“Nanoantibiotics”: A new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant era

Journal of Controlled Release 156 (2011) 128–145

Contents 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

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

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.

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

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

3.

Nanoantibiotics: Nanomaterials for infection control . . . . . . . 3.1. Antimicrobial nanomaterials . . . . . . . . . . . . . . 3.1.1. Silver (Ag) NPs . . . . . . . . . . . . . . . . 3.1.2. Zinc oxide (ZnO) NPs . . . . . . . . . . . . . 3.1.3. Titanium dioxide (TiO2) NPs . . . . . . . . . . 3.1.4. Gold (Au) NPs . . . . . . . . . . . . . . . . . 3.1.5. Aluminum (Al) and copper (Cu) NPs . . . . . . 3.1.6. Antimicrobial peptides and chitosan . . . . . . . 3.1.7. Fullerenes (C60) and fullerene-derivatives . . . . 3.1.8. Carbon nanotubes (CNTs) . . . . . . . . . . . 3.1.9. Nitric oxide (NO)-releasing NPs . . . . . . . . . 3.1.10. Surfactant-based nanoemulsions . . . . . . . . 3.2. NPs for efficient antimicrobial drug delivery . . . . . . . 3.2.1. Liposomes for antimicrobial drug delivery . . . . 3.2.2. Solid lipid (SL) NPs . . . . . . . . . . . . . . 3.2.3. Polymeric NPs . . . . . . . . . . . . . . . . . 3.2.4. Dendrimers . . . . . . . . . . . . . . . . . . 4. Translation of nanoantibiotics from bench to bedside . . . . . . 4.1. Advantages of nanoantibiotics . . . . . . . . . . . . . . 4.2. Disadvantages of nanoantibiotics, including nanotoxicology 4.3. Treatment of drug-resistant microorganisms and biofilms . 4.4. Targeted therapy for infections using NPs . . . . . . . . 4.5. Local administration . . . . . . . . . . . . . . . . . . 5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction At the beginning of the 20th century, infectious diseases were the leading cause of death worldwide [1]. The decreases in morbidity and mortality from infectious diseases over the last century were attributed mainly to an introduction of antimicrobial agents. Nowadays, however, resistance to antibiotics has been reaching a critical level, invalidating major antimicrobial drugs that are currently used in the clinic [2,3]. The bacterial resistance to antimicrobial drugs has been attempted to be resolved by discovering new antibiotics and chemically modifying existing antimicrobial drugs. Unfortunately, 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. For example, drugresistant infections in hospitals and in the communities caused by both Gram-positive and Gram-negative bacterial pathogens are growing [4], and the continued evolution of antimicrobial resistance threatens human health by seriously compromising our ability to treat serious infections [5]. 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]. One of the recent efforts in addressing this challenge lies in exploring antimicrobial nanomaterials, to which microbial pathogens may not be able to develop resistance, and novel nanosized platforms for efficient antibiotics delivery. For example, it has been suggested in recent studies that some metal nanoconstructs are known to possess antimicrobial activities, which is utilized in controlling infectious diseases [7–9]. Antimicrobial nanoparticles (NPs) offer many distinctive advantages in reducing acute toxicity, overcoming resistance, and lowering cost, when compared to conventional antibiotics [10,11]. Various nanosized drug carriers are also available to efficiently administer antibiotics by improving pharmacokinetics and accumulation, while reducing the adverse effects of antibiotics. Theoretically, NPs are retained much longer in the body than small molecule antibiotics, which could be beneficial for achieving sustained therapeutic effects. On the other hand, the safety profiles of NPs and nanosized antibiotics drug carriers, particularly upon long-term exposure, could be an overriding safety factor and must be considered with therapeutic effects [12]. This review

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

129

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . .

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

introduces employing nanotechnology as a new paradigm in controlling infectious diseases, especially in overcoming antimicrobial drug resistance, in the context of research and clinical prospectives of this novel and promising strategy. 2. Challenges and use of nanotechnology in treating infectious diseases 2.1. 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. In the ongoing race of the development of antimicrobial agents, however, microbes appear to be the winner, and the pipeline for new drugs is verging on empty (Fig. 1) [13]. Development of antimicrobial drugs gives a low return on investment, contributing to the current crisis in fighting against drug-resistant pathogens [3]. Despite extensive efforts in research and enormous investment of resources, the pace of drug development has not kept up with the development of resistance (Fig. 2). Increasing rates of bacterial resistance also invalidate the utility of even the most potent antibiotics, resulting in mortality due to failure in infection control and high health care costs [14]. Changes in societal activities, progress of technology, and evolving microorganisms themselves are cooperatively contributing to the escalation of emerging and re-emerging infectious diseases, and to the development of antimicrobial resistance. 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 [1,5]. The first serious clinical threat in treating infectious diseases using antibiotics was the emergence of vancomycinresistant Enterococcus (VRE); which has intrinsic resistance to several commonly used antibiotics and, perhaps more importantly, a capability of acquiring resistance to all currently available antibiotics [2]. More than 40% of Staphylococcus aureus strains collected from hospitals were resistant to methicillin (methicillin-resistant S. aureus, MRSA) [1] and some of them were found to be resistant to vancomycin. Treating vancomycin-resistant S. aureus (VRSA) strains is a global and daunting medical challenge for the twenty-first century because vancomycin is

130

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

Fig. 1. FDA approval on new antibiotics [13].

the latest generation of antibiotics and is assumed at the moment to be the most effective for S. aureus infection [15,16]. Multi-drug resistance has been increasing particularly among nosocomial Gram-negative bacteria that are capable of developing many different mechanisms for antimicrobial resistance, often rendering them multiplication-resistant [2]. This also explains the increasing antimicrobial resistance of nosocomial Gram-negative bacteria to extended-spectrum cephalosporin, a class of the newest and most powerful antibiotics [4]. Resistance to antimicrobial drugs becomes a threatening problem not only in hospitals but also in communities, resulting in fewer effective drugs available to control infections by “old” established bacteria such as Streptococcus pneumoniae (S. pneumoniae) [17]. Drug-resistant Neisseria gonorrheae (N. gonorrheae) and Haemophilus influenzae (H. influenzae) were already recognized worldwide in the 1970s [18]. Recently, more than 1500 people in Germany have been infected by a new virulent strains of Escherichia coli (E. coli), which was not previously known to be involved in any outbreaks but turned out to be highly infectious and toxic, leading to a number of fatal cases. Moreover, bioinformatics analysis revealed that this deadly bacterial strain carries several antibiotic resistance genes, including resistance to aminoglycosides, macrolides, and β-lactam antibiotics. This implicates that treating this virulent bacteria with antibiotics is extremely difficult [19–21]. The spread of resistance to many currently used antimicrobial agents among fungi, viruses, and parasites is a high level alert to find paradigm-shifting approaches for treating microbial infections as a top priority in

medicine. Therefore, design, discovery, and delivery of antimicrobial drugs with improved efficacy and avoidance of resistance are highly demanded [22]. There have been considerable efforts in searching for new natural product-derived antibiotics to control infections by VRE, VRSA, MRSA, and other multidrug-resistant microorganisms [23]. An attractive alternative to using antibiotics is utilizing agents that cause physical damages to antimicrobial resistant strains. For example, selective photothermal therapy for in vivo antimicrobial treatment using pulsed laser was reported [24]. Another challenge in antimicrobial therapy is the treatment of chronically infected conditions such as cystic fibrosis and other chronic obstructive pulmonary diseases. Treating such conditions necessitates frequent intravenous administrations of high-dose antibiotics, which cause serious adverse effects from a high concentration of antibiotics in serum. Even with aggressive antibiotic treatment, complete eradication of infection under such conditions is hard to achieve because of bacteria's ability to form biofilms [25]. The persistent infection also leads to the rise of bacterial strains that possess elevated tolerance to current antibiotics. Therefore, a new antimicrobial therapy employing a cuttingedge technology that is more effective and safer than the currently available ones is desperately desired [26]. 2.2. Potential impact of nanomedicine on the control of infectious diseases Use of nanotechnology in immunization, design and delivery of antimicrobial drugs, and diagnosis and control of cross-infections, in particular in overcoming antibiotics-resistant pathogens, has been explored as a promising alternative to the current antibiotics-based approaches [6,12]. This section introduces various challenges in controlling infectious diseases, encompassing diagnosis of bacterial resistance, delivery of antimicrobial agents, and vaccination, using nanotechnology. 2.2.1. Nanotechnology-assisted detection of antimicrobial infection and resistance Despite their high sensitivity and reproducibility, conventional diagnostic methods for a microbial infection require cumbersome sample preparation and long readout times [27]. Unique electrical, magnetic, luminescent, and catalytic properties of nanomaterials enable fast, sensitive, and cost-effective diagnosis as well as rapid determination of the susceptibility and resistance of anti-bacterial drugs [28,29]. Antibody-conjugated NPs amplify the signals for bioanalysis and enumeration of highly pathogenic bacteria such as E. coli O157:H7, resulting in highly selective, convenient, and rapid

Fig. 2. History of antimicrobial agent development vs. subsequent acquaintance of resistance by microorganisms.

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

detection of single bacterium within 20 min [30]. 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. coli antibodies [31]. It was shown that NPs with specific Raman spectroscopic fingerprints can distinguish antibioticresistant bacteria, such as MRSA from non-resistant strains, by detecting single-nucleotide polymorphisms in microarray-based systems [32]. The use of magnetic NPs also could be a very sensitive and rapid strategy to detect microbial infection. For example, dextrancoated supermagnetic iron oxide NPs were clustered by Con-A treatment, or equipped with Con A-conjugated nanosensors [33]. These NPs were able to assess the microbial metabolic activity and determine antimicrobial susceptibility in blood, by rapidly quantifying polysaccharides. Supermagnetic iron oxide nanoprobes greatly assisted the identification of Mycobacterium avium spp. paratuberculosis (MAP) as well as the quick quantification of MAP in milk and blood with high sensitivity [34]. The broad absorption spectra (i.e., 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]. These characters suggest that QDs are a promising modality for the analysis of complex samples for histology, pathology and cytology, and can facilitate double or even triple immunostaining of bacterial cells (e.g., Listeria monocytogenes [L. monocytogenes]) [36]. A great deal of efforts have been invested in developing affordable, robust, and reproducible nanodiagnostic assays to be globally accessible and applicable even in rural areas of developing countries [27,37]. Furthermore, recent studies using nanotechnology have demonstrated the feasibility of achieving fast and reliable pharmaceutical assays for microbial infections in opaque media (e.g., whole blood and milk), without any sample preparations [38,39].

2.2.2. 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]. In particular, nanosized silver, zinc, and their compounds have been reported to be effective in inactivating various microorganisms [40,41]. 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]. Recently, antibiotics formulated in polymeric NPs have demonstrated enhanced antimicrobial activities and anti-MRSA activities, compared with nonpolymerized forms of penicillin and N-methylthio β-lactams [22,44]. 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. Vancomycincapped gold (Au) NPs has also exhibited enhanced antimicrobial activities against VRE strains and E. coli strains [45]. Selective killing of target bacteria by irradiating Au NP-attached bacterial surface with a laser has been recently demonstrated [46]. This technology leads to effective and irreparable damage to the bacterium bound with Au NPs of different sizes conjugated with antiprotein A antibodies. A new photothermal approach to antimicrobial nanotherapy and pathogen detection at a single bacterium level has also been developed using carbon nanotubes (CNTs) [47]. This study revealed CNTs' threefold roles: high near-infrared (NIR) contrast agents, high affinity and clustering agents for bacteria, and highly efficient converter of optical energy into thermal energy, especially in liquid environment [24]. A wide range of antimicrobial agents can be effectively administered using various NPs. Many types of lipophilic and water-soluble antibiotics can be conjugated inside or on the surface of NPs, or carried via encapsulation [48]. Key pharmacokinetic characteristics of antibiotics, including improved solubility, controlled release, and

131

specific site-targeted delivery, can be achieved by employing appropriate nanocarriers [12]. 2.2.3. Nanotechnology for vaccination and prevention of infectious diseases Use of NPs as novel adjuvants and colloidal vaccine carriers for immunization has been explored [12]. Particulate systems provide several benefits for vaccine delivery [49] in such that micro- and nanoparticles are approximately the sizes of bacteria and viruses that the immune system recognizes. The size, chemical composition, charge, and surface properties of particulate vaccine carriers can also be tuned for enhanced uptake by mononuclear phagocytic system (MPS), stimulation of antigen presenting cells (APs), and immune presentation of antigens [50,51]. For example, amphipathically coated NPs efficiently deliver antigens to dendritic cells (DCs) that concomitantly orchestrate cellular and humoral immunity [51,52]. In in vivo studies, mixtures of nanoemulsions with either whole viruses (e.g., influenza A virus) or proteins (e.g., recombinant Bacillus anthracis [B. anthracis] protective antigens) have been explored as potential vaccines [53,54]. This type of vaccine does not require cold storage and can be administered via mucosal routes, which would be particularly desirable for vaccination in developing countries [12]. 3. Nanoantibiotics: Nanomaterials for infection control Nanomaterials, which either show antimicrobial activity by themselves [43] or elevate the effectiveness and safety of antibiotics administration [7,48,55], are called “nanoantibiotics” and their capability of controlling infections in vitro and in vivo has been explored and demonstrated. Unlike many antimicrobial agents currently being used in the clinic, antimicrobial NPs may not pose direct and acute adverse effects, although potential toxicity upon long-term exposure is questionable. Most importantly, antimicrobial NPs tackle multiple biological pathways found in broad species of microbes (Fig. 3) and many concurrent mutations would have to occur in order to develop resistance against NPs' antimicrobial activities. Preparation of antimicrobial NPs could be cost-effective, compared with antibiotics synthesis, and they are quite stable enough for long-term storage with a prolonged shelf-life [11]. In addition, some NPs can withstand harsh conditions, such as high temperature sterilization, under which conventional antibiotics are inactivated. Antibiotics delivery using nanomaterials offer multiple advantages: 1) controllable and relatively uniform distribution in the target tissue, 2) improved solubility, 3) sustained and controlled release, 4) improved patient-compliance, 5) minimized side effects, and 6) enhanced cellular internalization [56–58]. 3.1. Antimicrobial nanomaterials Antibacterial NPs consist of metals and metal oxides, naturally occurring antibacterial substances, carbon-based nanomaterials, and surfactant-based nanoemulsions [43]. High surface area to volume ratios and unique chemico-physical properties of various nanomaterials are believed to contribute to effective antimicrobial activities [11]. A recent study also demonstrated that naturally occurring bacteria do not develop antimicrobial resistance to metal NPs [40]. Antimicrobial mechanisms of nanomaterials include: 1) photocatalytic production of reactive oxygen species (ROS) that damage cellular and viral components, 2) compromising the bacterial cell wall/membrane, 3) interruption of energy transduction, and 4) inhibition of enzyme activity and DNA synthesis [10,11,41–43,55,59] (Fig. 3). Table 1 also summarizes nanomaterials with their antimicrobial mechanisms, and potential clinical and industrial uses. Recently, intracellular or extracellular synthesis of metallic NPs (cadmium sulfide [CdS], gold [Au], and silver [Ag]) using microbial cells or enzymes has also been explored as novel biological and environment-friendly NP preparation [60–64].

132

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

medical devices and surgical masks, impregnated textile fabrics, nanogels, and nanolotions [76–79]. Prolonged exposure to soluble silver-containing compounds may produce an irreversible pigmentation in the skin (argyria) and the eyes (argyrosis), in addition to other toxic effects, including organ damages (e.g., liver and kidney), irritation (e.g., eyes, skin, respiratory, and intestinal tract), and changes in blood cell counts [80]. On the contrary, metallic silver appears to pose a minimal risk to health and Ag NPs are suggested to be non-toxic in some studies [81,82], but some studies reported concentration-dependent adverse effects of Ag NPs on the mitochondrial activity [83,84]. The advent of Ag NPs as promising antimicrobial nanomaterials, therefore, requires clear and full elucidations of their potential toxicity.

Fig. 3. Various antimicrobial mechanisms of nanomaterials.

