Antimicrobial magnetic nanoparticles based-therapies for controlling infectious diseases

Accepted Manuscript Review Antimicrobial magnetic nanoparticles based-therapies for controlling infectious diseases Gisele Regina Rodrigues, Carlos López-Abarrategui, Inés de la Serna Gómez, Simoni Campos Dias, Anselmo J. Otero-González, Octavio Luiz Franco PII: DOI: Reference:

S0378-5173(18)30868-8 https://doi.org/10.1016/j.ijpharm.2018.11.043 IJP 17936

To appear in:

International Journal of Pharmaceutics

Received Date: Revised Date: Accepted Date:

28 July 2018 13 November 2018 15 November 2018

Please cite this article as: G. Regina Rodrigues, C. López-Abarrategui, I. de la Serna Gómez, S. Campos Dias, A.J. Otero-González, O. Luiz Franco, Antimicrobial magnetic nanoparticles based-therapies for controlling infectious diseases, International Journal of Pharmaceutics (2018), doi: https://doi.org/10.1016/j.ijpharm.2018.11.043

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Antimicrobial magnetic nanoparticles based-therapies for controlling infectious diseases. Gisele Regina Rodrigues2, Carlos López-Abarrategui1, Inés de la Serna Gómez2, Simoni Campos Dias2, Anselmo J. Otero-González1 and Octavio Luiz Franco2,3 1- Center for Protein Studies, Faculty of Biology, University of Havana, Cuba. 2- Center for Biochemical and Proteomics Analyses, Catholic University of Brasilia, Brasilia, Brazil. 3- S-Inova Biotech, Post-Graduate in Biotechnology, Catholic University Dom Bosco, Campo Grande, Brazil.

Corresponding author . Phone: (61) 3448-7167/ Fax: (61) 33474797/ e- mail: [email protected]. Center for Biochemical and Proteomics Analyses, Catholic University of Brasilia, Brazil. 70790-160.

Antimicrobial magnetic nanoparticles based-therapies for controlling infectious diseases Abstract In the last years, the antimicrobial resistance against antibiotics has become a serious health issue, arise as global threat. This has generated a search for new strategies in the progress of new antimicrobial therapies. In this context, different nanosystems with antimicrobial properties have been studied. Specifically, magnetic nanoparticles seem to be very attractive due to their relatively simple synthesis, intrinsic antimicrobial activity, low toxicity and high versatility. Iron oxide NPs (IONPs) was authorized by the World Health Organization for human used in biomedical applications such as in vivo drug delivery systems, magnetic guided therapy and contrast agent for magnetic resonance imaging have been widely documented. Furthermore, the antimicrobial activity of different magnetic nanoparticles has recently been demonstrated. This review elucidates the recent progress of IONPs in drug delivery systems and focuses on the treatment of infectious diseases and target the possible detrimental biological effects and associated safety issues.

Keywords: Magnetic nanoparticles, iron oxide nanoparticles, antimicrobial activity, antimicrobial drugs delivery.

