (2008) 235–246. Umamaheshwari. Chen. Glyconanobiotics: novel carbohydrate nanoparticle antibiotics for MRSA and Bacillus anthracis. R. Leavitt. 283 (2002) L648–L654. J. R.R. Toxicol. Med. Am. Curr. Borm. Int. Mann.L. Hunter. S. biodistribution. A. Care Med. [212] C. [209] R. FASEB J. Pegylated lysine based copolymeric dendritic micelles for solubilization and delivery of artemether. Kulkarni. Gerrier. Q. P.A. [254] P. Fattal. Heifets. M. J. Chem. [255] D. G. S. Gander. Pillukat.A.Y. Release 125 (2) (2008) 121–130. Wespe.A. A. Fontana. Preparation and characterization of water-soluble pH-sensitive nanocarriers for drug delivery. Stasko. L. Bactericidal activity of combinations of silver–water dispersion with 19 antibiotics against seven microbial strains. Merkle. [220] O. Schillaci. Fundam. Nihei. [246] S.P. J. Biomater. 1 (2) (1984) 119–123. [259] X. East. Z. J. Vauthier. [230] M. E. Pradeep. Treatment of experimental salmonellosis in mice with ampicillin-bound nanoparticles. Fishburn. J. Biomaterials 22 (2001) 2857–2865.C. Precise engineering of targeted nanoparticles by using selfassembled biointegrated block copolymers.C. Espuelas. Biomaterials 28 (2007) 869–876. P. Tom. Xu. Sherifi.M. 86 (1) (2008) 105–112. Wen. P. Chang.T. [268] K. Rahaman.A. Res. Biomaterials 31 (2010) 5227–5236. A 1:78 (3) (2006) 532–540. Ohya. Biomed. Antimicrob. 29 (1) (2009) 196–212. Peyman. G. T. D. Li. J.R. Res. Huh.J. Drug Deliv. Rev. Novel borate glass/chitosan composite as a delivery vehicle for teicoplanin in the treatment of chronic osteomyelitis. Nanomedicine and nanotoxicology: two sides of the same coin.F. Vij. In vitro antileishmanial activity of amphotericin B loaded in poly(1-Caprolactone) nanospheres. A. Huang. 12 (3) (1988) 175–182. In vitro and in vivo release of gentamicin from biodegradable discs.A. D. P. [272] L. Biomater. C. Mater. Jia.C. P. Baxter. Hydrophobically modified biodegradable poly(ethylene glycol) copolymers that form temperature-responsive nanogels. 22 (2005) 501–510. Chougule.J. Mäkinen. Nanoparticle formulations in pulmonary drug delivery. J. J. 48 (2001) 333–344. Int. Galanakis.M. Misra. Nanomedicine 1 (4) (2005) 313–316. E. J. van der Mei.N. Karagianakos. C. Shvedova. 80 (5) (2009) 514–519. Bakker-Woudenberg. [278] R.M. P.C. [280] M. Chen. Kluin. . Deng. D. Res. J. Recent advances in liposomal dry powder formulations: preparation and evaluation. Giamarellos-Bourboulis. A biodegradable antibiotic delivery system based on poly-(trimethylene carbonate) for the treatment of osteomyelitis. Int. Xie. Li. Berkland. I. M. Giamarellou.J. Yamamoto. Y. 294 (2005) 103–112. SLN and NLC for topical delivery of ketoconazole. Wang. M. Hsu.C.W. 77 (2) (2006) 329–337.J. Rifiotis.B. B. Liu. Irache. C. W. [264] I. G. Niesman. N. Kanellakopoulou. E. M.K.A. Bailey. Hashizume. Carrier systems for the local delivery of antibiotics in bone infections.H. 46 (2) (2000) 311–314.C. K.J. Biomed. J. Ouchi. Aro. Chu. Guan Lee. Koort. B Appl.H. Fu.K. Injectable biodegradable temperature-responsive PLGA-PEG-PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels. I. Lee. Treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with a biodegradable system of lactic acid polymer releasing pefloxacin. J. 6 (2010) 812–819. Naraharisetti. J. N.M. [265] A. D. A. C.C. Zhang. P. Antimicrob. J. Hsu. Luo. [271] P.Q. D. Legrand. 6 (1) (2009) 71–89. D. Roy. [277] K. H.H. Drug Target.S. Schiffelers. Neut. K. Zhang. H. Intravitreal liposome-encapsulated drugs: a preliminary human report. Price. Liu. Khoobehi.E.T. Wang. Grijpma. Med. Souto. Qiao. Res. Giamarellos-Bourboulis.Q.P. Kanellakopoulou. H. Stephens. Chen. 10 (8) (2002) 593–599.S. Y. J. Veiranto. D. R. Z. H. [275] K. [276] M. Loiseau. Chemother. Ophthalmol. X. [267] C. Surg. [270] J. 49 (2) (1990) 174–178. H. P.J. Bories.J. O. S. Jalava.J.W. Mater. Müller. E. Langmuir 25 (17) (2009) 9734–9740. Suokas.M. Expert Opin. M.J. Nanomedicine 6 (2010) 237–244. C. Nanodelivery in airway diseases: challenges and therapeutic applications. Liu. Barratt. Espuelas.I. Horton. H. Ma. Bayir. M. Andreopoulos. Liposome encapsulated aminoglycosides in pre-clinical and clinical studies. Papakostas. R. Acta Orthop. T. Lalani. Jinturkat. Microencapsul. B. Adv. Kagan. X.E. Acta Biomater. Chemother. Polyanhydride implant for antibiotic delivery-from the bench to the clinic. J. Day.R. Y. Y. [281] V.H. H. Treatment of osteomyelitis with teicoplanin-encapsulated biodegradable thermosensitive hydrogel nanoparticles. In vitro and in vivo testing of bioabsorbable antibiotic containing bone filler for osteomyelitis treatment. Y. W. Crielaard. Charles. K. [269] K.H.M. [279] E. Dounis. Rev. 145 [273] D. J. Törmälä. Drugs 59 (6) (2000) 1223–1232.T. Kwon / Journal of Controlled Release 156 (2011) 128–145 [263] M. Patel. Peng. Pharm. E. [266] G. Storm. C. J. Busscher. J.J. H. Topical liposomal delivery of antibiotics in soft tissue infection.W. 54 (2002) 963–986. X. Nagahama. [274] W. Drug Deliv.