3.1.1. Silver (Ag) NPs The antibacterial property of silver has been noticed since ancient times. Silver has been used for burn wound treatment, dental work, catheters, and bacterial infection control, in the forms of metallic silver, silver nitrate, and silver sulfadiazine [65]. Using silver to treat bacterial infections became unpopular after penicillin was introduced in the 1940s [66]. The recent emergence of antibiotics-resistant bacteria and the limited effectiveness of antibiotics revived the clinical use of silver (e.g., wound dressings) [13]. Among the many different types of metallic and metal oxide NPs, Ag NPs have proven to be the most effective against bacteria, viruses, and other eukaryotic microorganisms [67–70]. Ag NPs attack the respiratory chain and cell division that finally lead to cell death, while concomitantly releasing silver ions that enhance bactericidal activity [71]. The antimicrobial activity of Ag NPs is inversely dependent on size [72,73] and shape [10]. Combined use of Ag NPs with antibiotics, such as penicillin G, amoxicillin, erythromycin, and vancomycin, resulted in enhanced and synergistic antimicrobial effects against Gram-positive and Gram-negative bacteria (e.g., E. coli and S. aureus) [7,74,75]. Diverse applications of Ag NPs include wound dressings, coating for

3.1.2. 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]. For example, ZnO NPs, which are nontoxic and biocompatible, have been utilized as drug carriers, cosmetics ingredients, and medical filling materials [88,89]. Recently, ZnO NPs were found to have antibacterial activity against important food borne pathogens, such as E. coli O157:H7 and enterotoxigenic E. coli [67,85,90]. These studies suggested that the application of ZnO NPs may be effective for preserving agricultural products and food. ZnO NPs have advantages over Ag NPs, such as a low production cost, a white appearance, and UV-blocking properties [91]. The nano-ZnO multilayer deposited on cotton fabrics showed excellent antibacterial activity against S. aureus [92]. ZnO NPs are believed to destruct lipids and proteins of the bacterial cell membrane, resulting in a leakage of intracellular contents and eventually the death of bacterial cells [41,67]. In addition, generation of hydrogen peroxide and Zn+ 2 ions were suggested to be key antibacterial mechanisms of ZnO NPs [93]. Increased membrane permeability, cellular internalization, and intracellular structural change of polyvinyl alcohol (PVA)-coated ZnO NPs were also reported [41]. 3.1.3. 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]. A great amount of information accumulated over the last 20 years [95] demonstrated the strong bactericidal

Table 1 Antimicrobial nanomaterials. Nanomaterial Ag NPs

Antimicrobial mechanism +

TiO2 NPs

Release of Ag ions; disruption of cell membrane and electron transport; DNA damage Intracellular accumulation of NPs; cell membrane damage; H2O2 production; release of Zn2+ ions Production of ROS; cell membrane and wall damage

Au NPs

Interaction with cell membranes; strong electrostatic attraction

Chitosan

Increased permeability and rupture of membrane; chelation of trace metals; enzyme inactivation Destruction of cell membrane integrity; enhancing activity of infiltrating neutrophil Cell membrane damage by ROS; oxidation of cell membrane proteins and lipids NO release and production of ROS

ZnO NPs

Fullerenes CNTs NO-releasing NPs Nanoemulsion

Membrane disruption; disruption of the spore coat

Clinical and industrial applications

References

Dressing for surgical wound and diabetic foot; coatings for medical devices; portable water filters; antibacterial agent; antifungal agent Antibacterial creams; lotions and ointment; surface coating of medical device; mouthwash Antibacterial agent; food sterilizing agent; air purifiers; water treatment systems Photothermal therapy with near infrared light; adjuvant treatment after serious infections antibacterial agent; antifungal agent Drinking water disinfectants; bacteria immobilizer; microbiocide in biomedical products Potential disinfection applications

[10,43,71–73] [41,91,92] [42,95,96,98] [68,81] [43,59,113] [124–128]

Antibacterial agent; biofouling-resistant membranes; water filter; surface-coating Infected wound and diabetic foot treatment

[146,148,149]

Antimicrobial inhaler; anti-biofilm agent; nasal application; vaccine delivery agents

[168,254]

[154]

Abbreviations Ag NPs, silver nanoparticles; ZnO NPs, zinc oxide nanoparticles; TiO2 NPs, titanium oxide nanoparticles; Au NPs, gold nanoparticles; CNT, carbon nanotubes, NO, nitric oxide.

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

activity of TiO2 upon receiving irradiation with near-UV light and UVA. The required concentration for killing bacteria varies in the range of 100–1000 ppm, depending on the TiO2 NP size as well as the intensity and wavelength of the light source [42]. A new study reported the TiO2 NPs' antibacterial efficiency in the order of E. coliN P. aeruginosa N S. aureusN E. faeciumN C. albicans, is seemingly determined by the complexity and the density of the cell membrane/wall [96]. It was also reported that the photocatalytic antimicrobial efficiency of TiO2 NPs was in the order of virusN bacterial wall N bacterial spore, depending on the thickness of microbial surface structure [96]. Growth inhibition of Enterobacter cloacae by UVA-irradiated TiO2 NPs was less effective than that of E. coli and P. aeruginosa [97]. The photocatalytic antibacterial activity of TiO2 is attributed to the production of ROS such as free hydroxyl radicals and peroxide [98]. Hydroxyl radicals generated by photocatalytic TiO2 are very potent oxidants with a broad reactivity, and the microbial surface is the primary target of the initial oxidative attack by irradiated TiO2 NPs, in direct contact with or close to a microbe. Damaged membrane structure impairs many crucial biological functions, such as semipermeability, respiration, and oxidative phosphorylation reactions [42]. Irradiationindependent bacterial death also indicates other unknown nonphotocatalytic antimicrobial activity of TiO2 NPs [99]. An attractive feature of disinfection by TiO2 is its potential for activation by visible light (e.g., sunlight). In addition, metal doping (e.g., Ag/TiO2) improved the light absorbance of TiO2 and increased its photocatalytic inactivation of bacteria and viruses [95,100]. Very interestingly, Ag/(C,S)-TiO2 NPs were shown to have strong light-independent antimicrobial activities against both E. coli and B. subtilis spores, by exploiting the combined bactericidal activity of Ag and TiO2 together [101]. TiO2 is particularly suitable for water treatment because it is stable in water, non-toxic by ingestion, and cost-effective. The photocatalytic activity by UV-A and the potential activation by visible light, when doped with novel metals, make TiO2-mediated disinfection especially useful in developing countries where electricity is not available for sterilization [43]. According to recent studies, TiO2 also inactivates various microorganisms that are highly resistant to desiccation and UV radiation, which makes TiO2 a promising agent for improving process hygiene and product safety in food industry and cosmetics [95,100]. Antibacterial effects of TiO2 on Lactobacillus acidophilus would also be used in orthodontic appliances, such as pit and fissure sealants, toothbrushes, dental implants, and screws [98]. 3.1.4. Gold (Au) NPs Near-infrared (NIR) light-absorbing Au NPs, nanorods, nanoshells, and nanocages have been employed to treat bacterial infections via irradiation with focused laser pulses of suitable wavelengths [69,102]. The antimicrobial activity of Au NPs seems to be initially mediated by strong electrostatic attractions to the negatively charged bilayer of the cell membrane [68,81], which was also supported by the observation that cationic particles were found to be moderately toxic while anionic particles were not [8]. Au NPs conjugated with antimicrobial agents and antibodies have been explored to obtain selective antimicrobial effects [103]. For example, selective killing of S. aureus by Au NPs conjugated with anti-protein A antibodies, which target the bacterial surface, was demonstrated [40]. It was found that strong laser-induced hyperthermic effects accompanied by bubble-formation around clustered Au NPs effectively damaged bacteria [40]. Many studies have reported strong antimicrobial effects against Gram-positive and Gram-negative bacteria, including antibiotic-resistant strains [69,104], by Au/drug nanocomposites (e.g., Au NPs coated with antibiotics such as streptomycin, gentamicin, and neomycin). In a recent study, chitosan-capped Au NPs coupled with ampicillin showed a 2-fold increase in antimicrobial activity, compared with that of free ampicillin [68]. Therefore, Au NPs are promising adjuvants for antibiotics therapy in treating serious bacterial infections at a reduced antibiotics dosage with minimal adverse effects.

133

3.1.5. 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. aeruginosa and S. aureus in a recent study [106]. Copper is a structural constituent of many enzymes in many living microorganisms. However, free ionic Cu 2+ at a high concentration can generate toxic effects by generating ROS that disrupts the amino acid synthesis and DNA [107]. Although antibacterial activity of Ag NPs is well established and proven to be most effective in general among the metallic NPs [55,70,108], the antibacterial activity of NPs vary depending on the microbial species [109]. For example, 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, hence, superior antibacterial activity [109,110]. Copper oxide (CuO) is cheaper than silver, easily miscible with polymers, and relatively stable chemically and physically [111]. 3.1.6. 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]. It is only recently when these materials have been engineered into a form of NPs, that the nano-scale chitosan as well as its derivatives exhibit antimicrobial effects against bacteria, viruses, and fungi [59,112,113]. Chitosan was found to be more effective for controlling fungal and viral infections than bacterial ones [59], and the antimicrobial activity of chitosan has previously been considered greater for Gram-positive bacteria than Gram-negative ones [113,114]. A further elucidated tendency has been shown by recent studies [115,116]. 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]. A study also showed chitosan's synergistic antimicrobial activity against drug resistant P. aeruginosa when used with sulfamethoxazole [118]. The clinical potential for such combinatory uses of chitosan in overcoming untreatable resistant infections could be immense. Chitosan's antimicrobial mechanisms have been explained by various theories. One of them is the binding to the negatively charged bacterial surface to cause agglutination, increasing the permeability of the microbial wall, which eventually induces a leakage of intracellular components [113]. According to another proposed mechanism, chitosan chelates trace metals and thereby inhibits enzyme activities and the microbial growth [119]. 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]. The limited solubility only in acidic media and precipitation in the culture medium prevent from correctly investigating the antibacterial activity and its mechanisms [112]. Water-soluble derivatives of chitosan showed a higher antimicrobial activity, by disrupting the outer and inner membranes of bacteria, than native chitosan [120]. 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]. Even with distinctively different internalization pathways in E. coli and S. aureus, potent antimicrobial activities of oleoyl-chitosan NPs against both bacteria were observed [121]. Utilizing chitosan is a promising, cost-effective, and technologically affordable disinfection method that is particularly useful in developing countries. Nano-scale chitosan could be used to disinfect microbes in membranes, sponges, or surface coatings of water storage tanks [113]. It has several advantages over other disinfectants, such as a high antibacterial activity, a broad spectrum of activity, a high microbe-killing efficiency, and a low toxicity on mammalian cells [59].

134

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

3.1.7. Fullerenes (C60) and fullerene-derivatives Fullerenes' antimicrobial properties are of very recent findings based on limited knowledge [122]. Although native fullerenes are nearly aqueous-insoluble, they can be dispersed in water by the several recently developed methods [123]. In particular, numerous techniques for creating stable colloidal C60 aggregates (nC60) in water are noted for their potent and broad antibacterial activity [43,124]. The debatable antibacterial mechanism for nC60 includes photocatalytic ROS production in eukaryotic cells [125–127]. Some studies assert that antibacterial activity of nC60 to prokaryotic cells is mediated via lipid peroxidation in the cell membrane [124,128]. Lacking protein oxidation as well as light- and oxygen-independent antibacterial properties of nC60 indicate the ROS-independent toxicity mechanism [127]. Recently, new observations suggest that the observed toxicity of nC60 in both human cells and microorganisms may be due to solvent contaminants (e.g., tetrahydrofuran [THF] or its oxidative by-products) that were used or generated during C60 preparation [43,123,129]. The suspension of nC60 prepared via THFindependent methods was demonstrated to be nontoxic, particularly after γ-irradiation [123,130,131]. Moreover, nC60 prepared without using any polar organic solvent resulted in no acute or subacute toxicity in rodents, and also protected the livers from damages by free-radicals in a dose-dependent manner [132]. The antimicrobial activity of carboxyfullerene is mediated by insertion into the cell wall, followed by disruption of the cell membrane structure [122]. Alkylated C60-bis(N,N-dimethylpyrrolidinium iodide) derivatives affect the respiratory chain and effectively inhibit bacteria growth, which is comparable to the antimicrobial effects of vancomycin [133]. Polyhydroxylated fullerenes [C60(OH)n], known as fullerols, exhibited a strong antimicrobial activity over a wide-range of microorganisms with lower toxicity than that of nC60 [134]. Fullerol can also be used as a drug carrier that bypasses the blood ocular barriers [135]. Although the acute toxicity of fullerols is low, long retention in the body raises concerns about chronic toxic effects [136–138]. Aggregated form of C60 in water (fullerene water suspensions [FWS]) has unique physicochemical properties, including antimicrobial activity different from those of bulk solid C60 [43,139]. For example, FWS prepared by using THF as a solvent (THF/nC60), sonicating C60 dissolved in toluene with water (son/nC60), stirring C60 powder in water (aq/nC60), and using polyvinylpyrrolidone (PVP/C60) as a solubilizing agent exhibited strong antibacterial activity [139]. 3.1.8. Carbon nanotubes (CNTs) CNTs are cylindrical nanostructures made of pure carbon atoms covalently bonded in hexagonal arrays [140], and their unique optical, electrical, mechanical, and thermal properties have been of great interest [141]. Single-walled nanotubes (SWNTs) are a single pipe with a diameter in the range of 1–5 nm, while multi-walled tubes (MWNTs) have several nested tubes with lengths varying from 100 nm up to several tens of micrometers [43]. Early studies indicate profound cytotoxicity of CNTs in alveolar macrophage, in the order of SWNTs N MWNTs N quartz N C60 [142,143]. A transient inflammation and lung injury after SWNTs instillation in vivo was also reported [144,145]. Although it was suggested that SWNTs have antimicrobial properties [146], the poor aqueous dispersion of pure CNTs undermined the promise as an antibacterial and antiviral agent [43]. Recently, it was demonstrated that the aqueous dispersity of CNTs can be greatly improved after being stabilized by surfactants or polymers (e.g., sodium dodecyl benzene sulfate [SDBS], PVP, and Triton-X) [140]. Among various carbon-based nanomaterials, which are cytotoxic in general, SWNTs exhibit the strongest antimicrobial activity [141,146,147] via combination of membrane and oxidative stress, possibly in a synergic way [146,148]. The latest work proposed detailed antimicrobial mechanisms of SWNTs in three-steps: initial SWNTbacteria contact, membrane perturbation, and membrane oxidation in an electronic structure (i.e., metallic vs. semiconducting)-dependent

manner [149]. Biofilm formation and subsequent biofouling of surfaces (e.g., water filtration membranes) may be sufficiently prevented by SWNTs [43,150]. High chemical stability and ease of functionalization make SWNTs additionally attractive antimicrobial biomaterials [148]. In order to exploit fully effective antimicrobial properties, the degree of aggregation, the stabilization effects by natural organic matter, and the bioavailability of CNTs must be considered [140]. For example, rope-like CNT agglomerates are more cytotoxic than well-dispersed CNTs at the same concentrations [142]. Utilizing CNTs for water purification, effective inactivation of E. coli and poliovirus, and removal of MS2 bacteriophage has been increasingly explored [24,147,150]. Unlike conventional filters, CNT filters can be cleaned repeatedly to regain their full filtering efficiency [150,151]. CNTs can also be used for antimicrobial photothermal therapy by delivering CNT nanoclusters to an infected area, followed by spontaneous bacterial adsorption to the clusters and selective destruction of drug-resistance microorganisms upon near infrared irradiation [21,152]. 3.1.9. Nitric oxide (NO)-releasing NPs Nitric oxide (NO), a diatomic free radical, is a molecular modulator for immune responses to infection, and NO-releasing NPs can be a promising antimicrobial alternative [153]. NO and its derivatives known as ‘reactive nitrogen species (RNS)’ generate broad antibacterial activity [154]. While NO has been reported to effectively act in combination with other agents [155], the antimicrobial efficacy of independent NO donors were not well-documented. Recently, both Gram-negative and positive bacteria, including MRSA, have been found to be susceptible to gaseous NO and small molecule NO donors [156]. Unfortunately, the lack of suitable vehicles for NO storage and delivery has been a limiting factor for utilizing NO as an antibacterial agent. Treating cutaneous infections using acidified nitrite was reported to be effective but also caused inflammation [157]. [A large quantity of NO can be reversibly constrained within the lattice structure of zeolites [158]. Recently, 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]. Gram-negative (P. aeruginosa and E. coli) and Gram-positive (S. aureus and S. 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 [159,162]. NOreleasing silane hydrogen-based NPs showed antimicrobial activity against MRSA in vitro as well as in abscesses that frequently lead to serious complications (e.g., sepsis, tissue damage, and death) [156,163]. The physico-chemical properties of NO-releasing NPs (e.g., hydrophilicity/hydrophobicity, surface charge, and size) are easily tunable in comparison with small molecular NO donors [161]. In addition, NO-releasing NPs can be used to treat infected wounds [154,160], whereas NO donor molecules were reported to be effective in healing wounds in diabetic mice [157]. 3.1.10. Surfactant-based nanoemulsions Nanoemulsions, mixed water-immiscible and aqueous phases (oil-in-water [O/W], bicontinuous, and water-in-oil [W/O] emulsions, determined by water to oil ratios) via high-stress mechanical extrusion, have been investigated for their antimicrobial activity [164–166]. In recent years, some O/W micro- and nanoemulsions, which were found to be thermodynamically stable and either transparent or translucent, showed antimicrobial properties [165,167–170]. Bactericidal properties of soybean oil-based nanoemulsion against Gram-positive, but not against enteric Gram-negative species, were documented [167,171]. Stable and antimicrobial O/W microemulsions with various compositions of Tween 80, pentanol, and ethyl oleate [169,170] were also obtained. These microemulsions were found to be effective in killing S. aureus and resistant P. aeruginosa [169] as well as biofilms of P. aeruginosa [170]. BCTP, aqueous nanoemulsions of soybean oil, Triton