1

1-Introduction

2 In recent years, antimicrobial resistance against antibiotics has become a serious health 3 issue, posing a global threat [1-2]. The lack of development of new antibiotics for treating 4 illnesses (only two new classes of antibiotics have appeared in the last four decades) [3], 5 as well as the appearance of multidrug-resistant strains, have worsened the scenario. In 6 fact, it is estimated that by 2050 antibiotic resistance will have caused approximately 300 7 million deaths, with an economic loss of $100 trillion [4], and according to the World 8 Health Organization antibiotic resistance is one of the major health problems of the 9 century. These concerns have generated a search for innovative strategies in antimicrobial 10 therapies [5]. Among the strategies that have been under investigation are the use of 11 antimicrobial peptides, phage therapy, therapeutic antibodies, quorum sensing inhibitors 12 and, finally, antimicrobial nanoparticles [6]. Nanoparticles (NPs)are an alternative for 13 overcoming these problems. The advantage of NP formulations compared to conventional 14 systems is that they can increase the efficacy of treatment and reduce side effects, due to 15 specific targeting action [7-9]. Since the development of the first drug carrier systems 16 (Bonventre and Gregoriadis, 1978 [10]), a large number of nanoparticles have been 17 developed. [10]. In addition, NPs have been used and tested in the most varied fields, 18 including nanopharmaceuticals (i.e., intended for drug delivery), nanodiagnostics (i.e., 19 used for imaging and diagnostics), nanotheranostics (i.e., combined therapeutic and 20 diagnostic), and nanobiomaterials (i.e., medical implants) [8,11]. Among these, 21 nanopharmaceuticals are predominant and represent 75% of the market share of approved 22 nanoparticles. The nanopharmaceutical market is still at an early stage, but these products 23 have significantly improved the therapeutic efficacy of many small-molecule drugs. 24 Those products approved for the global market are segmented by class of delivery system 25 in Table 1 [11]. According to Ragelle et al. [11], there are currently 29 principal 26 nanoparticle-based drug delivery systems in clinical trials in different phases in various 27 countries [11]. Furthermore, the action mechanism of these nanoparticles is type 28 dependent. While these antimicrobial mechanisms are not fully understood, some of them 29 are related to the damage caused by the physical structure of the nanoparticles itself, 30 whereas others could be associated with the generation of reactive oxygen species (ROS) 31 or linked to the release of metal ions from nanoparticle surfaces [12]. In addition, 32 magnetic nanoparticles (MNPs) have other attractive properties, compared with their 33 metallic, semiconducting, silica- or carbon-based analogs, intended for pharmaceutical

1

34 and biological applications [13]. Magnetic nanoparticles could be remotely guided 35 through the influence of an external magnetic field to selected targets. Also, the 36 application of a fluctuating magnetic field makes MNPs dissipate energy as heat, causing 37 a localized increase in temperature around them. This phenomenon is known as magnetic 38 fluid hyperthermia [14,15]. In order to isolate and/or concentrate analyses, molecular 39 markers and cells from different MNP fluids have been successfully used [16,17]. 40 Furthermore, their capacity for molecule delivery in vitro and in vivo [18-19] 41 magnetically guided immunotherapy, [20,21] and as a contrast agent for magnetic 42 resonance imaging through the tuning of transverse relaxation time [22] has been widely 43 demonstrated. Although all these approaches seem to be effective, magnetic nanoparticles 44 (MNPs) are amongst the most promising strategies regarding potential translation to 45 clinics in the field of antibiotic therapy [6]. MNPs have unique physical properties and 46 the capacity to function at the cellular and molecular level, intended for pharmaceutical 47 and biological applications [13,22-26]. Furthermore, MNP drug delivery systems 48 improve the ability to define specific locations in the body; they decrease the necessary 49 amount of drug to reach the target; and they reduce the concentration of the drug at non50 target sites, minimizing severe side effects [27]. These advantages arise because some 51 metals like zinc, silver and copper exhibit antimicrobial properties in their bulk form. 52 Furthermore, the antimicrobial effect of these metals is inversely proportional to the 53 nanoscale dimensions [28]. For iron oxide nanoparticles (IONPs), the synthesis is 54 relatively simple and economical; it can be achieved practically without toxic by55 products, and its tolerance for biological systems is high. Nevertheless, the greatest 56 concern around IONPs is associated with biocompatibility, biodegradability and 57 cytotoxicity, especially in in vivo tests [24, 25, 27, 29, 30]. Thus, this review elucidates 58 recent progress of IONPs in drug delivery systems, and focuses on the treatment of 59 infectious diseases, aiming to emphasize the potential adverse biological effects and 60 associated safety issues. 61

2-Magnetic nanoparticle (MNP) synthesis and functionalization

62

MNPs are being extensively investigated for biomedical use, for their low cost and

63

toxicity, and unique magnetic properties [22,27,31]. MNPs are based on a metal such as

64

iron, nickel, silver and cobalt, or on a metal oxide [25]. Among metal oxides, iron oxide

65

NPs (IONPs) have wide distribution in nature and are easily synthesized [8,31-33].