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

X-100, and tri-n-butyl phosphate [65], disrupt the membranes of enveloped viruses and bacteria, and inactivate the spores of different Bacillus species [168]. NB-401, a mixture of BCTP and P10 liposomes (Tween 60, soybean oil, glycerol monooleate, refined soya sterols, and the cationic cetylpyridinium chloride), is a fast-working antimicrobial agent against bacteria that are planktonically grown, as a biofilm, or in the sputum [164,170]. 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]. 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 [171,172]. 3.2. NPs for efficient antimicrobial drug delivery Despite the well-established efficacy of antimicrobial drugs, a suboptimized therapeutic index and local/systemic adverse reactions need to be addressed in order to obtain maximized therapeutic effects [173]. In addition, intracellular infections and acquired resistance of infectious microbes are also key challenges for many antimicrobial drugs [174]. Novel nanomaterials, NPs in particular, have unique physicochemical properties (e.g., ultrasmall and controllable size, large surface area to mass ratio, high interactions with microorganisms and host cells, and structural/functional versatility) and are a promising platform to overcome those limitations [173,175]. The advantages of NP-based antimicrobial drug delivery include improved solubility of poorly water-soluble drugs, prolonged drug half-life and systemic circulation time, and sustained and stimuli-responsive drug release, which eventually lowers administration frequency and dose [57,175]. Moreover, minimized systemic side effects via targeted delivery of antimicrobial drugs as well as combined, synergistic, and resistance-overcoming effects via co-delivery of multiple antimicrobial drugs can be achieved using NP carriers [173,175]. 3.2.1. Liposomes for antimicrobial drug delivery Liposomes are nano- to micro-sized vesicles comprising of a phospholipid bilayer with an aqueous core. Since Doxil (doxorubicinencapsulating PEGylated liposomes) became the first liposomal drug approved by the Food and Drug Administration (FDA) in 1995 [176], liposomes have been popularly studied as promising clinically acceptable delivery carriers of enzymes, proteins, and drugs for treating many different diseases [177]. Liposomes are also the most widely used antimicrobial drug delivery vehicles [48,58] because their lipid bilayer structure mimics the cell membrane and can readily fuse with infectious microbes [173]. In addition, both hydrophilic and hydrophobic antimicrobial drugs can be encapsulated and retained, without chemical modifications, in aqueous core and in the phospholipids bilayer, respectively [58,178]. A number of parameters such as the physico-chemical properties of lipids, drugs to be loaded, particle size and polydispersity, surface charge (zeta-potential), stability in storage (shelf-life), and reproducibility and feasibility for large-scale production should be considered in utilizing liposomes for antimicrobial drug delivery [173]. Upon administration, liposomes are rapidly cleared from the blood by mononuclear phagocytic system (MPS) [57] so various strategies to extend circulation were developed in the 1980s [178,179]. For example, incorporation of certain glycolipids (e.g., 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]. Conjugating “stealth” material (e.g., polyethylene glycol, PEG) on the surface of liposomes not only resulted in enhanced in vivo stability (i.e., long-circulation) but also enabled targeted delivery of antimicrobial drugs after tethered with various targeting ligands (e.g., antibody, antibody segments, aptamers, peptides and small molecule) [173,174,179]. Imaging infectious and inflammatory

135

foci using radioactively labeled PEGylated liposomes was also demonstrated [180]. Systemic administration of polymyxin B, which is effective in controlling infections by P. aeruginosa, has been limited due to its toxic side effects (e.g., nephrotoxicity, ototoxicity, and neuromuscular blockade) [183]. Formulation of polymyxin B in liposomes dramatically diminished side effects of the drug, while improving its antimicrobial activity [184]. Aminoglycosides-loaded liposomes interact with the outer membrane of multidrug resistant P. aeruginosa, leading to the membrane deformation, which was confirmed by transmission electron microscopy (TEM), flow cytometry, lipid mixing assay, and immunocytochemistry [185]. A high dosage of antimicrobial agents is immediately dumped into the bacteria when a liposome fuses with the cell membrane, potentially outriding the efflux pumps and suppressing the drug resistance of microbes [173,183]. Lauric acids loaded in liposomes can be an innate, safe, and effective formulation for treating acne vulgaris and other Propionibacterium acnes-associated diseases [186,183]. The drug stability and antimicrobial activity against Micrococcus luteus were shown to be greatly enhanced when ampicillin was loaded in liposomes, in comparison with free drugs [187]. Completely inhibited growth of S. 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]. 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, which suggests that liposomal ciprofloxacin can be an effective therapy for systemic salmonella infection [189]. Altered distribution in tissue and significantly extended half-life (blood 24.5 h, tissue 63–465 h) were obtained with liposomal amikacin [190]. Successful treatment of Mycobacterium aviuminfected mice by liposomal streptomycin was also demonstrated [191]. Liposomal gentamicin and ceftazidime showed prolonged blood circulation and enhanced localization at the infection site [192]. Encapsulation of vancomycin and teicoplanin in liposomes resulted in significantly improved elimination of intracellular MRSA infection [193]. Liposomal carriers for antimicrobial drug delivery are summarized in Table 2. 3.2.2. Solid lipid (SL) NPs SLNPs offer combined advantages of traditional solid NPs and liposomes, while avoiding some of their disadvantages [194,195]. Improved bioavailability and targeted delivery of antimicrobial drug using SLNPs have been investigated [196], via parenteral, topical, ocular, oral, and pulmonary administration routes [197–199]. When applied onto the skin, 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, increased transdermal diffusion of water-insoluble azole antifungal drugs (e.g., clotrimazole, miconazole, econazole, oxiconazole, and ticonazole) was reported by encapsulating them in SLNPs [173,201–203]. SLNPs in various formulations for oral administration (e.g., tablets, capsules, and pellets) can also be used for antimicrobial drug delivery [204]. P-glycoproteins (P-gp), an ATP-dependent efflux pump on the brush border of small intestine actively export the drugs, resulting in poor intestinal absorption of tobramycin [199], which was proposed to be overcome by tobramycin-loaded SLNPs [197]. High area under curve (AUC), low amounts trapped in the kidneys, and high concentrations in the lungs was achieved after intravenous administration of tobramycin-encapsulating SLNPs, which also markedly improved capability of crossing blood–brain barriers [197]. 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. SLNPs are also a promising means for

136

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

Table 2 Lipid-based nanocarriers for antimicrobial drug delivery. Nanocarrier type

Composition

Encapsulated antibiotics

Target microorganism

Mechanism for improved therapeutic effects

Ref.

Liposomes

PG, PC, and Chol

Streptomycin

Mycobacterium avium

[191]

DPPC and Chol

Ciprofloxacin

Salmonella dubli

EPC, DCP, and Chol SPC and Chol

Vancomycin or Teicoplanin Ampicillin

MRSA

HS PC, Chol, and DSPG PHEPC, Chol, and PEG-DSPE DPPC and Chol

Amikacin

Micrococcus luteus and Salmonella typhimurium Gram-negative bacteria

Gentamicin

Klebsiella pneumoniae

Polymyxin B

Pseudomonas aeruginosa

DPPC, Chol, and DC-Chol SA, SPC, and STC GB, and SDC SA

Benzyl penicillin

Staphylococcus aureus

Tobramycin Ketoconazole Rifampicin, isoniazid, pyrazinamide Econazole nitrate

Pseudomonas aeruginosa fungi Mycobacterium tuberculosis

Ciprofloxacin hydrochloride

Gram-negative bacteria, Gram-positive bacteria, and mycoplasma

Increased antimicrobial activity by drug encapsulation; targeted delivery to the site of bacterial multiplication Decreased mortality of animals; distribution of liposomes to all areas of infection Enhanced drug uptake by macrophages; enhanced intracellular antimicrobial effect Increased stability; activity against extracellular bacterial colonies Prolonged drug residence in tissue and plasma; reduced renal clearance and excretion Increased survival rate of animal models; increased therapeutic efficacy Decreased bacterial colony count in lung; decreased lung injury caused by bacteria; increased bioavailability Lower drug concentrations and shorter time of exposure Increased drug bioavailability Prolonged drug release; high physical stability Increased drug bioavailability and residence time; decreased administration frequency Controlled drug release profile; high encapsulation efficiency; enhanced drug penetration through stratum corneum Prolonged drug release

Solid lipid NPs

GPS

SA, SPC, and STC

Fungi

[189] [193] [187] [190] [278] [183]

[188] [199] [279] [196] [203]

[205]

Abbreviations Chol, cholesterol; DC-Chol, dimethylammonium ethane carbamoyl cholesterol; DCP, diacetylphosphate; DSPG, distearoyl phosphatidylglycerol; DPPC, 1,2-dipalmitoylphosphatidylcholine; EPC, egg PC; GB, glyceryl behenate; GPS, Glycerol palmitostearate; HSPC, hydrogenated soybean phosphatidyl choline; PC, phosphatidyl choline; PEGDSPE, 1-2-disteroyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol-2000); PG, phosphatidyl glycerol; PHEPC, partially hydrogenated egg phosphatidyl choline; SA, stearic acid; SDC, sodium deoxycholate; SPC, soybean phosphatidyl choline; STC, sodium taurocholate.

prolonged ciprofloxacin release, particularly in ocular and skin infections via local delivery [205]. Intravenously injected colloidal drug carriers are undesirably taken up by the MPS, therefore, improving drug targeting and accumulation necessitates an alternative administration route such as pulmonary drug delivery [198]. Unlike liposomes and polymeric NPs, inhalable SLNPs are stable, have a high drug incorporation capability, and offer a significantly reduced risk of retaining residual organic solvents [195]. SLNPs are assumed to be phagocyted by alveolar macrophages in the lungs, and subsequently transported to the lymphoid tissues [196–198]. For example, no tubercle bacilli were detected in the lungs and spleens after rifampicin, isoniazid, and pyrazinamide-encapsulating SLNPs were nebulized to infected guinea pigs every 7 days, whereas daily oral administrations of the free drugs for the same period were required in order to obtain equivalent therapeutic effects [196,206]. These results propose a cost-effective and patient-friendly approach to obtain a high chemotherapeutic potential for tuberculosis treatment using antimicrobial drug-loaded SLNPs. Table 2 summarizes SLNPs investigated for antimicrobial drug delivery. 3.2.3. Polymeric NPs Shortly after the first polymer-based delivery of macromolecules (e.g., albumin and peptide hormones using poly[ethylene vinyl acetate] polymer) was demonstrated in 1976 [207–209], 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]. Antimicrobial drug delivery using polymeric NPs offers several advantages: 1) structural stability in biological fluids and under harsh and various conditions for preparation (e.g., spray drying and ultra-

fine milling) and storage, 2) precisely tunable properties (e.g., size, zeta-potentials, and drug release profiles) by manipulating polymer lengths, surfactants, and organic solvents used for NP preparation [48,173], and 3) facile and versatile surface functionalization for conjugating drugs and targeting ligands [57]. It was demonstrated that lectin-conjugated gliadin NPs selectively adhered to the carbohydrate receptors on the surface of microbes, such as Helicobacter pylori, and released antimicrobial agents into the bacteria [211]. Two major types of polymeric NPs have been explored for antimicrobial drug delivery: linear polymers (e.g., polyalkyl acrylates and polymethyl methacrylate) and amphiphilic block copolymers. Majority of polymeric NPs prepared with linear polymers are either nanocapsules or solid nanospheres [58]. In polymeric nanocapsules, a polymeric membrane that controls the release rate surrounds the drugs that are solubilized in aqueous or oily solvents. In contrast, drugs are homogeneously distributed in the polymeric matrices of variable porosities in solid nanospheres [212,213]. Amphiphilic block copolymers spontaneously self-assemble micellar NPs with the drugencapsulating hydrophobic core and the hydrophilic corona shielding the core from opsonization and degradation [214,215]. A library of biodegradable polymers, including poly(lactic acid) (PLA), poly(glycolic acid)(PGA), poly(lactide-co-glycolide)(PLGA), poly(ε-carprolactone) (PCL), and poly(cyanoacrylate)(PCA), has been used as hydrophobic segments (forming drug-encapsulating core for controlled drug release) of the amphilphilic copolymers, whereas PEG has been most commonly used as a hydrophilic segment [173]. Often targeting ligands (e.g., aptamers, Apt) are conjugated on the termini of PEG (e.g., PLGA-b-PEGb-Apt) for selective delivery [216,217]. 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. For example, ampicillin

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

encapsulated in poly(isohexyl cyanoacrylate) (PIHCA) NPs resulted in 120-fold enhanced efficacy in treating Salmonella typhimurium infections in mice [218]. Similarly, efficiently controlled intracellular L. monocytogenes infection in mouse peritoneal macrophages was reported by using ampicillin-encapsulating NPs [219]. 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]. There have been efforts to overcome the limited oral administration of the drugs, which are unstable or inadequately absorbed in the gastrointestinal tract, using polyethylcyanoacrylate (PECA) NPs [221]. In addition, PEGylation of PECA NPs reduced phagocytosis, dramatically increased the half-life in serum, and rendered mucoadhesivei capabilities [222]. Penicillin incorporated in the polyacrylate NPs, which were prepared by free radical emulsion polymerization in water, was able to retain its full antimicrobial activity against MRSA even in the presence of β-lactamase at high concentrations [19,48]. 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]. Cyanoacrylate NPs and their antimicrobial therapeutic potentials with a variety of antibiotics are well-documented [212]. Meanwhile, 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]. Polymeric NPs for antimicrobial drug delivery are summarized in Table 3.

3.2.4. Dendrimers Dendrimers are hyperbranched polymers with precise nanoarchitecture and low polydispersity, which are synthesized in a layer-bylayer fashion around a core unit, resulting in a high level control of size, branching points (drug conjugation capability), and surface functionality [225]. Polyamidoamine (PAMAM) is the initial and most commonly studied dendrimer and also a variety of dendritic building blocks have become exponentially available [226]. The highlybranched nature of dendrimers provides enormous surface area to size ratios that generate great reactivity to microorganisms in vivo [173]. The highly dense surface of functional groups allows the

137

synthesis of dendrimers with specific and high binding affinities to a wide variety of viral and bacterial receptors [227]. 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]. In addition, the dendrimers functionalized with quaternary ammonium, which is known as antimicrobials, on the surface at a high density displayed greater antibacterial activity than free antibiotics [173,229]. 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]. 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]. Carboxylic- or hydroxyl-terminated PAMAM dendrimers, which appear to be more biocompatible and less toxic than unmodified ones, can be easily conjugated with antimicrobial agents via abundant functional groups [58,227]. Sulfamethoxazole (SMZ)-encapsulating PAMAM dendrimers led to sustained release of the drug in vitro and 4–8 folds increased antibacterial activity against E. coli, compared to free SMZ [230]. Aqueous insoluble quinolones, which prevents their liquid formulations and restricts their use in topical application [225], were loaded in PAMAM dendrimers, generating not only excellent solubility but also similar or increased antibacterial activity [228]. Solubilization and controlled delivery of a hydrophobic antimalarial drug, artemether, were also achieved using PEGylated lysine-based dendrimers [231]. Many other antimicrobial drugs have been successfully incorporated into dendrimer NPs for improved solubility and, hence, therapeutic efficacy (Table 3).

4. Translation of nanoantibiotics from bench to bedside 4.1. 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]. Antimicrobial

Table 3 Polymer-based nanocarriers for antimicrobial drug delivery. Nanocarrier type

Polymer Encapsulated antibiotics

Target microorganism

Mechanism for improved therapeutic effects

Ref.

Solid NPs

PIHCA

Ampicillin

Salmonella typhimurium

[218]

PIHCA

Ampicillin

Listeria monocytogenes

PCL

Amphotericin B

Leishmania donovani

PAA

N-methylthiolated β-lactams Penicillin

MRSA

Increased drug concentration in liver and spleen; increased cellular drug uptake by macrophages; 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.e., ergosterol) Enhanced activity for water-insoluble drug conjugated with PAA; 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; higher therapeutic efficacy by the antibiotics-conjugated with GPAA High payload; prolonged circulation half -life

PAA

PLCP

N-sec-butylthio β-lactam, Staphylococcus aureus and Bacillus Ciprofloxacin anthracis Silver salts Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli Artemether Plasmodium falciparum

PAMAM

Sulfamethoxazole

Escherichia coli

PAMAM

Nadifloxacin and Prulifloxacin

Escherichia coli

GPAA Dendrimers

MSSA and MRSA

PAMAM

[219] [280] [223] [22]

[213] [239]

Increased drug stability; enhanced solubility; prolonged drug [231] circulation half-life Sustained drug release; increased antibacterial activity via enhanced [230] penetration of antibiotics through the bacterial membrane, 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, polyisohexylcyanoacrylate; PCL, poly(ε-carprolactone); PAA, polyacrylate; GPAA, glycosylated polyacrylate; PAMAM, polyamidoamine; PLCP, pegylated lysine based copolymeric dendrimer.

138

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

NPs propose several clinical advantages. First, nanocarriers can be engineered to be activated by stimuli (e.g., chemical, magnetic field, heat, and pH) for targeted delivery as well as biological sensors [232,233]. For example, amoxicillin was freeze-dried in formulation with chitosan and polyvinyl pyrrolidone for acid-responsive release of antibiotics [234]. This system could be particularly useful for treating abscess which is frequently acidic and reduces the potency of conventional antimicrobial therapy. Generally, most molecules poorly cross the blood brain barriers (BBB), a tight barrier to protect the brain from the penetration of xenobiotics. However, it was also reported that antimicrobial NPs made of certain materials and at varying particle sizes (e.g., Fe2O3 280 nm; TiO2 25, 80, 155 nm; Mn2O3 30 nm; 13 C NPs 36 nm) were capable of efficiently targeting infectious diseases by overcoming anatomic barriers (e.g., BBB) [235]. Second, 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., hepatotoxicity of cephalosporins, and ototoxicity and nephrotoxicity of aminoglycosides) [236]. Nanocarriers seem to be able to reduce the side effects by improving the solubility and stability of antimicrobial agents [173,237]. Third, NP-based antimicrobial drug delivery is promising in overcoming resistance to traditional antibiotics developed by many pathogenic bacteria [13]. Fourth, administration of antimicrobial agents using NPs can improve therapeutic index, prolong drug circulation (i.e., extended half-life), and achieve controlled drug release, enhancing the overall pharmacokinetics [173]. Many studies demonstrated greater efficacy of antimicrobial NPs than their constituent antibiotics alone [236]. For example, vancomycin-capped Au NPs (Au@Van NPs) exhibited 64-fold improved efficacy against VRE strains and Gram-negative bacteria such as E. coli over vancomycin alone [45]. For another example, mesoporous silica NPs were used as controlled release ionic liquids with proven bactericidal efficacy against E. coli K12 [238]. In addition, antimicrobial NPs can be prepared and administered in convenient and cost-effective ways via various routes with lowered administration frequency [11]. NP-based antimicrobial drug delivery can achieve improved solubility and suspension of drugs, and concurrent delivery of multiple agents for synergistic antimicrobial therapy [173,175]. Thus, antimicrobial NPs are of great interest as they provide a number of benefits over free antimicrobial agents (Table 4).

teractions of nanoantibiotics with cells, tissues, and organs, which consequently recalibrates doses and identifies proper administration routs to obtain desired therapeutic effects [232,239]. Profound knowledge about the potential toxicity of nanoantibiotics is also required to warrant successful clinical translation [240]. It has been shown that intravenously injected NPs can be accumulated in colon, lung, bone marrow, liver, spleen, and lymphatics [241]. Inhaled NPs also can enter the systemic circulation and reach lung, liver, heart, spleen, and brain [240,242], 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]. 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 [240,242]. Many recent studies suggest the possibility of multi-organ nanotoxicity that therapeutically administered antimicrobial NPs may generate. For example, free radical-mediated oxidative stress generated by the interaction of antimicrobial NPs with cells may result in hepatotoxicity and pulmonary toxicity [243,244]. Various metabolic changes suggest mitochondrial failure, and enhanced ketogenesis, fatty acid βoxidation, and glycolysis, contributing to hepatotoxicity and nephrotoxicity [244]. The toxic effects of antimicrobial NPs on central nervous system (CNS) are still unknown, and the interactions of NPs with the cells and tissues in CNS are poorly understood [235]. Besides, 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 [240,247]. Table 5 presents potential multiorgan nanotoxicity that has been implicated to be generated by therapeutically used antimicrobial NPs. NPs exhibit size-specific properties that limit the use of currently available in vitro assays in a universal way, and there is no standardized definition for NP dose in mass, number, surface area, and biological specimens (e.g., blood, urine, and inside organs) [241,248]. 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]. Toxicogenomics, coupled with other emerging technologies (e.g., proteomics and metabonomics), could reveal the mechanisms of NPs' toxic action at a molecular and genomic level [242].

4.2. Disadvantages of nanoantibiotics, including nanotoxicology

4.3. Treatment of drug-resistant microorganisms and biofilms

Although nanoantibiotics promises significant benefits and advances in addressing the key hurdles in treating infectious disease, there are foreseeable challenges in translating this exciting technology for clinical use. These include thoroughly evaluating the in-

Antimicrobial resistance to classical antibiotics is attributed to the altered bacterial growth phase, in particular the decreased susceptibility by halted division, genetic polymorphisms, and overexpression of efflux pumps [174,232]. One alternative antimicrobial drug delivery

Table 4 Advantages and disadvantages of antimicrobial NPs over free antimicrobial agents. Antimicrobial NPs Advantage

Disadvantage

Free antimicrobial agents 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, kidney, liver, brain, germ cell, metabolic, etc.) Lack of characterization techniques that are not affected by NPs' properties

Disadvantage

Advantage

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

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

139

Table 5 Potential toxicity of therapeutically used NPs. Toxicity type

Mechanism for toxicity

Ref.

Pulmonary toxicity Renal toxicity

Acute inflammatory change; granuloma formation; oxidative stress Renal glomerulus swelling; proximal tubular necrosis; mitochondrial failure; enhanced ketogenesis, fatty acid beta-oxidation, and glycolysis ROS generation; mitochondrial dysfunction; GSH depletion; LDH leakage Reduced neuro viabilities; exacerbation of cytoskeletal and blood-brain barrier (BBB) disruption; diminished ability to form neuritis in response to NGF; mild cognitive impairment, edema formation Sperm fragmentation; parital vacuolation of seminiferous tubules and cellular adhesion of seminiferous epithelium; suppressed proliferation of Leydig cell Abnormal protein functions generated by structural and conformational changes upon adsorption to NPs; raising protein potential for autoimmune effects Embryo neurotoxicity; embryo death; metabolic alkalosis

[243,281] [244]

Hepatotoxicity Neurotoxicity Spermatotoxicity NP-protein interactions

Others

[244] [235,240] [246,247] [237,240]

[240,246]

Abbreviations GSH, glutathione; LDH, lactic dehydrogenase; NGF nerve growth factor.

strategy to overcome antibiotics-resistance is to incorporate more than one antimicrobial agent in the same NPs for concurrent delivery [173]. Combining antibiotics and antimicrobial NPs (e.g., Ag NPs) is also a promising approach to improve antimicrobial activity and potentially overcome resistance to the current antibiotics. For example, the antibacterial activities of chloramphenicol, kanamycin, erythromycin, and ampicillin against Gram-positive and Gramnegative bacteria were increased in the presence of Ag NPs [249]. It was also reported that the antibacterial activity of cefoperazone against MRSA was enhanced when it was used with colloidal silver [250]. Vancomycin-capped gold NPs (Au@Van) were demonstrated to enhance antibacterial activity against VRE in vitro [45]. A similar result has been reported for ciprofloxacin-coated Au NPs [251]. In addition to vancomycin- and teicoplanin-encapsulating liposomes, antibioticsconjugated polyacrylate and carbohydrate NPs showed potent antibacterial properties against MRSA [22,193,213,223]. A folic acidtagged chitosan NPs loaded with vancomycin were found to be an effective drug delivery carrier for VRSA treatment [15]. It is highly foreseeable that the use of NP-based drug delivery systems will continue to improve treating bacterial infections, especially by MRSA, VRE, VRSA, and multidrug-resistant P. aeruginosa. Bacterial biofilms, a common cause of recurring infections, are not responsive to antimicrobial drugs [188]. Benzyl penicillin-encapsulating cationic liposomes and NO-releasing silica NPs showed antimicrobial and antibiofilm activities [156,188]. Recently, magnesium fluoride (MgF2) NPs prepared by microwave-assisted MgF2 coating on the glass surfaces prevented the formation of bacterial biofilms [252]. It was shown that vancomycin-encapsulating cationic liposomes have strong affinity to biofilms and efficiently penetrated into the skin layers [253]. Some micro- and nanoemulsions with antimicrobial properties might be effective anti-biofilm agents. For example, it was found that BCTP and TEOP (O/W microemulsion of ethyl oleate, Tween 80, n-pentanol) were highly effective in eradicating biofilms of MRSA and P. aeruginosa [254] which are common nosocomial pathogens and very difficult to eliminate, especially when forming biofilms [255]. Carvacrol and eugenol, two essential oil compounds, encapsulated in a micellar nonionic surfactant solution, also showed anti-biofilm activities against food pathogens such as E. coli O157:H7 and L. monocytogenes [256] A study reported that BCTP has higher activity against the biofilms of S. typhimurium, E. coli O157:H7, and S. aureus than those P. aeruginosa or L. monocytogenes [254].

4.4. Targeted therapy for infections using NPs Targeted antimicrobial drug delivery to the site of infection, especially intracellular infections, using NPs is an exciting prospect in treating infectious diseases [38,173]. Intracellular microorganisms, such

as M. tuberculosis, C. pneumoniae, L. pneumophila, and L. monocytogenes, are taken up by alveolar macrophages (AMs), intracellulary survive or multiply, and are resistant to the antimicrobial agents [257]. Antibioticsloaded NPs can enter host cells through endocytosis, followed by releasing the payloads to eliminate intracellular microbes [174,193]. Delivery of antimicrobial agents to the lung via systemic NP administration is invasive and potentially harmful upon systemic exposure to the drugs [39]. Alternatively, various NPs displaying preferential accumulation in the lung and other organs have been attempted [210,258]. 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, spleen, bone, and kidney [259]. 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]. Recently, ciprofloxacin-loaded, mannose-conjugated liposomes led to efficient drug targeting to AMs by pulmonary administration [257]. Other in vivo studies reported substantially higher AM-targeted antimicrobial drug delivery than alveolar epithelial type II cells using mannose-coated liposomes [261,262]. In contrast, the low endocytic capacity of non-MPS cells interferes with targeted antimicrobial drug delivery to the cells that are intracellulary infected [174]. The delivery to infected non-MPS tissue was improved with MPS-avoiding liposomes or stealth liposomes [176].

4.5. Local administration Antibiotics are generally administered via oral or intravenous routes in order to treat infections, often resulting in undesired systemic side effects by nonspecific drug distributions in many different tissues and organs. Therefore, local administrations, if feasible, are the ideal mode of antimicrobial drug administration. For example, local antibiotics delivery to the lung via inhalation can avoid drug loss and alteration by metabolism and enzymes in the gut and liver, while minimizing systemic adverse effects [258,263]. In addition, both low- and high-molecular weight drugs can be selectively delivered to nasal epithelia and the lung using NP delivery platforms [264]. NPs can be formulated for enhanced suspension of waterinsoluble drugs, better control of the drug morphology than in a dry powder form, and optimized low-density microstructure for delivery to the peripheral lung [58,263]. However, the toxicity caused by high local drug concentration should be evaluated. NPs may have adverse effects on respiratory mucosa, including drastically reduced mitochondrial function, increased membrane leakage, necrosis/apoptosis induction, and inflammation in the lung, cardiovascular system, and central nervous system, upon long-term exposure [240]. Assessing the respiratory toxicity of inhaled pharmaceuticals is greatly affected by

140

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

the nature of the administered materials [265]. Among many currently available methods (e.g., histopathology of lung sections, bronchoalveolar lavage, sputum cytology, and evaluations on pulmonary function, mucociliary clearance, immune response, and enzyme and mediators), bronchoalveolar lavage coupled with biochemical analysis is regarded as a proper way of assessment for the respiratory toxicity of NPs [133,265]. How various antimicrobial NPs and antimicrobial drug carriers affect the respiratory function, mucociliary clearance, and immune response needs to be fully elucidated in order to achieve efficient and safe treatment of pulmonary infections. Antibiotics-loaded SLNPs were explored to treat ocular infections by intravitreously administering antimicrobial drugs for sustained drug release at a high drug concentration [199,201,205]. Antibiotics encapsulated in SLNPs produced significantly lower ocular irritation than most antimicrobial drugs are known to cause [174]. Preliminary clinical studies indicated that intravitreal injection of antibioticsencapsulating liposomes and SLNPs can be more advantageous than using free drugs, for treatment of ‘resistant’ pseudomonal keratitis, or for preoperative prophylaxis against endophthalmitis [199,266]. The local delivery of tobramycin-encapsulating liposomes to surgical wound infections in soft tissue by P. aeruginosa reduced bacterial counts more significantly and for a longer period than the free antibiotics [267]. Biodegradable carriers have also recently been introduced in orthopedic surgery for prophylaxis of postoperative osteomyelitis and treatment of chronic osteomyelitis [268]. For example, D,L-dilactide achieved sustained drug release of pefloxacin, reaching the drug concentration peak, which is 100 times higher than the minimum inhibitory concentration (MIC) of pefloxacin for MRSA, and completely eradicated the bacteria in the MRSA osteomyelitis in rabbits [269]. Prolonged and controlled release of antibiotics can be achieved, without surgical removal, using several FDA-approved biodegradable polymers, including PLA and/or PGA and their variants [268,270,271]. High local therapeutic efficacy by septacin, a gentamicin sulfatecontaining polyanhydride implant, was demonstrated in the rat skinabscess, horse-joint infections, and infections in human prosthetic hip and knee joint [272]. In contrast to PLA/PGA, poly (trimethylene carbonate) (PTMC) generate non-acidic products after uniform surface erosion by enzymatic degradation, providing sustained and high antibiotics release rates [273]. Several types of bioceramics, including silicate-based bioactive glass and calcium phosphate-based materials (e.g., synthetic hydroxyapatite and tricalcium phosphate), not only locally deliver antibiotics but also contribute to the bone regeneration process. For example, it was demonstrated that teicoplanin-loaded borate bioactive glass and chitosan (TBGC) implants treated chronic osteomyelitis in rabbit, while simultaneously playing roles in bone regeneration [274]. Temperature-responsive polymers are attractive for the injectable antimicrobial drug delivery because of the minimally invasive administration, easy preparation without using harmful organic solvents, and high drug encapsulation efficiency [275,276]. An in vivo study showed treatment of osteomyelitis in rabbits via sustained release of teicoplanin from biodegradable thermosensitive PEG-PLGA hydrogel NPs [277]. 5. Concluding remarks For more than a half century antibiotics have been saving an enormous number of lives from many infectious diseases. However, the emergence of resistance to antibiotics acquired by microbial variants is a serious threat in combating against infectious diseases. It becomes clear that overcoming antibiotic resistance by developing more powerful antibiotics, which has been attempted by pharmaceutical companies, can lead to an only limited and temporary success and eventually contribute to developing greater resistance. Because of high surface area to volume ratio and unique physicochemical properties, nanomaterials are promising antimicrobial agents of a new class. NPs themselves have been employed as potent

antimicrobial agents for a variety of medical applications, such as NPbased dressings, NP-coated medical devices, nanogels, and nanolotions. Of many different approaches to overcome antimicrobial resistance, using NPs as antibiotics carriers seems to hold highest promise. Various NPs have been investigated as efficient antibiotics delivery vehicles which also protect antimicrobial drugs from a resistant mechanism in a target microbe (e.g., degradation by βlactamases). Most importantly, NPs enable combining multiple independent and potentially synergistic approaches on the same platform, in order to enhance antimicrobial activity and overcome resistance to antibiotics. The field of nanomaterial-based or assisted antibiotics (“nanoantibiotics”) is barely in its infancy, compared to cancer- and cardiovascular diseases-targeted nanomedicine. At the moment, there are very little data on the clinical applications and toxicity of NPs as antibiotics themselves and carriers of antimicrobial drugs. As briefly introduced in this review, “nanoantibiotics” strategies to develop efficient, safe, cost-effective, and targeted therapy for infectious diseases in antibiotics resistant era require interdisciplinary knowledge and tools of microbiology, immunology, biomaterials, polymers, pathology, toxicology, pharmacology, and nanotechnology.

Acknowledgment The authors thank Kellie Komoda (UC Irvine) for proofreading the manuscript.