66

Although many pure phases of iron oxide exist in nature, the most popular MNPs are 2

67

nanoscale zero-valent iron (nZVI) Fe3O4 and αFe2O3. They have different

68

physicochemical properties arising from the variation in their iron oxidation states.

69

Among them, magnetite (Fe3O4), which is a ferromagnetic oxide of both Fe(II) and

70

Fe(III), has been broadly studied. Magnetite is the preferred type considering the

71

presence of the Fe2+state with the capability of acting like an electron donor. [8,31]. In

72

addition, IONPs are nanomaterials that exhibit magnetic properties such as

73

ferromagnetism, ferrimagnetism, and paramagnetism or superparamagnetism, different

74

magnetic properties that occur during the crystallization of iron [8,14,25].

75

Superparamagnetic nanoparticles (SIONPs) exhibit superparamagnetism in a size-

76

dependent manner, and when exposed to the external magnetic field they are

77

magnetized and become neutral upon removal of the field [25,34,35]. Therefore, the

78

magnetic properties can define size, shape, composition and their biological applications

79

[8,13, 31-37]. Fig. 1.

80

MNPs can be synthesized by different methods, namely chemical, physical and

81

biological [38]. Chemical methods are most frequently used due to their simplicity,

82

controllable handling, and efficiency. Besides that, the composition, size, and shape of

83

the NPs can be designed (i.e., using co-precipitation [39], microemulsion [40],

84

hydrothermal [41], etc.), and these syntheses use one of two main methods [29]. First,

85

physical methods consist of elaborate procedures which in general cannot control the

86

size of particles in the nanometer range but are easy to perform (i.e., gas phase

87

deposition [42], electron beam lithography [43], etc). Second, a biological method or

88

bacterial synthesis can be a new option to substitute chemical synthesis, as it takes place

89

under mild conditions and avoids the use of toxic chemicals; it thus may offer a new

90

non-toxic, biocompatible composite for biomedical and environmental applications.

91

[8,44,45]. As a natural product, magnetic nanoparticles are uniform particles of 20–45

92

nm core diameter and single-domain crystals [8,44]. These methods are advantageous

93

with respect to yield, reproducibility and scalability, but the fermentation process is

94

time-consuming. (i.e., bacterium and fungus mediated) [45]. Furthermore, bare MNPs

95

are generally unstable and they easily aggregate, due to high surface energy [31].

96

Aggregation significantly affects MNP dispersion into the aqueous medium;

97

furthermore, the oxidation process could occur in the presence of oxygen [29,31]. In

98

order to overcome such disadvantages, different methods of surface modification can be

99

used, including the use of chemicals (i.e., oleic acid [46)] citric acid [47], polymers [48-

3

100

50)] etc.) or of biological molecules (i.e., chitosan [25,51], albumin [52], dextran

101

[53,54], etc.) Fig. 2.

102

Among various functionalization methods, dopamine is the most common organic

103

material with a high-affinity connection group used for the stabilization of IONPs in

104

water and physiologic buffers [29]. The catechol unit of dopamine can coordinate the

105

IONP surface. Amstad et al. [55] described catechol-derived anchor groups, which have

106

a specific binding affinity to iron oxide and thus can disperse superparamagnetic

107

nanoparticles under physiologic conditions. Silica is widely known as a coating material

108

and frequently used for encapsulating IONPs in the sol-gel reaction (also known as the

109

Stober process). It is synthesized via the hydrolysis and condensation of silicon

110

orthoester (Si(OR)4) (e.g., tetraethyl orthosilicate (TEOS) and tetramethyl orthosilicate

111

(TMOS)) [56]. This functionalization has a great impact on the biocompatibility of

112

MNPs, as well as improving biomarker targeting [41,57]. Besides, different molecules

113

have been conjugated to or entrapped in MNPs in order to add new functionalities to the

114

nanosystems [3]. Fig. 3.