References [1] M.L. Cohen, Changing patterns of infectious disease, Nature 406 (2000) 762–767. [2] H.S. Gold, R.C. Moellering, Antimicrobial-drug resistance, N. Engl. J. Med. 335 (1996) 1445–1453. [3] C. Walsh, Molecular mechanisms that confer antibacterial drug resistance, Nature 406 (2000) 775–781. [4] H.W. Boucher, G.H. Talbot, J.S. Bradley, J.E. Edwards Jr., D. Gilbert, L.B. Rice, M. Scheld, B. Spellberg, J. Bartlett, Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America, Clin. Infect. Dis. 48 (2009) 1–12. [5] L.B. Rice, The clinical consequences of antimicrobial resistance, Curr. Opin. Microbiol. 12 (2009) 476–481. [6] P.W. Talyor, P.D. Stapleton, J.P. Luzio, New ways to treat bacterial infections, Drug Discov. Today 7 (21) (2002) 1086–1091. [7] M. Rai, A. Yadav, A. Gade, Silver nanoparticles as a new generation of antimicrobials, Biotechnol. Adv. 27 (2009) 76–83. [8] C.M. Goodman, C.D. McCusker, T. Yilmaz, V.M. Rotello, Toxicity of gold nanoparticles functionalized with cationic and anionic side chains, Bioconjug. Chem. 15 (2004) 897–900. [9] M. Schaller, J. Laude, H. Bodewaldt, G. Hamm, H.C. Korting, Toxicity and antimicrobial activity of a hydrocolloid dressing containing silver particles in an ex vivo model of cutaneous infection, Skin Pharmacol. Physiol. 17 (2004) 31–36. [10] S. Pal, Y.K. Tak, J.M. Song, Dose the antibacterial activity of silver nanoparticles depend on the shape of the nanoparticle? A study of the gram-negative bacterium Escherichia coli, Appl. Environ. Microbiol. 27 (6) (2007) 1712–1720. [11] E. Weir, A. Lawlor, A. Whelan, F. Regan, The use of nanoparticles in anti-microbial materials and their characterization, Analyst 133 (2008) 835–845. [12] R.P. Allaker, G. Ren, Potential impact of nanotechnology on the control of infectious disease, Trans. R. Soc. Trop. Med. Hyg. 102 (1) (2008) 1–2. [13] G. Taubes, The bacteria fight back, Science 321 (2008) 356–361. [14] R.E. Siegel, Emerging gram-negative antibiotic resistance: daunting challenges, declining sensitivities, and dire consequences, Respir. Care 53 (4) (2008) 471–479. [15] S.P. Chakraborty, S.K. Sahu, S.K. Mahapatra, S. Susmita, M. Bal, S. Roy, P. Pramanik, Nanoconjugated vancomycin: new opportunities for the development of anti-VRSA agents, Nanotechnology 21 (2010) 1–9. [16] B. Périchon, P. Courvalin, VanA-type vancomycin-resistant Staphylococcus aureus, Antimicrob. Agents Chemother. 53 (11) (2009) 4580–4587. [17] H.M. Lode, Clinical impact of antibiotic-resistant gram-positive pathogens, Clin. Microbiol. Infect. 15 (3) (2009) 212–217. [18] F.E. Berkowitz, Antibiotic resistance in bacteria, South. Med. J. 88 (8) (1995) 797–804. [19] Eurosurveillance editorial team, information resources and latest news about the Shiga toxin-producing Escherichia coli (STEC) outbreak in Germany available from ECDC, Euro Surveill. 16 (23) (2011) 19886. [20] A. Tuffs, Bean sprouts are identified as cause of E. coli outbreak, BMJ 14 (2011) 342. [21] R. Hyde, Germany reels in the wake of E. coli outbreak, Lancet 377 (2011) 9782.

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145 [22] E. Turos, G.S. Reddy, K. Greenhalgh, P. Ramaraju, S.C. Abeylath, S. Jang, S. Dickey, D.V. Lim, Penicillin-bound polyacrylate nanoparticles: restoring the activity of βlactam antibiotics against MRSA, Bioorg. Med. Chem. Lett. 17 (2007) 3468–3472. [23] S. Hemaiswarya, A.K. Kruthiventi, M. Doble, Synergism between natural products and antibiotics against infectious diseases, Phytomedicine 15 (2008) 639–652. [24] J.W. Kim, E.V. Shashkov, E.I. Galanzha, N. Ktagiri, V.P. Zharov, Photothermal antimicrobial nanotherapy and nanodiagnostics with self-assembling carbon nanotube clusters, Lasers Surg. Med. 39 (2007) 622–634. [25] C. Beaulac, S. Clement-Major, J. Hawari, J. Legace, Eradication of mucoid Pseudomonas aeruginosa with fluid liposome-encapsulated tobramycin in an animal model of chronic pulmonary infection, Antimicrob. Agents Chemother. 40 (1996) 665–669. [26] K.M. Hindi, A.J. Ditto, M.J. Panzner, D.A. Medvetz, D.S. Han, C.E. Hovis, J.K. Hilliard, J.B. Taylor, Y.H. Yun, C.L. Cannon, W.J. Youngs, The antimicrobial efficacy of sustained release silver-carbene complex-loaded L-tyrosine polyphosphate nanoparticles: Characterization, in vitro and in vivo studies, Biomaterials 30 (2009) 3771–3779. [27] C. Kaittanis, S. Santra, J.M. Perez, Emerging nanotechnology-based strategies for the identification of microbial pathogenesis, Adv. Drug Deliv. Rev. 62 (4–5) (2010) 408–423. [28] K.K. Jain, Applications of nanobiotechnology in clinical diagnostics, Clin. Chem. 53 (11) (2007) 2002–2007. [29] N.L. Rosi, C.A. Mirkin, Nanostructures in biodiagnostics, Chem. Rev. 105 (2005) 1547–1562. [30] M. Look, A. Bandyopadhyay, J.S. Blum, T.M. Fahmy, Application of nanotechnologies for improved immune response against infectious diseases in the developing world, Adv. Drug Deliv. Rev. 62 (4–5) (2010) 378–393. [31] A. de la Escosura-Muñiz, A. Merkoçi, A nanochannel/nanoparticle-based filtering and sensing platform for direct detection of a cancer biomarker in blood, Small 7 (5) (2011) 675–682. [32] M. Li, B. Hu, J. Li, R. Chen, X. Zhang, H. Chen, Extractive electrospray ionization mass spectrometry toward in situ analysis without sample pretreatment, Anal. Chem. 81 (18) (2009) 7724–7731. [33] X. Zhao, L.R. Hilliard, S.J. Mechery, Y. Wang, R.P. Bagwe, S. Jin, W. Tan, A rapid bioassay for single bacterial cell quantitation using bioconjugated nanoparticles, Rroc. Natl. Acad. Sci. U. S. A. 101 (42) (2004) 15027–15032. [34] M. Basu, S. Seggerson, J. Henshaw, J. Jiang, R. Cordna, C. Lefave, P.J. Boyle, A. Miller, M. Pugia, S. Basu, Nano-biosensor development for bacterial detection during human kidney infection: use of glycoconjugate-specific antibody-bound gold nanowire arrays (GNWA), Glycoconj. J. 21 (2004) 487–496. [35] Y.C. Cao, R. Jin, C.A. Mirkin, Nanoparticles with Raman spectroscopic fingerprints for DNA and RNA detection, Science 297 (2002) 1536–1540. [36] C. Kaittanis, S. Nath, J.M. Perez, Rapid nanoparticle-mediated monitoring of bacterial metabolic activity and assessment of antimicrobial susceptibility in blood with magnetic relaxation, PLoS One 3 (9) (2008) e3253. [37] C. Kaittanis, S.A. Naser, J.M. Perez, One-step, nanoparticle-mediated bacterial detection with magnetic relaxation, Nano Lett. 7 (2) (2007) 380–383. [38] H.L. Grossman, W.R. Myers, V.J. Vreeland, R. Bruehl, M.D. Alper, C.R. Bertozzi, J. Clarke, Detection of bacteria in suspension by using a superconducting quantum interference device, Proc. Natl. Acad. Sci. 101 (1) (2004) 129–134. [39] E. Tully, S. Hearty, P. Leonard, R. O'Kennedy, The development of rapid fluorescence-based immunoassays, using quantum dot-labelled antibodies for the detection of Listeria monocytogenes cell surface proteins, Int. J. Biol. Macromol. 39 (1–3) (2006) 127–134. [40] M. Mühling, A. Bradford, J.W. Readman, P.J. Somerfield, R.D. Handy, An investigation into the effects of silver nanoparticles on antibiotic resistance of naturally occurring bacteria in an estuarine sediment, Mar. Environ. Res. 68 (2009) 278–283. [41] Z. Huang, X. Zheng, D. Yan, G. Yin, X. Liao, Y. Kang, Y. Yao, D. Huang, B. Hao, Toxicological effect of ZnO nanoparticles based on bacteria, Langmuir 24 (8) (2008) 4140–4144. [42] P.C. Maness, S. Smolinski, D.M. Blake, Z. Huang, E.J. Wolfrum, W.A. Jacoby, Bactericidal activity of photocatalytic TiO2 reaction: toward an understanding of its killing mechanism, Appl. Environ. Microbiol. 65 (9) (1999) 4094–4098. [43] Q. Li, S. Mahendra, D.Y. Lyon, L. Brunet, M.V. Liga, D. Li, P.J. Alvarez, Antimicrobial nanomaterials for water disinfection and microbial control: potential applications and implications, Water Res. 42 (2008) 4591–4602. [44] E. Turos, J.Y. Shim, Y. Wang, K. Greenhalgh, G. Suresh Kumar Reddy, S. Dickey, D.V. Lim, Antibiotic-conjugated polyacrylate nanoparticles: new opportunities for development of anti-MRSA agents, Bioorg. Med. Chem. Lett. 17 (1) (2007) 53–56. [45] H. Gu, P.L. Ho, E. Tong, L. Wang, B. Xu, Presenting vancomycin on nanoparticles to enhance antimicrobial activities, Nano Lett. 3 (2003) 1261–1263. [46] V.P. Zharov, K.E. Mercer, E.N. Galitovskaya, M.S. Smeltzer, Photothermal nanotherapeutics and nanodiagnostics for selective killing of bacterial targeted with gold nanoparticles, Biophys. J. 90 (2) (2006) 619–627. [47] V.P. Zharov, E.I. Galanzha, E.V. Shashkov, J.W. Kim, N.G. Khlebtsov, V.V. Tuchin, Photoacoustic flow cytometry: principle and application for real-time detection of circulating single nanoparticles, pathogens, and contrast dyes in vivo, J. Biomed. Opt. 12 (5) (2007) 051503. [48] S.C. Abeylath, E. Turos, Drug delivery approaches to overcome bacterial resistance to β-lactam antibiotics, Expert Opin. Drug Deliv. 5 (9) (2008) 931–949. [49] L.J. Peek, C.R. Middaugh, C. Berkland, Nanotechnology in vaccine delivery, Adv. Drug Deliv. Rev. 60 (8) (2008) 915–928. [50] M. Singh, A. Chakrapani, D. O'Hagan, Nanoparticles and microparticles as vaccine-delivery systems, Expert Rev. Vaccines 6 (5) (2007) 797–808.

141

[51] A.C. Rice-Ficht, A.M. Arenas-Gamboa, M.M. Kahl-McDonagh, T.A. Ficht, Polymeric particles in vaccine delivery, Curr. Opin. Microbiol. 13 (1) (2010) 106–112. [52] P. Johansen, C. Raynaud, M. Yang, M.J. Colston, R.E. Tascon, D.B. Lowrie, Antimycobacterial immunity induced by a single injection of M. leprae Hsp65encoding plasmid DNA in biodegradable microparticles, Immunol. Lett. 90 (2–3) (2003) 81–85. [53] A. Myc, J.F. Kukowska-Latallo, A.U. Bielinska, P. Cao, P.P. Myc, K. Janczak, T.R. Sturm, M.S. Grabinski, J.J. Landers, K.S. Young, J. Chang, T. Hamouda, M.A. Olszewski, J.R. Baker Jr., Development of immune response that protects mice from viral pneumonitis after a single intranasal immunization with influenza A virus and nanoemulsion, Vaccine 21 (25–26) (2003) 3801–3814. [54] A.U. Bielinska, K.W. Janczak, J.J. Landers, P. Makidon, L.E. Sower, J.W. Peterson, J.R. Baker Jr., Mucosal immunization with a novel nanoemulsion-based recombinant anthrax protective vaccine protects against Bacillus anthracis spore challenge, Infect. Immun. 75 (8) (2007) 4020–4029. [55] J.S. Kim, E. Kuk, K.N. Yu, J.H. Kim, S.J. Park, H.J. Lee, S.H. Kim, Y.K. Park, Y.H. Park, C.Y. Hwang, Y.K. Kim, Y.S. Lee, D.H. Jeong, M.H. Cho, Antimicrobial effects of silver nanoparticles, Nanomedicine 3 (2007) 95–101. [56] H.M. Mansour, Y.S. Rhee, X. Wu, Nanomedicine in pulmonary delivery, Int. J. Nanomedicine 4 (2009) 299–319. [57] N.S. Santos-Magalhães, V.C. Mosqueira, Nanotechnology applied to the treatment of malaria, Adv. Drug Deliv. Rev. 62 (2010) 560–575. [58] A. Sosnik, A.M. Carcaboso, R.J. Glisoni, M.A. Moretton, D.A. Chiappetta, New old challenges in tuberculosis: potentially effective nanotechnologies in drug delivery, Adv. Drug Deliv. Rev. 62 (2010) 547–559. [59] E.I. Rabea, M.E. Badawy, C.V. Stevens, G. Smagghe, W. Steurbaut, Chitosan as antimicrobial agent: applications and mode of action, Biomacromolecules 4 (6) (2003) 1457–1465. [60] A. Nanda, M. Saravanan, Biosynthesis of silver nanoparticles from Staphylococcus aureus and its antimicrobial activity against MRSA and MRSE, Nanomedicine 5 (4) (2009) 452–456. [61] D.S. Balaji, S. Basavaraja, R. Deshpande, D.B. Mahesh, B.K. Prabhakar, A. Venkataraman, Extracellular biosynthesis of functionalized silver nanoparticles by strains of Cladosporium cladosporioides fungus, Colloids Surf. B Biointerfaces 68 (2009) 88–92. [62] S. Basavaraja, S.D. Balaji, A. Lafashetty, A.H. Rajasab, A. Venkataraman, Extracellular biosynthesis of silver nanoparticles using the fungus Fusarium semitectum, Mater. Res. Bull. 43 (2008) 1164–1170. [63] J.D. Holmes, P.R. Smith, R. Evans-Gowing, D.J. Richardson, D.A. Russell, J.R. Sodeau, Energy-dispersive X-ray analysis of the extracellular cadmium sulfide crystallites of Klebsiella aerogenes, Arch. Microbiol. 163 (2) (1995) 143–147. [64] M. Saravanan, A. Nanda, Extracellular synthesis of silver bionanoparticles from Aspergillus clavatus and its antimicrobial activity against MRSA and MRSE, Colloids Surf. B Biointerfaces 77 (2010) 214–218. [65] P. Dibrov, J. Dzioba, K.K. Gosink, C.C. Häse, Chemiosmotic mechanism of antimicrobial activity of Ag+ in Vibrio cholera, Antimicrob. Agents Chemother. 46 (8) (2002) 2668–2670. [66] I. Chora, The increasing use of silver-based products as antimicrobial agents: a useful development or a cause for concern? J. Antimicrob. Chemother. 59 (2007) 587–590. [67] Y. Liu, L. He, A. Mustapha, H. Li, Z.Q. Hu, M. Lin, Antibacterial activities of zinc oxide nanoparticles against Escherichia coli O157:H7, J. Appl. Microbiol. 107 (2009) 1193–1201. [68] M. Chamundeeswari, S.S. Sobhana, J.P. Jacob, M.G. Kumar, M.P. Devi, T.P. Sastry, A.B. Mandal, Preparation, characterization and evaluation of a biopolymeric gold nanocomposite with antimicrobial activity, Biotechnol. Appl. Biochem. 55 (2010) 29–35. [69] W.C. Huang, P.J. Tsai, Y.C. Chen, Multifunctional Fe3O4@Au nanoeggs as photothermal agents for selective killing of nosocomial and antibiotic-resistant bacteria, Small 5 (1) (2009) 51–56. [70] V.K. Sharma, R.A. Yngard, Y. Liu, Silver nanoparticles: green synthesis and their antimicrobial activities, Adv. Colloid Interface Sci. 145 (1–2) (2008) 83–96. [71] H.J. Klasen, Historical review of the use of silver in the treatment of burns. I. Early uses, Burns 26 (2000) 117–130. [72] F. Raimondi, G.G. Scherer, R. Kötz, A. Wokaun, Nanoparticles in energy technology: examples from electrochemistry and catalysis, Angew. Chem. Int. Ed Engl. 44 (2005) 2190–2209. [73] I. Sondi, B. Salopek-Sondi, Silver nanoparticles as antimicrobial agent: a case study on E. coli as a model for gram-negative bacteria, J. Colloid Interface Sci. 275 (2004) 177–182. [74] A.R. Shahverdi, A. Fakhimi, H.R. Shahverdi, S. Minaian, Synthesis and effect of silver nanoparticles on the antibacterial activity of different antibiotics against Staphylococcus aureus and Escherichia coli, Nanomedicine 3 (2) (2007) 168–171. [75] A.M. Fayaz, K. Balaji, M. Girilal, R. Yadav, M. Tech, P.T. Kalaichelvan, R. Venketesan, Biogenic synthesis of silver nanoparticles and their synergistic effect with antibiotics: a study against gram-positive and gram-negative bacteria, Nanomedicine 6 (2010) 103–109. [76] F. Furno, K.S. Morley, B. Wong, B.L. Sharp, P.L. Arnold, S.M. Howdle, R. Bayston, P.D. Brown, P.D. Winship, H.J. Reid, Silver nanoparticles and polymeric medical devices: a new approach to prevention of infection? J. Antimicrob. Chemother. 54 (2004) 1019–1024. [77] M. Ip, S.L. Lui, V.K. Poon, I. Lung, A. Burd, Antimicrobial activities of silver dressings: an in vitro comparison, J. Med. Microbiol. 55 (2006) 59–63. [78] D.J. Leaper, Silver dressings: their role in wound management, Int. Wound J. 3 (4) (2006) 282–294. [79] Y. Li, P. Leung, L. Yao, Q.W. Song, E. Newton, Antimicrobial effect of surgical masks coated with nanoparticles, J. Hosp. Infect. 62 (2006) 58–63.

142

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

[80] P.L. Drake, K.J. Hazelwood, Exposure-related health effects of silver and silver compounds: a review, Ann. Occup. Hyg. 49 (7) (2005) 575–585. [81] H.J. Johnston, G. Hutchison, F.M. Christensen, S. Peters, S. Hankin, V. Stone, 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, Crit. Rev. Toxicol. 40 (4) (2010) 328–346. [82] G. Oberdörster, E. Oberdörster, J. Oberdörster, Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles, Environ. Health Perspect. 113 (7) (2005) 823–939. [83] L. Braydich-Stolle, S. Hussainn, J.J. Schlager, M.C. Hofmann, In vitro cytotoxicity of nanoparticles in mammalian germline stem cells, Toxicol. Sci. 88 (2005) 412–419. [84] S.M. Hussain, K.L. Hess, J.M. Gearhart, K.T. Geiss, J.J. Schlager, In vitro toxicity of nanoparticles in BRL 3A rat liver cells, Toxicol. In Vitro 19 (2005) 975–983. [85] R. Brayner, R. Ferarri-Iliou, N. Brivois, S. Djediat, M.F. Benedetti, F. Fiévet, Toxicological impact studies based on Escherichia coli bacteria in ultrafine ZnO nanoparticles colloidal medium, Nano Lett. 6 (2006) 866–870. [86] K.M. Reddy, K. Feris, J. Bell, D.G. Wingett, C. Hanley, A. Punnoose, Selective toxicity of zinc oxide nanoparticles to prokaryotic and eukaryotic systems, Appl. Phys. Lett. 90 (2007) 2139021–2139023 (213902). [87] G. Fu, P.S. Vary, C.T. Lin, Anatase TiO2 nanocomposites for antimicrobial coatings, J. Phys. Chem. B 109 (2005) 8889–8898. [88] P. Jiang, J.J. Zhou, H.F. Fang, C.Y. Wang, Z.L. Wang, S.S. Xie, Hierarchical shelled ZnO structures made of bunched nanowire arrays, Adv. Funct. Mater. 17 (2007) 1303–1310. [89] J. Zhou, N. Xu, Z.L. Wang, Dissolving behavior and stability of ZnO wires in biofluids: a study on biodegradability and biocompatibility of ZnO nanostructures, Adv. Mater. 18 (2006) 2432–2435. [90] M. Roselli, A. Finamore, I. Garaguso, M.S. Britti, E. Mengheri, Zinc oxide protects cultured enterocytes from the damage induced by Escherichia coli, J. Nutr. 133 (12) (2003) 4077–4082. [91] R. Dastjerdi, M. Montazer, A review on the application of inorganic nanostructured materials in the modification of textiles: focus on anti-microbial properties, Colloids Surf. B Biointerfaces 79 (1) (2010) 5–18. [92] S.S. Uğur, M. Sarıışık, A.H. Aktaş, M.C. Uçar, E. Erden, Modifying of cotton fabric surface with nano-ZnO multilayer films by layer-by-layer deposition method, Nanoscale Res. Lett. 5 (2010) 1204–1210. [93] J. Sawai, Quantitative evaluation of antibacterial activities of metallic oxide powders (ZnO, MgO and CaO) by conductimetric assay, J. Microbiol. Methods 54 (2) (2003) 177–182. [94] S. Gelover, L.A. Gómez, K. Reyes, M.T. Leal, A practical demonstration of water disinfection using TiO2 films and sunlight, Water Res. 40 (2006) 3274–3280. [95] M.P. Reddy, A. Vengopal, M. Subrahmanyam, Hydroxyapatite-supported Ag-TiO2 as Escherichia coli disinfection photocatalyst, Water Res. 41 (2007) 379–386. [96] K.P. Kühn, I.F. Cahberny, K. Massholder, M. Stickler, V.W. Benz, H. Sonntag, L. Erdinger, Disinfection of surfaces by photocatalytic oxidation with titanium dioxide and UVA light, Chemosphere 53 (2003) 71–77. [97] O.J. Oppezzo, R.A. Pizarro, Sublethal effects of ultraviolet A radiation on Enterobacter cloacae, J. Photochem. Photobiol. B 62 (2001) 158–165. [98] J.Y. Choi, K.H. Kim, K.C. Choy, K.T. Oh, K.N. Kim, Photocatalytic antibacterial effect of TiO2 film formed on Ti and TiAg exposed to Lactobacillus acidophilus, J. Biomed. Mater. Res. B Appl. Biomater. 80 (2) (2007) 353–359. [99] L.K. Adams, D.Y. Lyon, P.J. Alvarez, Comparative eco-toxicity of nanoscale TiO2, SiO2, and ZnO water suspensions, Water Res. 40 (19) (2006) 3527–3532. [100] P. Muranyi, C. Schraml, J. Wunderlich, Antimicrobial efficiency of titanium dioxide-coated surfaces, J. Appl. Microbiol. 108 (6) (2010) 1966–1973. [101] D.B. Hamal, J.A. Haggstrom, G.L. Marchin, M.A. Ikenberry, K. Hohn, K.J. Klabunde, A multifunctional biocide/sporocide and photocatalyst based on Titanium dioxide (TiO2) codoped with silver, carbon, and sulfur, Langmuir 26 (4) (2010) 2805–2810. [102] B.S. Sekhon, S.R. Kamboj, Inorganic nanomedicine—part 2, Nanomedicine 6 (5) (2010) 612–618. [103] D. Pissuwan, C.H. Cortie, S.M. Valenzuela, M.B. Cortie, Functionalised gold nanoparticles for controlling pathogenic bacteria, Trends Biotechnol. 28 (4) (2010) 207–213. [104] A.N. Grace, K. Pandian, Antibacterial efficacy of aminoglycosidic antibiotics protected gold nanoparticles—a brief study, Colloids Surf., A 297 (2007) 63–70. [105] I.M. Sadiq, B. Chowdhury, N. Chandrasekaran, A. Mukherjee, Antimicrobial sensitivity of Escherichia coli to alumina nanoparticles, Nanomedicine 5 (2009) 282–286. [106] J.J. Buckley, P.L. Gai, A.F. Lee, L. Olivi, K. Wilson, Silver carbonate nanoparticles stabilized over alumina nanoneedles exhibiting potent antibacterial properties, Chem. Commun. (Camb.) 14 (34) (2008) 4013–4015. [107] L. Esteban-Tejeda, F. Malpartida, A. Esteban-Cubillo, C. Pecharromán, J.S. Moya, Antibacterial and antifungal activity of a soda-lime glass containing copper nanoparticles, Nanotechnology 20 (50) (2009) 505701. [108] H.L. Pape, F.S. Serena, P. Contini, C. Devillers, A. Maftah, P. Leprat, Evaluation of the anti-microbial properties of an activated carbon fibre supporting silver using a dynamic method, Carbon 40 (2002) 2947–2954. [109] J.P. Ruparelia, A.K. Chatterijee, S.P. Duttagupta, S. Mukherji, Strain specificity in antimicrobial activity of silver and copper nanoparticles, Acta Biomater. 4 (2008) 707–716. [110] K.Y. Yoon, J. Hoon Byeon, J.H. Park, J. Hwang, Susceptibility constants of Escherichia coli and Bacillus subtilis to silver and copper nanoparticles, Sci. Total Environ. 373 (2–3) (2007) 572–575. [111] G. Ren, D. Hu, E.W. Cheng, M.A. Vargas-Reus, P. Reip, R.P. Allaker, Characterisation of copper oxide nanoparticles for antimicrobial applications, Int. J. Antimicrob. Agents 33 (6) (2009) 587–590.

[112] Y.C. Chung, H.L. Wang, Y.M. Chen, S.L. Li, Effect of abiotic factors on the antibacterial activity of chitosan against waterborne pathogens, Bioresour. Technol. 88 (2003) 179–184. [113] L. Qi, Z. Xu, X. Jiang, C. Hu, X. Zou, Preparation and antibacterial activity of chitosan nanoparticles, Carbohydr. Res. 339 (2004) 2693–2700. [114] T.M. Don, C.C. Chen, C.K. Lee, W.Y. Cheng, L.P. Cheung, Preparation and antibacterial test of chitosan/PAA/PEGDA bi-layer composite membranes, J. Biomater. Sci. Polym. Ed. 16 (12) (2005) 1503–1519. [115] H.K. No, N.Y. Park, S.H. Lee, S.P. Meyers, Antibacterial activity of chitosans and chitosan oligomers with different molecular weights, Int. J. Food Microbiol. 74 (1) (2002) 65–72. [116] J.C. Fernandes, F.K. Tavaria, J.C. Soares, O.S. Ramos, M. João Monteiro, M.E. Pintado, F. Xavier Malcata, Antimicrobial effects of chitosans and chitooligosacharides, upon Staphylococcus aureus and Escherichia coli, in food model systems, Food Microbiol. 25 (2008) 922–928. [117] J.C. Fernandes, F.K. Tavaria, S.C. Fonseca, O.S. Ramos, M.E. Pintado, F.X. Malcata, In vitro screening for anti-microbial activity of chitosans and chitooligosaccharides, aiming at potential uses in functional textiles, J. Microbiol. Biotechnol. 20 (2) (2010) 311–318. [118] S. Tin, K.R. Sakharkar, C.S. Lim, M.K. Sakharkar, Activity of chitosans in combination with antibiotics in Pseudomonas aeruginosa, Int. J. Biol. Sci. 5 (2) (2009) 153–160. [119] R.G. Cureo, G. Osuji, A. Washington, N-carboxymethylchitosan inhibition of aflatoxin production: role or zinc, Biotechnol. Lett. 13 (1991) 441–444. [120] J.Y. Je, S.K. Kim, Chitosan derivatives killed bacteria by disrupting the outer and inner membrane, J. Agric. Food Chem. 54 (18) (2006) 6629–6633. [121] K. Xing, X.G. Chen, C.S. Liu, D.S. Cha, H.J. Park, Oleoyl-chitosan nanoparticles inhibits Escherichia coli and Staphylococcus aureus by damaging the cell membrane and putative binding to extracellular or intracellular targets, Int. J. Food Microbiol. 132 (2009) 127–133. [122] N. Tsao, T.Y. Luh, C.K. Chou, T.Y. Chang, J.J. Wu, C.C. Liu, H.Y. Lei, In vitro action of carboxyfullerene, J. Antimicrob. Chemother. 49 (2002) 641–649. [123] J.A. Brant, J. Labille, J.Y. Bottero, M.R. Wiesner, Characterizing the impact of preparation method on fullerene cluster structure and chemistry, Langmuir 22 (2006) 3878–3885. [124] D.Y. Lyon, J.D. Fortner, C.M. Sayes, V.L. Colvin, J.B. Hughe, Bacterial cell association and antimicrobial activity of a C60 water suspension, Environ. Toxicol. Chem. 24 (11) (2005) 2757–2762. [125] C.M. Sayes, A.M. Gobin, K.D. Ausman, J. Mendez, J.L. West, V.L. Colvin, Nano-C60 cytotoxicity is due to lipid peroxidation, Biomaterials 26 (2005) 7587–7595. [126] Z. Markovic, B. Todorovic-Markovic, D. Kleut, N. Nikolic, S. Vranjes-Djuric, M. Misirkic, L. Vucicevic, K. Janjetovic, A. Isakovic, L. Harhaji, B. Babic-Stojic, M. Dramicanin, V. Trajkovic, The mechanism of cell-damaging reactive oxygen generation by colloidal fullerenes, Biomaterials 28 (2007) 5437–5448. [127] D.Y. Lyon, L. Brunet, G.W. Hinkal, M.R. Wiesner, P.J. Alvarez, Antibacterial activity of fullerene water suspensions (nC60) is not due to ROS-medicated damage, Nano Lett. 8 (5) (2008) 1539–1543. [128] J. Fang, D.Y. Lyon, M.R. Weisner, P.J. Alvarez, Effect of a fullerene water suspension on bacterial phospholipids and membrane phase behavior, Environ. Sci. Technol. 41 (7) (2007) 2636–2642. [129] X.R. Xia, N.A. Monteiro-Riviere, J.E. Riviere, Intrinsic biological property of colloidal fullerene nanoparticles (nC60): lack of lethality after high dose exposure to human epidermal and bacterial cells, Toxicol. Lett. 197 (2) (2010) 128–134. [130] A. Isakovic, Z. Markovic, N. Nikolic, B. Todorovic-Markovic, S. Vranjes-Djuric, L. Harhaji, N. Raicevic, N. Romcevic, D. Vasiljevic-Radovic, M. Dramicanin, V. Trajkovic, Inactivation of nanocrystalline C60 cytotoxicity by gamma-irradiation, Biomaterials 27 (29) (2006) 5049–5058. [131] G.L. Baker, A. Gupta, M.L. Clark, B.R. Valenzuela, L.M. Staska, S.J. Harbo, J.T. Pierce, J.A. Dill, Inhalation toxicity and lung toxicokinetics of C60 fullerene nanoparticles and microparticles, Toxicol. Sci. 101 (1) (2008) 122–131. [132] N. Gharbi, M. Pressac, M. Hadchouel, H. Szwarc, S.R. Wilson, F. Moussa, [60] fullerene is a powerful antioxidant in vivo with no acute or subacute toxicity, Nano Lett. 5 (12) (2005) 2578–2585. [133] T. Mashino, D. Nishikawa, K. Takahashi, N. Usui, T. Yamori, M. Seki, T. Endo, M. Mochizuki, Antibacterial and antiproliferative activity of cationic fullerene derivatives, Bioorg. Med. Chem. Lett. 13 (24) (2003) 4395–4397. [134] H. Aoshima, K. Kokubo, S. Shirakawa, M. Ito, S. Yamana, T. Oshima, Antimicrobial activity of fullerenes and their hydroxylated derivatives, Biocontrol Sci. 14 (2) (2009) 69–72. [135] Z.Q. Ji, H. Sun, H. Wang, Q. Xie, Y. Liu, Z. Wang, Biodistribution and tumor uptake of C60(OH)x in mice, J. Nanopart. Res. 8 (2006) 53–63. [136] A. Isakovic, Z. Markovic, B. Todorovic-Markovic, N. Nikolic, S. Vranjes-Djuric, M. Mirkovic, M. Dramicanin, L. Harhaji, N. Raicevic, Z. Nikolic, V. Trajkovic, Distinct cytotoxic mechanisms of pristine versus hydroxylated fullerene, Toxicol. Sci. 91 (1) (2006) 173–183. [137] J.E. Roberts, A.R. Wielgus, W.K. Boyes, U. Andley, C.F. Chignell, Phototoxicity and cytotoxicity of fullerol in human lens epithelial cells, Toxicol. Appl. Pharmacol. 228 (1) (2007) 49–58. [138] A.R. Wielgus, B. Zhao, C.F. Chignell, D.N. Hu, J.E. Roberts, Phototoxicity and cytotoxicity of fullerol in human retinal pigment epithelial cells, Toxicol. Appl. Pharmacol. 242 (1) (2010) 79–90. [139] D. Lyon, L. Adams, J. Falkner, Antibacterial activity of fullerene water suspensions: effect of preparation method and particle size, Environ. Sci. Technol. 40 (2006) 4360–4366. [140] H. Hyung, J.D. Fortner, J.B. Hughes, J.H. Kim, Natural organic matter stabilizes carbon nanotubes in the aqueous phase, Environ. Sci. Technol. 41 (1) (2007) 179–184.