115

3-Antimicrobial activity of MNPs

116

The intrinsic antimicrobial property of MNPs promotes their study as potential

117

therapeutic agents against infectious diseases. Indeed, the direct antimicrobial activity of

118

MNPs has been confirmed by many researchers [9,13,26,59,60]. The antimicrobial

119

activity of nanomaterials mainly functions via three mechanisms: cell membrane

120

damage; releasing toxic metals, which can react with proteins, causing a loss of protein

121

function, and thus inhibiting or killing microbes; and generating reactive oxygen (ROS),

122

an active reactant that damages DNA, RNA, and proteins, thus damaging microbes

123

[13,25].

124

Among the MNPs, IONPs are of great importance for biomedical applications, due to

125

various physicochemical properties [29,61-63]. For example, Prucek et al. [63]

126

synthesized two types of MNPs, Ag@Fe3O4 and α- -Fe2O3@Ag. Ag@Fe3O4 ultra small

127

silver nanoparticles (~5 nm) were caught on the surface of Fe3O4 magnetic core (~70

128

nm). The Ag@Fe3O4 nanocomposite revealed a higher large silver nanocore (20-40

129

nm), surrounded by ultra-small α-Fe2O3-Fe2O3@Ag. These nanoparticles demonstrated

130

important antibacterial and antifungal activities, against 10 tested for bacterial strains

4

131

and four Candida species. This nanoparticle can be used for the targeted transport of an

132

antimicrobial agent, and its removal is made by an external magnetic field [63,64].

133

As regards the antibacterial activities of bare iron oxide nanoparticles, iron-oxide

134

nanoparticles were synthesized in a co-precipitation method and characterized by

135

absorption spectrophotometer (UVVIS), particle size analyzer (PD), X-ray diffraction

136

(XRD), and scanning electron microscope (SEM). IONPs of 66 nm were tested against

137

eight pathogenic strains (six Gram-positive and two Gram-negative). The antimicrobial

138

activity effect was better for Gram-positive bacteria than Gram-negative [65]. In the

139

studies cited above, the IONPs were not coated, and thus could have a harmful effect on

140

the stability and the antimicrobial efficacy of nanoparticles; on the other hand, the

141

antimicrobial activity may be linked to the small size of IONPs. Other studies have

142

demonstrated similar effects regarding the small size of nanoparticles [66-69]. Yao et al.

143

[70] reported the synthesis of magnetic TMP-based amine N-halamine nanoparticles

144

(Fe3O4@SiO2/CTMP NPs) as recyclable antimicrobial agents by arming Fe3O4@SiO2

145

NPs with amine N-halamines. The magnetic/antibacterial bi-functional products have

146

three components, magnetic Fe3O4 (inner), inert SiO2 (middle), and antibacterial N-

147

calamine (outer), forming core/shell structure. The nanoparticle exhibited a strong

148

antimicrobial effect. Such fact was demonstrated in the time-kill assay with different

149

concentrations of oxidative chlorine (0.11, 0.24, and 0.58 Cl+%) against E. coli as a

150

function of contact time (from 0 to 80 min), the results indicated 100% bacterial killing

151

in 20 min with concentration 0.58 Cl+% [70]. Furthermore, in this study the authors

152

tested the effect of iron-oxide nanoparticles on biofilm structure on different

153

biomaterials and surfaces, such as poly (methyl methacrylate) (PMMA), polystyrene

154

(PS), tissue culture polystyrene well plates (TCPS), glass slide and surfaces (PMMA

155

and TCPS) coated with a hydrophilic polyethylene oxide (PEO). The nanoparticle

156

showed an important decline in biofilm growth and demonstrated antimicrobial activity

157

against E. coli, S. aureus and P. aeruginosa [71]. A reduction in biofilm formation was

158

described for all bacteria tested. The growth of bacteria as biofilm structures helps them

159

resist adverse environmental conditions, and bacterial biofilms are refractory to

160

antibiotic treatments and immune clearance. Thus, novel anti-biofilm therapies are

161

urgently required [72]. In this regard, Grumezescu et al. [73] reported the use of matrix-

162

assisted pulsed laser evaporation (MAPLE), an effective technique to obtain novel anti-

163

biofilm nanocoatings based on Fe3O4/sodium lauryl sulfate (Fe3O4/SLS), core/shell

5

164

nanoparticles loaded with cephalosporin (cefotaxime (CTX) and cefrom (CEF)) ATB

165

adsorption shell. The nanoparticle showed an important decline in biofilm growth; the

166

highest reduction was observed in the presence of iron-oxide nanoparticles at 0.15 mg.

167

mL-1 concentration and inhibition 29 mm was detected for S. aureus compared E. coli

168

and P. aeruginosa [73]. Additionally, the interaction of superparamagnetic iron oxide

169

(SPONs) nanoparticles was evaluated regarding the biological activity of a bacterial

170

biofilm (Streptococcus mutans). The authors synthesized two bare SPIONs, one

171

positively and other negatively charged, in order to prove that the diffusion of the

172

nanoparticles through biofilms would depend on their surface feature. They observed

173

that SPIONs with positive charge were more effective in killing bacteria than the

174

negatively charged ones. Besides, different concentrations of SPION were tested and the

175

activity of antimicrobials for both concentrations, lower and higher, was the same. This

176

study proposes that the surface characteristics of the nanoparticle seem to be a relevant

177

parameter to adjust the efficiency of antimicrobial agents. Additionally, these

178

nanoparticles have the equivalent antibacterial activity against planktonic cells or

179

biofilms. Furthermore, the positively charged SPIONs were more effective in killing

180

bacteria than the negatively charged ones. It is proposed that the surface characteristics

181

of nanoparticle seem to be a relevant parameter in adjusting the efficiency of

182

antimicrobial agents. Additionally, these nanoparticles have the equivalent antibacterial

183

activity against planktonic cells or biofilms [74]. Agarwala et al. [75], described the

184

antibacterial activity of CuO and Fe2O3 nanoparticles against methicillin resistant

185

Staphylococcus aureus (MRSA) and E. coli. The CuO showed antibacterial activity

186

with inhibition of (22 ± 1) mm against Staphylococcus aureus (MRSA) and (18 ± 1)

187

mm for E. coli. The Fe2O3 results for MRSA (14 ± 1) mm and E. coli (12 ± 1) mm CuO.

188

These results demonstrated that CuO has better antibacterial activity than Fe2O3. In

189

contrast, three different magnetite nanoparticles synthesized by three different

190

laboratories (Brown University, US Research Nanomaterial Inc, and NovaCentrix) were

191

unable to inhibit P. aeruginosa biofilm formation at concentrations up to 200 µg. mL-1

192

[76]. This result corroborates those reported by Borcherding et al. [77], in which

193

magnetic nanoparticles (α- Fe2O3) of different sizes did not inhibit P. aeruginosa

194

biofilm growth. Specifically, the authors found that smaller nanoparticles (2 nm)

195

increased biofilm formation significantly more than larger nanoparticles (540 nm). They

196

hypothesized that Fe+3 ions released by magnetic nanoparticles increase bacterial

197

growth. Nevertheless, despite the role of Fe ions in bacterial growth, the antimicrobial 6

198

effect of these ions has been reported [78,79]. Recently Gao et al. [80] described the