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145 [141] L.R. Arias, L. Yang, Inactivation of bacterial pathogens by carbon nanotubes in suspensions, Langmuir 25 (2009) 3003–3012. [142] P. Wick, P. Manser, L.K. Limbach, U. Dettlaff-Weglikowska, R. Krumeich, S. Roth, W.J. Stark, A. Bruinink, The degree and kind of agglomeration affect carbon nanotube cytotoxicity, Toxicol. Lett. 168 (2007) 121–131. [143] G. Jia, H. Wang, L. Yan, X. Wang, R. Pei, T. Yan, T. Zhao, X. Guo, Cytotoxicity of carbon nanomaterials: single-wall nanotube, multi-wall nanotube, and fullerene, Environ. Sci. Technol. 39 (5) (2005) 1378–1383. [144] D.B. Warheit, B.R. Laurence, K.L. Reed, D.H. Roach, G.A. Reynolds, T.R. Webb, Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats, Toxicol. Sci. 77 (1) (2004) 117–125. [145] C.W. Lam, J.T. James, R. McCluskey, R.L. Hunter, Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation, Toxicol. Sci. 77 (1) (2004) 126–134. [146] S. Kang, M. Pinault, L.D. Pfefferle, M. Elimelech, Single-walled carbon nanotubes exhibit strong antimicrobial activity, Langmuir 23 (2007) 8670–8673. [147] A.S. Brady-Estévez, T.H. Nguyen, L. Gutierrez, M. Elimelech, Impact of solution chemistry on viral removal by a single-walled carbon nanotube filter, Water Res. 44 (2010) 3773–3780. [148] S. Aslan, C.Z. Loebick, S. Kang, M. Elimelech, L.D. Pfefferle, P.R. Van Tassel, Antimicrobial biomaterials based on carbon nanotubes dispersed in poly(lacticco-glycolic acid), Nanoscale 2 (9) (2010) 1789–1794. [149] C.D. Vecitis, K.R. Zodrow, S. Kang, M. Elimelech, Electronic-structure-dependent bacterial cytotoxicity of single-walled carbon nanotubes, ACS Nano 4 (9) (2010) 5471–5479. [150] A.S. Brady-Estévez, S. Kang, M. Elimelech, A single-walled-carbon-nanotube filter for removal of viral and bacterial pathogens, Small 4 (4) (2008) 481–484. [151] A. Srivastava, O.N. Srivastava, S. Talapatra, R. Vajtai, P.M. Ajayan, Carbon nanotube filters, Nat. Mater. 3 (2004) 610–614. [152] T. Maisch, A new strategy to destroy antibiotic resistant microorganisms: antimicrobial photodynamic treatment, Mini Rev. Med. Chem. 9 (8) (2009) 974–983. [153] F.C. Fang, Antimicrobial reactive oxygen and nitrogen species: concepts and controversies, Nat. Rev. Microbiol. 2 (2004) 820–832. [154] R.B. Weller, Nitric oxide-containing nanoparticles as an antimicrobial agents and enhancer of wound healing, J. Invest. Dermatol. 129 (2009) 2335–2337. [155] R. Weller, R.J. Price, A.D. Ormerod, N. Benjamin, C. Leifert, Antimicrobial effect of acidified nitrite on dermatophyte fungi, Candida and bacterial skin pathogens, J. Appl. Microbiol. 90 (2001) 648–652. [156] L.R. Martinez, G. Han, M. Chacko, M.R. Mihu, M. Jacobson, P. Gialanella, A.J. Friedman, J.D. Nosanchuk, J.M. Friedman, Antimicrobial and healing efficacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infection, J. Invest. Dermatol. 129 (2009) 2463–2469. [157] R. Weller, M.J. Finnen, The effects of topical treatment with acidified nitrite on wound healing in normal and diabetic mice, Nitric Oxide 15 (2006) 395–399. [158] M. Mowbray, X. Tan, P.S. Wheatley, R.E. Morris, R.B. Weller, Topically applied nitric oxide induces T-lymphocyte infiltration in human skin, but minimal inflammation, J. Invest. Dermatol. 128 (2009) 352–360. [159] E.M. Hetrick, J.K. Shin, H.S. Paul, M.H. Schoenfisch, Anti-biofilm efficacy of nitric oxide-releasing silica nanoparticles, Biomaterials 30 (14) (2009) 2782–2789. [160] E.M. Hetrick, J.H. Shin, N.A. Stasko, C.B. Johnson, D.A. Wespe, E. Holmuhamedov, M.H. Schoenfisch, Bactericidal efficacy of nitric oxide-releasing silica nanoparticles, ACS Nano 2 (2) (2008) 235–246. [161] R.P. Bagwe, L.R. Hilliard, W. Tan, Surface modification of silica nanoparticles to reduce aggregation and nonspecific binding, Langmuir 22 (2006) 4357–4362. [162] N. Barraud, D.J. Hassett, S.H. Hwang, S.A. Rice, S. Kjelleberg, J.S. Webb, Involvement of nitric oxide in biofilm dispersal of Pseudomonas aeruginosa, J. Bacteriol. 188 (2006) 7344–7353. [163] G. Han, L.R. Martinez, M.R. Mihu, A.J. Friedman, J.M. Friedman, Nitric oxide releasing nanoparticles are therapeutic for Staphylococcus aureus abscesses in a murine model of infection, PLoS One 4 (11) (2009) 1–7 e7804. [164] J.J. LiPuma, S. Rathinavelu, B.K. Foster, J.C. Keoleian, P.E. Makidon, L.M. Kalikin, J.R. Baker Jr., In vitro activities of a novel nanoemulsion against Burkholderia and other multidrug-resistant cystic fibrosis-associated bacterial species, Antimicrob. Agents Chemother. 53 (1) (2009) 249–255. [165] M.J. Lawrencea, G.D. Reesb, Microemulsion-based media as novel drug delivery systems, Adv. Drug Deliv. Rev. 45 (2000) 89–121. [166] Y. Cao, J. Sheng, Microstructure of microemulsion in MEEKC, Electrophoresis 31 (4) (2010) 672–678. [167] T. Hamouda, J.R. Baker Jr., Antimicrobial mechanism of action of surfactant lipid preparations in enteric gram-negative bacilli, J. Appl. Microbiol. 89 (2000) 397–403. [168] T. Hamouda, M.M. Hayes, Z. Cao, R. Tonda, K. Johnson, D.C. Wright, J. Brisker, J.R. Baker Jr., A novel surfactant nanoemulsion with broad-spectrum sporicidal activity against Bacillus species, J. Infect. Dis. 180 (1999) 1939–1949. [169] I.S. Al-Adham, E. Khalil, N.D. Al-Hmoud, M. Kierans, P.J. Collier, Microemulsions are membrane-active, antimicrobial, self-preserving systems, J. Appl. Microbiol. 89 (2000) 32–39. [170] I.S. Al-Adham, N.D. Al-Hmoud, E. Khalil, M. Kierans, P.J. Collier, Microemulsions are highly effective anti-biofilm agents, Lett. Appl. Microbiol. 36 (2003) 97–100. [171] P.E. Makidon, A.U. Bielinska, S.S. Nigaverkar, K.W. Janczak, J. Knowlton, A.J. Scott, N. Mank, Z. Cao, S. Rathinavelu, M.R. Beer, J.E. Wilkinson, L.P. Blanco, J.J. Landers, J.R. Baker Jr., Pre-clinical evaluation of a novel nanoemulsion-based hepatitis B mucosal vaccine, PLoS One 3 (8) (2008) e2954. [172] A.U. Bielinska, K.W. Janczak, J.J. Landers, P. Makidon, L.E. Sower, J.W. Peterson, J.R. Baker Jr., Mucosal immunization with a novel nanoemulsion-based recombinant

[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]

143

anthrax protective antigen vaccine protects against Bacillus anthracis spore challenge, Infect. Immun. 75 (8) (2007) 4020–4029. L. Zhang, D. Pornpattananangkul, C.M. Hu, C.M. Huang, Development of nanoparticles for antimicrobial drug delivery, Curr. Med. Chem. 17 (2010) 585–594. H.P. Alphandary, A. Andremont, P. Couvreur, Targeted delivery of antibiotics using liposomes and nanoparticles: research and applications, Int. J. Antimicrob. Agents 13 (2000) 155–168. L. Zhang, F.X. Gu, J.M. Chan, A.Z. Wang, R.S. Langer, O.C. Farokhzad, Nanoparticles in medicine: therapeutic applications and developments, Clin. Pharmacol. Ther. 83 (5) (2008) 761–769. T. Lian, R.J. Ho, Trends and developments in liposome drug delivery systems, J. Pharm. Sci. 90 (6) (2001) 667–680. V.P. Torchilin, Recent advances with liposomes as pharmaceutical carriers, Nat. Rev. Drug Discov. 4 (2) (2005) 145–160. D.D. Lasic, Novel applications of liposomes, Trends Biotechnol. 16 (7) (1998) 307–321. K. Maruyama, S.J. Kennel, L. Huang, Lipid composition is important for highly efficient target binding and retention of immunoliposomes, Proc. Natl. Acad. Sci. U.S.A. 87 (1990) 5744–5748. I.A. Bakker-Woudenberg, Long-circulating sterically stabilized liposomes as carriers of agents for treatment of infection or for imaging infectious foci, Int. J. Antimicrob. Agents 19 (2002) 299–311. M. Moonis, I. Ahmad, B.K. Bachhawat, Effect of elimination of phagocytic cells by liposomal dichloromethylene diphosphonate on aspergillosis virulence and toxicity of liposomal amphotericin B in mice, Antimicrob. Chemother. 33 (3) (1994) 571–583. T.M. Allen, C. Hansen, J. Rutledge, Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues, Biochem. Biophys. Acta 981 (1) (1989) 27–35. A. Omri, Z.E. Suntres, P.N. Shek, Enhanced activity of liposomal polymyxin B against Pseudomonas aeruginosa in a rat model of lung infection, Biochem. Pharmacol. 64 (2002) 1407–1413. M. Alipour, M. Halwani, A. Omri, Z.E. Suntres, Antimicrobial effectiveness of liposomal polymyxin B against resistant gram-negative bacterial strains, Int. J. Pharm. 355 (2008) 293–298. C. Mugabe, M. Halwani, A.O. Azghani, R.M. Lafrenie, A. Omri, Mechanism of enhanced activity of liposome-entrapped aminoglycosides against resistant strains of Pseudomonas aeruginosa, Antimicrob. Agents Chemother. 50 (6) (2006) 2016–2022. D. Yang, D. Pornpattananangkul, T. Nakatsuji, M. Chan, D. Carson, C.M. Huang, L. Zhang, The antimicrobial activity of liposomal lauric acids against Propionibacterium acnes, Biomaterials 30 (2009) 6035–6040. I. Schumacher, R. Margalit, Liposome-encapsulted ampicillin: physicochemical and antibacterial properties, J. Pharm. Sci. 86 (5) (1997) 635–641. H.J. Kim, M.N. Jones, The delivery of benzyl penicillin to Staphylococcus aureus, J. Liposome Res. 14 (3–4) (2004) 123–139. M. Magallanes, J. Dijkstra, J. Fierer, Liposome-incorporated ciprofloxacin in treatment of murine salmonellosis, Antimicrob. Agents Chemother. 37 (11) (1993) 2293–2297. P.R. Gangadhanun, D.A. Ashtekar, N. Gborf, J.A. Goldstein, R.J. Debs, N.D. fizgfines, Chemotherapentic potential of free and liposome encapsulated streptomycin against experimental Mycobacterium avium complex infections in beige mice, J. Antimicrob. Chemother. 28 (1991) 425–435. R.M. Fielding, R.O. Lewis, L.M. McDermott, Altered tissue distribution and elimination of amikacin encapsulated in unilamellar, low-clearance liposomes (MiKasome®), Pharm. Res. 15 (11) (1998) 1775–1781. I.A. Bakker-Woudenberg, M.T. ten Kate, L.E. Stearne-Cullene, M.C. Woodle, Efficacy of gentamicin or ceftazidime entrapped in liposomes with prolonged blood circulation and enhanced localization in Klebsiella pneumoniae-infected lung tissue, J. Infect. Dis. 171 (4) (1995) 938–947. C.O. Onyeji, C.H. Nightingale, M.N. Marangos, Enhanced killing of methicillinresistant Staphylococcus aureus in human macrophages by liposome-entrapped vancomycin and teicoplanin, Infection 22 (5) (1994) 338–342. S.A. Wissing, R.H. Müller, Cosmetic applications for solid lipid nanoparticles (SLN), Int. J. Pharm. 254 (2003) 65–68. R.H. Müller, K. Mäder, S. Gohla, Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art, Eur. J. Pharm. Biopharm. 50 (1) (2000) 161–177. R. Pandey, G.K. Khuller, Solid lipid particle-based inhalable sustained drug delivery system against experimental tuberculosis, Tuberculosis 85 (2005) 227–234. A. Bargoni, R. Cavalli, G.P. Zara, A. Fundarò, O. Caputo, M.R. Gasco, Transmucosal transport of tobramyin incorporated in solid lipid nanoparticles (SLN) after duodenal administration to rats. Part II—tissue distribution, Pharmacol. Res. 43 (5) (2001) 497–502. M.A. Videira, M.F. Botelho, A.C. Santos, L.F. Gouveia, J.J. de Lima, A.J. Almeida, Lymphatic uptake of pulmonary delivered radiolabelled solid lipid nanoparticles, J. Drug Target. 10 (8) (2002) 607–613. R. Cavalli, M.R. Gasco, P. Chetoni, S. Burgalassi, M.F. Saettone, Solid lipid nanoparticles (SLN) as ocular delivery system for tobramycin, Int. J. Pharm. 238 (2002) 241–245. E.B. Souto, R.H. Müller, Cosmetic features and applications of lipid nanoparticles (SLN, NLC), Int. J. Cosmet. Sci. 30 (3) (2008) 157–165. E.B. Souto, S.A. Wissing, C.M. Barbosa, R.H. Müller, Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery, Int. J. Pharm. 278 (2004) 71–77.