199

catalytic nanoparticle (CAT-NP/H2O2), has degradation effect against the biofilm

200

matrix and concurrently as able to kill dental caries bacteria. They used a Streptococcus

201

mutans UA159 as biofilm at in vitro analyses they observed notably antibacterial effect

202

within biofilms, with >99.9% killing in 5 min. Moreover at in vivo tests, the results

203

demonstrated that CAT-NP-H2O2 interrupted outset and the severity dental caries. The

204

same group study the ferumoxytol nanoparticle approved by U.S. Food and Drug

205

Administration used for treat iron deficiency. The results demonstrated that ferumoxytol

206

binds in the biofilm formed by Streptococcus mutans and produce free radicals from

207

hydrogen peroxide (H2O2), lead to bacterial death via cell membrane disruption and

208

extracellular polymeric substances matrix degradation [80]. The studies described above

209

have antimicrobial, antifungal and anti-biofilm activity, and their excellent activity can

210

be related to the small size of IONPs, independently of the type of cover used for NPs.

211

In Table 2 we summarized others nanoparticle with their mechanisms of action. The

212

main mechanism proposed for the antimicrobial action of iron oxide nanoparticles is the

213

oxidative stress generated by reactive oxygen species (ROS). ROS include different

214

radicals such as superoxide, hydroxyl, hydrogen peroxide, and singlet oxygen, which

215

could cause chemical flaw in the proteins and DNA in bacteria [100]. Furthermore,

216

electrostatic interactions between nanoparticles and microbial cell membranes can result

217

in physical disorder, which eventually leads to microbial growth inhibition or cell death

218

[101-104]. Through the Fenton reaction (Eq. 1), which involves the reduction of

219

hydrogen peroxide by ferrous iron, hydroxyl radicals that have the ability to oxidize

220

most organic molecules are generated [105,106] Fig. 4.

221

Fe (II) + H2O2 → Fe (III) + OH- + OH

222

In fact, the peroxidase activity of MNPs has been widely demonstrated. This activity, in

223

addition to ROS generation, has a direct impact on the development of different

224

analytical techniques [17, 107-112]. Furthermore, the physicochemical properties of

225

MNPs (i.e., size, surface area, shape, solubility, and aggregation status) correlate with

226

their potential to generate ROS [104]. As described above, the surface potential of

227

MNPs influences their antimicrobial activity. In fact, spherical magnetite nanoparticles

228

of 10-20 nm diameter, synthesized by the co-precipitation method, were found to have a

229

negative surface potential.

(Eq. 1)

7

230 231

Arakha et al. [104], es ed 50 μM f

b NP g

ed ed pp x m ely 30% f m ell

s B. s b l s

bl y f

w sm

d E. coli, and n-IONP g

sm’s

bl y f

232

both bacterial, while p-IONP reduced 70% for both microorganisms. These changes

233

play a crucial role in determining the IONPs antimicrobial propensity. This study

234

mentions the higher ROS production upon p-IONP bacterial treatment, and it also

235

indicated that chitosan coating of IONP results in communication that enhances ROS

236

production, boosting antimicrobial activity. These changes play a crucial role in

237

determining the antimicrobial propensity of IONPs. This study mentions the higher

238

ROS production upon n-IONP treatment of the bacteria, and it also indicated that

239

chitosan coating of IONP results in communication that enhances ROS production,

240

boosting antimicrobial activity. [105] Besides, Fe3O4 nanoparticles coated with

241

poly(ethylenimine) (PEI) and poly (ethylene glycol) (PEG) present distinct surface

242

positive charges. Indeed, Fe3O4-PEI nanoparticles, which had a higher surface charge

243

than Fe3O4-PEI-PEG nanoparticles, exhibited greater cytotoxicity and ROS formation in

244

different cell lines [112]. Fu et al. [113] demonstrated that magnetite (Fe3O4) and

245

maghemite (Fe2O3) can present distinct cellular responses due to their skill in bearing