144

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145

[202] A.K. Gupta, E.A. Cooper, Update in antifungal therapy of dermatophytosis, Mycopathologia 166 (2008) 353–367. [203] V. Sanna, E. Gavini, M. Cossu, G. Rassu, P. Giunchedi, Solid lipid nanoparticles (SLN) as carriers for the topical delivery of econazole nitrate: in-vitro characterization, ex-vivo and in-vivo studies, J. Pharm. Pharmacol. 59 (8) (2007) 1057–1064. [204] C.W. Pouton, Lipid formulations for oral administration of drugs: nonemulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems, Eur. J. Pharm. Sci. 11 (Suppl. 2) (2000) S93–S98. [205] D. Jain, R. Banerjee, Comparison of ciprofloxacin hydrochloride-loaded protein, lipid, and chitosan nanoparticles for drug delivery, J. Biomed. Mater. Res. B Appl. Biomater. 86 (1) (2008) 105–112. [206] S. Gelperina, K. Kisich, M.D. Iseman, L. Heifets, The potential advantages of nanoparticle drug delivery systems in chemotherapy of tuberculosis, Am. J. Respir. Crit. Care Med. 172 (12) (2005) 1487–1490. [207] J. Murray, L. Brown, R. Langer, Controlled release of microquantities of macromolecules, Cancer Drug Deliv. 1 (2) (1984) 119–123. [208] R.A. Siegel, R. Langer, Controlled release of polypeptides and other macromolecules, Pharm. Res. 1 (1) (1984) 2–10. [209] R. Langer, J. Folkman, Polymers for the sustained release of proteins and other macromolecules, Nature 263 (1976) 797–800. [210] K.S. Soppimath, T.M. Aminabhavi, A.R. Kulkarni, W.E. Rudzinski, Biodegradable polymeric nanoparticles as drug delivery devices, J. Control. Release 70 (2001) 1–20. [211] R.B. Umamaheshwari, N.K. Jain, Receptor mediated targeting of lectin conjugated gliadin nanoparticles in the treatment of Helicobacter pylori, J. Drug Target. 11 (7) (2003) 415–424. [212] C. Vauthier, C. Dubernet, E. Fattal, H. Pinto-Alphandary, P. Couvreur, Poly (alkylcyanoacrylates) as biodegradable materials for biomedical applications, Adv. Drug Deliv. Rev. 55 (2003) 519–548. [213] S.C. Abeylath, E. Turos, S. Dickey, D.V. Limb, Glyconanobiotics: novel carbohydrate nanoparticle antibiotics for MRSA and Bacillus anthracis, Bioorg. Med. Chem. 16 (5) (2008) 2412–2418. [214] D.E. Owens 111, N.A. Peppas, Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles, Int. J. Pharm. 307 (2006) 93–102. [215] S.R. Croy, G.S. Kwon, Polymeric micelles for drug delivery, Curr. Pharm. Des. 12 (2006) 4669–4684. [216] J. Cheng, B.A. Teply, I. Sherifi, J. Sung, G. Luther, F.X. Gu, E. Levy-Nissenbaum, A.F. Radovic-Moreno, R. Langer, O.C. Farokhzad, Formulation of functionalized PLGA– PEG nanoparticles for in vivo targeted drug delivery, Biomaterials 28 (2007) 869–876. [217] F. Gu, L. Zhang, B.A. Teply, N. Mann, A. Wang, A.F. Radovic-Moreno, R. Langer, O.C. Farokhzad, Precise engineering of targeted nanoparticles by using selfassembled biointegrated block copolymers, Proc. Natl. Acad. Sci. U.S.A. 105 (7) (2008) 2586–2591. [218] E. Fettal, M. Youssef, P. Couvreur, A. Andremont, Treatment of experimental salmonellosis in mice with ampicillin-bound nanoparticles, Antimicrob. Agents Chemother. 33 (9) (1989) 1540–1543. [219] F. Forestier, P. Gerrier, C. Chaumard, A.M. Quero, P. Couvreurr, C. Labarre, Effect of nanoparticle-bound ampicillin on the survival of Listeria monocytogenes in mouse peritoneal macrophages, J. Antimicrob. Chemother. 30 (1992) 173–179. [220] O. Balland, H. Pinto-Alphandary, A. Viron, E. Puvion, A. Andremont, P. Couvreur, Intracellular distribution of ampicillin in murine macrophages infected with Salmonella typhimurium and treated with (3H)ampicillin-loaded nanoparticles, J. Antimicrob. Chemother. 37 (1996) 105–115. [221] G. Fontana, G. Pitarresi, V. Tomarchio, B. Carlisi, P.L. San Biagio, Preparation, characterization and in vitro antimicrobiral activity of ampicillin-loaded polyethylcyanoacrylate nanoparticles, Biomaterials 19 (1998) 1009–1017. [222] G. Fontana, M. Licciardi, S. Mansueto, D. Schillaci, G. Giammona, Amoxicillinloaded polyethylcyanoacrylate nanoparticles: Influence of PEG coating on the particle size, drug release rate and phagocytic uptake, Biomaterials 22 (2001) 2857–2865. [223] E. Turos, J.Y. Shim, Y. Wang, K. Greenhalgh, G.S. Reddy, S. Dickey, D.V. Lim, Antibiotic-conjugated polyacrylate nanoparticles: New opportunities for development of anti-MRSA agents, Bioorg. Med. Chem. Lett. 17 (1) (2007) 53–56. [224] S. Prior, C. Gamazo, J.M. Irache, H.P. Merkle, B. Gander, Gentamicin encapsulation in PLA/PLGA microspheres in view of treating Brucella infections, Int. J. Pharm. 196 (2000) 115–125. [225] S. Svenson, Dendrimers as versatile platform in drug delivery applications, Eur. J. Pharm. Biopharm. 71 (2009) 445–462. [226] H.K. Sajja, M.P. East, H. Mao, Y.A. Wang, S. Nie, L. Yang, Development of multifunctional nanoparticles for targeted drug delivery and noninvasive imaging of therapeutic effect, Curr. Drug Discov. Technol. 6 (1) (2009) 43–51. [227] E.R. Gillies, J.M. Fréchet, Dendrimers and dendritic polymers in drug delivery, Drug Discov. Today 10 (1) (2005) 35–43. [228] Y. Cheng, H. Qu, M. Ma, Z. Xu, P. Xu, Y. Fang, T. Xu, Polyamidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: an in vitro study, Eur. J. Med. Chem. 42 (2007) 1032–1038. [229] C.Z. Chen, S.L. Cooper, Interactions between dendrimer biocides and bacterial membranes, Biomaterials 23 (16) (2002) 3359–3368. [230] M. Ma, Y. Cheng, Z. Xu, P. Xu, H. Qu, Y. Fang, T. Xu, L. Wen, Evaluation of Polyamidoamine (PAMAM) dendrimers as drug carriers of anti-bacterial drugs using sulfamethoxazole (SMZ) as a model drug, Eur. J. Med. Chem. 42 (2007) 93–98. [231] D. Bhadra, S. Bhadra, N.K. Jain, Pegylated lysine based copolymeric dendritic micelles for solubilization and delivery of artemether, J. Pharm. Pharmaceut. Sci. 8 (3) (2005) 467–482.

[232] S. Sandhiya, S.A. Dkhar, A. Surendiran, Emerging trends of nanomedicine—an overview, Fundam. Clin. Pharmacol. 23 (3) (2009) 263–269. [233] M.H. Dufresne, D.L. Garrec, V. Sant, J.C. Leroux, M. Ranger, Preparation and characterization of water-soluble pH-sensitive nanocarriers for drug delivery, Int. J. Pharm. 277 (2004) 81–90. [234] M.V. Risbud, A.A. Hardikar, S.V. Bhat, R.R. Bhonde, pH-sensitive freeze-dried chitosan-polyvinyl pyrrolidone hydrogels as controlled release system for antibiotic delivery, J. Control. Release 68 (1) (2000) 23–30. [235] Y.L. Hu, J.Q. Gao, Potential neurotoxicity of nanoparticles, Int. J. Pharm. 394 (1–2) (2010) 115–121. [236] E.M. Hetrick, J.H. Shin, N.A. Stasko, C.B. Johnson, D.A. Wespe, E. Holmuhamedov, M.H. Schoenfisch, Bactericidal efficacy of nitric oxide-releasing silica nanoparticles, ACS Nano 2 (2) (2008) 235–246. [237] S.M. Moghimi, A.C. Hunter, J.C. Murray, Nanomedicine: current status and future prospects, FASEB J. 19 (3) (2005) 311–330. [238] B.G. Trewyn, C.M. Whitman, V.S.Y. Lin, Morphological control of roomtemperature ionic liquid template mesoporous silica nanoparticles for controlled release of antibacterial agents, Nano Lett. 4 (11) (2004) 2139–2143. [239] S.S. Suri, H. Fenniri, B. Singh, Nanotechnology-based drug delivery systems, J. Occup. Med. Toxicol. 2 (2007) 16. [240] A. El-Ansary, S. Al-Daihan, On the toxicity of therapeutically used nanoparticles: an overview, J. Toxicol. (2009) 754810. [241] W.I. Hagens, A.G. Oomen, W.H. de Jong, F.R. Cassee, A.J. Sips, What do we (need to) know about the kinetic properties of nanoparticles in the body? Regul. Toxicol. Pharmacol. 49 (3) (2007) 217–229. [242] A. Poma, M.L. Di Giorgio, Toxicogenomics to improve comprehension of the mechanisms underlying responses of in vitro and in vivo systems to nanomaterials: a review, Curr. Genomics 9 (2008) 571–585. [243] W.H. De Jong, P.J. Borm, Drug delivery and nanoparticles: applications and hazards, Int. J. Nanomedicine 3 (2) (2008) 133–149. [244] R. Lei, C. Wu, B. Yang, H. Ma, C. Shi, Q. Wang, Q. Wang, Y. Yuan, M. Liao, Integrated metabolomic analysis of the nano-sized copper particle-induced hepatotoxicity and nephrotoxicity in rats: a rapid in vivo screening method for nanotoxicity, Toxicol. Appl. Pharmacol. 232 (2) (2008) 292–301. [245] D.C. Chalupa, P.E. Morrow, G. Oberdörster, M.J. Utell, M.W. Frampton, Ultrafine particle deposition in subjects with asthma, Environ. Health Perspect. 112 (8) (2004) 879–882. [246] S. Yoshida, K. Hiyoshi, S. Oshio, H. Takano, T. Ichinose, Effects of fetal exposure to carbon nanoparticles on reproductive function in male offspring, Fertil. Steril. 93 (5) (2010) 1695–1699. [247] T. Komatsu, M. Tabata, M. Kubo-Irie, T. Shimizu, K. Suzuki, Y. Nihei, K. Takeda, The effects of nanoparticles on mouse testis Leydig cells in vitro, Toxicol. In Vitro 22 (8) (2008) 1825–1831. [248] A. Kroll, M.H. Pillukat, D. Hahn, J. Schnekenburger, Current in vitro methods in nanoparticle risk assessment: limitations and challenges, Eur. J. Pharm. Biopharm. 72 (2009) 370–377. [249] A.M. Fayaz, K. Balaji, M. Girilal, R. Yadav, P.T. Kalaichelvan, R. Venketesan, Biogenic synthesis of silver nanoparticles and their synergistic effect with antibiotics: a study against gram-positive and gram-negative bacteria, Nanomedine 6 (2010) 103–109. [250] A. De Souza, D. Mehta, R.W. Leavitt, Bactericidal activity of combinations of silver–water dispersion with 19 antibiotics against seven microbial strains, Curr. Sci. 91 (2006) 926–929. [251] R.T. Tom, V. Suryanarayanan, P.G. Reddy, S. Baskaran, T. Pradeep, Ciprofloxacinprotected gold nanoparticles, Langmuir 20 (5) (2004) 1909–1914. [252] J. Lellouche, E. Kahana, S. Elias, A. Gedanken, E. Banin, Antibiofilm activity of nanosized magnesium fluoride, Biomaterials 30 (2009) 5969–5978. [253] N.M. Sanderson, M.N. Jones, Encapsulation of vancomycin and gentamicin within cationic liposomes for inhibition of growth of Staphylococcus epidermidis, J. Drug Target. 4 (3) (1996) 181–189. [254] P.C. Teixeira, G.M. Leite, R.J. Domingues, J. Silva, P.A. Gibbs, J.P. Ferreira, Antimicrobial effects of a microemulsion and a nanoemulsion on enteric and other pathogens and biofilms, Int. J. Food Microbiol. 118 (1) (2007) 15–19. [255] D.M. Livermore, Of Pseudomonas, porins, pumps and carbapenems, J. Antimicrob. Chemother. 47 (2001) 247–250. [256] D. Pérez-Conesa, L. McLandsborough, J. Weiss, Inhibition and inactivation of Listeria monocytogenes and Escherichia coli O157:H7 colony biofilms by micellarencapsulated eugenol and carvacrol, J. Food Prot. 69 (12) (2006) 2947–2954. [257] S. Chono, T. Tanino, T. Seki, K. Morimoto, Efficient drug targeting to rat alveolar macrophages by pulmonary administration of ciprofloxacin incorporated into mannosylated liposomes for treatment of respiratory intracellular parasitic infections, J. Control. Release 127 (2008) 50–58. [258] J.S. Patton, C.S. Fishburn, J.G. Weers, The lungs as a portal of entry for systemic drug delivery, Proc. Am. Thorac. Soc. 1 (4) (2004) 338–344. [259] X. He, H. Zhang, Y. Ma, W. Bai, Z. Zhang, K. Lu, Y. Ding, Y. Zhao, Z. Chai, Lung deposition and extrapulmonary translocation of nano-ceria after intratracheal instillation, Nanotechnology 21 (28) (2010) 285103. [260] J.M. Irache, H.H. Salman, C. Gamazo, S. Espuelas, Mannose-targeted systems for the delivery of therapeutics, Expert Opin. Drug Deliv. 5 (6) (2008) 703–724. [261] W. Wijagkanalan, S. Kawakami, M. Takenaga, R. Igarashi, F. Yamashita, M. Hashida, Efficient targeting to alveolar macrophages by intratracheal administration of mannosylated liposomes in rats, J. Control. Release 125 (2) (2008) 121–130. [262] D.L. Poelma, L.J. Zimmermann, H.H. Scholten, B. Lachmann, J.F. Van Iwaarden, In vivo and in vitro uptake of surfactant lipids by alveolar type II cells and macrophages, Am. J. Physiol. Lung Cell. Mol. Physiol. 283 (2002) L648–L654.

A.J. Huh, Y.J. Kwon / Journal of Controlled Release 156 (2011) 128–145 [263] M.M. Bailey, C.J. Berkland, Nanoparticle formulations in pulmonary drug delivery, Med. Res. Rev. 29 (1) (2009) 196–212. [264] I. Roy, N. Vij, Nanodelivery in airway diseases: challenges and therapeutic applications, Nanomedicine 6 (2010) 237–244. [265] A. Misra, K. Jinturkat, D. Patel, J. Lalani, M. Chougule, Recent advances in liposomal dry powder formulations: preparation and evaluation, Expert Opin. Drug Deliv. 6 (1) (2009) 71–89. [266] G.A. Peyman, H.C. Charles, K.R. Liu, B. Khoobehi, M. Niesman, Intravitreal liposome-encapsulated drugs: a preliminary human report, Int. Ophthalmol. 12 (3) (1988) 175–182. [267] C.I. Price, J.W. Horton, C.R. Baxter, Topical liposomal delivery of antibiotics in soft tissue infection, J. Surg. Res. 49 (2) (1990) 174–178. [268] K. Kanellakopoulou, E.J. Giamarellos-Bourboulis, Carrier systems for the local delivery of antibiotics in bone infections, Drugs 59 (6) (2000) 1223–1232. [269] K. Kanellakopoulou, N. Galanakis, E.J. Giamarellos-Bourboulis, C. Rifiotis, K. Papakostas, A. Andreopoulos, E. Dounis, P. Karagianakos, H. Giamarellou, Treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with a biodegradable system of lactic acid polymer releasing pefloxacin, J. Antimicrob. Chemother. 46 (2) (2000) 311–314. [270] J.K. Koort, E. Suokas, M. Veiranto, T.J. Mäkinen, J. Jalava, P. Törmälä, H.T. Aro, In vitro and in vivo testing of bioabsorbable antibiotic containing bone filler for osteomyelitis treatment, J. Biomed. Mater. Res. A 1:78 (3) (2006) 532–540. [271] P.K. Naraharisetti, H.C. Guan Lee, Y.C. Fu, D.J. Lee, C.H. Wang, In vitro and in vivo release of gentamicin from biodegradable discs, J. Biomed. Mater. Res. B Appl. Biomater. 77 (2) (2006) 329–337. [272] L.C. Li, J. Deng, D. Stephens, Polyanhydride implant for antibiotic delivery-from the bench to the clinic, Adv. Drug Deliv. Rev. 54 (2002) 963–986.

145

[273] D. Neut, O.S. Kluin, B.J. Crielaard, H.C. van der Mei, H.J. Busscher, D.W. Grijpma, A biodegradable antibiotic delivery system based on poly-(trimethylene carbonate) for the treatment of osteomyelitis, Acta Orthop. 80 (5) (2009) 514–519. [274] W.T. Jia, X. Zhang, S.H. Luo, X. Liu, W.H. Huang, M.N. Rahaman, D.E. Day, D.Q. Zhang, Z.P. Xie, J.Q. Wang, Novel borate glass/chitosan composite as a delivery vehicle for teicoplanin in the treatment of chronic osteomyelitis, Acta Biomater. 6 (2010) 812–819. [275] K. Nagahama, M. Hashizume, H. Yamamoto, T. Ouchi, Y. Ohya, Hydrophobically modified biodegradable poly(ethylene glycol) copolymers that form temperature-responsive nanogels, Langmuir 25 (17) (2009) 9734–9740. [276] M. Qiao, D. Chen, X. Ma, Y. Liu, Injectable biodegradable temperature-responsive PLGA-PEG-PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels, Int. J. Pharm. 294 (2005) 103–112. [277] K.T. Peng, C.F. Chen, I.M. Chu, Y.M. Li, W.H. Hsu, R.W. Hsu, P.J. Chang, Treatment of osteomyelitis with teicoplanin-encapsulated biodegradable thermosensitive hydrogel nanoparticles, Biomaterials 31 (2010) 5227–5236. [278] R. Schiffelers, G. Storm, I. Bakker-Woudenberg, Liposome encapsulated aminoglycosides in pre-clinical and clinical studies, J. Antimicrob. Chemother. 48 (2001) 333–344. [279] E.B. Souto, R.H. Müller, SLN and NLC for topical delivery of ketoconazole, J. Microencapsul. 22 (2005) 501–510. [280] M.S. Espuelas, P. Legrand, P.M. Loiseau, C. Bories, G. Barratt, J.M. Irache, In vitro antileishmanial activity of amphotericin B loaded in poly(1-Caprolactone) nanospheres, J. Drug Target. 10 (8) (2002) 593–599. [281] V.E. Kagan, H. Bayir, A.A. Shvedova, Nanomedicine and nanotoxicology: two sides of the same coin, Nanomedicine 1 (4) (2005) 313–316.