246

oxidation/reduction reactions. Indeed, magnetite was seen to cause higher levels of

247

toxicity in A549 human lung epithelial cell line, owing to its capacity to bear oxidation

248

[113,114]. This could explain why in many studies the antimicrobial activity of

249

magnetite is higher than that of maghemite. Furthermore, Wang et al. [115]

250

demonstrated that hematite (α-Fe2O3) and maghemite (γ-Fe2O3), which have different

251

surface structures, induced hydroxyl radicals at different levels. They synthesized a film

252

composed of iron oxide-coated graphene oxide nanomaterial with the chitosan hydrogel

253

matrix. The nanocomposite displayed significant antimicrobial activity against different

254

bacterial strains and Candida albicans. The authors also demonstrated the antimicrobial

255

efficacy of the individual chitosan-graphene oxide (CH-GO) and chitosan iron oxide

256

(CH-IO) hydrogel nanocomposite films. Additionally, the toxicity of the nanocomposite

257

films was evaluated by hemolytic activity and MTT assay. The films were not

258

cytotoxic, so it is possible that they may have a future application in biomedicine, as

259

well as in the food industry [115]. Furthermore, the development of antifungal

260

nanotherapies based on MNPs has also been conducted [116-118]. For this,

261

antimicrobial activity with citric acid-modified MnFe2O4-NPs of about 5 nm diameter

262

was evaluated. These nanoparticles inhibited C. albicans from growing at different

263

concentrations, and the minimal inhibitory concentration (MIC) of the MNPs was 8

264

reported at 250 µg. mL-1 in the RPMI medium. These nanoparticles were not effective

265

against Gram-positive S. aureus and Gram-negative E. coli bacteria. So, the

266

antimicrobial action of these nanoparticles is specific to yeast cells, and this can occur

267

due to the electrostatic connection among citric acid-coated MnFe2O4-NPs and the yeast

268

plasma membrane. In addition, these MNPs were demonstrated to be non-toxic to

269

macrophage [100]. Finally, targeted magnetic fluid hyperthermia (MFH) is also a

270

promising method for microbial therapy. In this regard, researchers evaluated the

271

antifungal efficacy of magnetic hyperthermia therapy by applying meso-2,3-

272

dimercaptosuccinic acid coated MNPs or anti-C. albicans immunomagnetic

273

nanoparticles. MFH based on both magnetic nanocomposites was effective against C.

274

albicans [119].

275

The experiments mentioned above prove the potential of MNPs to control infections.

276

Furthermore, the intrinsic antimicrobial activity of MNPs is very probably mediated by

277

ROS through the action of iron ions, which are also vital for the growth of

278

microorganisms, and it is therefore unlikely that resistance mechanisms will develop

279

against such nanoparticles. Using antimicrobial substances for coating MNPs or

280

creating nanocomposites could increase their therapeutic efficacy.

281

4-Antimicrobial drug delivery by MNPs

282

The basic purpose of MNP-based drug delivery is to direct a loaded magnetic drug

283

carrier system to a specific organ or tissue using an externally applied magnetic field for

284

drug accumulation. Compared with conventional drug administration, MNP drug

285

delivery could reduce the drug concentration administered, thus reducing systemic side

286

effects. In addition, this method raises the drug concentration in the affected tissue,

287

obtaining a better therapeutic effect [27,31]. The choice of coating material is crucial for

288

drug delivery application, which depends on the tailored drug loading and release

289

behaviors, and various materials can be used for coating bare IONPs before employing

290

them in drug delivery, like polymers (e.g., PEG, PAA, and chitosan) and mesoporous

291

silica [31].

292

Nowadays, there are few effective drugs available to control infections by pathogenic

293

bacteria, especially at the intracellular level [3]. Another concern in this regard is the

294

negligible inhibitory effect of therapeutics on the target microorganism, due to the

295

difficulty of transporting drugs across cellular membranes and of specifically targeting

9

296

drugs into the potential active site, together with their low activity and stability [120].

297

Antimicrobial toxicity adds another significant limitation to their use [15]. These

298

shortcomings have been the main reason for the development of novel strategies to

299

combat infectious diseases, such as the utilization of nanoparticles as drug carriers that

300

could enhance therapeutic effectiveness [18].

301

In this context, different molecules have been considered to be chemically and/or

302

physically bonded to MNPs, in order to increase their antimicrobial properties [11, 101].

303

Nonetheless, some uncertainties about the ability of MNPs to efficiently deliver

304

antimicrobial agents have recently been reported [79,121,122]. Masadeh et al. [122]

305

studied the effect of CeO2 and α-Fe2O3 with a mean diameter of 45 nm on the

306

antimicrobial activity of ciprofloxacin. Therefore, the minimal inhibitory concentration

307

(MIC) of only the antibiotic or a nanoformulated antibiotic against different bacteria

308

was compared. The authors demonstrated a considerable decrease in antibiotic activity

309

when it was tested in the presence of γ-Fe2O3. Moreover, Borcherding et al. [77]

310

evaluated the antimicrobial activity of a mixture of the antimicrobial molecules,

311

Lysozyme (600 μg. mL-1), Lactoferrin (200 μg. mL-1), HNP 1 (100 μg. mL-1) and

312

HNP 2 (100 μg. mL-1), in the presence of hematite nanoparticles (α-Fe2O3) of different

313

sizes (2, 43, 85 and 540 nm) in a system with synergic effect. The experiment was

314

conducted by 1-hour incubation of the antimicrobial cocktail with MNPs, following the

315

separation of the soluble molecules by centrifugation. Later, the antimicrobial activity

316

of the soluble medium was evaluated. Interestingly, the smallest nanoparticles inhibited

317

the antimicrobial action of the mixture of host defense molecules. Apparently, inhibition

318

of AMP activity could be attributable to the generation of Fe+3 ions by MNPs that

319

followed sequestering by bacteria, but in this work the higher capacity of the smallest

320

nanoparticles to adsorb antimicrobial polypeptides was also demonstrated. Thus, the

321

inhibition of antimicrobial polypeptide activity by α-Fe2O3 could be a consequence of

322

the removal of the antimicrobial assay of host defense molecules adsorbed to MNPs.

323

The utilization of antimicrobial activity of AMPs or antibiotics conjugated to MNPs has

324

been widely demonstrated [100,120-125]. Zhang et al. [125] showed that bacitracin was

325

covalently immobilized onto Fe3O4 nanoparticles via a CuI–catalyzed azide-alkyne 1,3-

326

dipolar cycloaddition (CuAAC) reaction, and biofunctionalized magnetic antibacterial

327

nanocomposites and nanoparticles (average size 12-15 nm). The conjugated

328

nanoparticles exhibited an antibacterial effect against both Gram-positive and Gram-

10

329

negative microorganisms, which was even higher than that of bacitracin itself. These

330

results allow the dosage and the side-effects of the antibiotic to be reduced, thus

331

increasing drug efficacy [125]. A similar study to compare the activity of bactericins,

332

cathalecidin, synthetic ceragenins and antibiotics like vancomycin and colestin against a

333

methicillin-resistant microorganism, these compounds were tested alone and in

334

combination with core-shell MNPs [126]. Three different nanosystems based on

335

magnetite (Fe3O4): aminosilane-coated nanoparticles (MNP@NH2), gold-coated

336

nanoparticles (MNP@Au), and quaternary ammonium derivative-coated MNPs

337

(MNP@PQAS) were evaluated. In most conditions, synergistic effects were observed in

338

combinations of core-shell MNPs with antimicrobial molecules. Furthermore, the

339

IONPs using antibacterial agents with core-shell MNPs also restrict biofilm formation.

340

Apparently, core-shell MNPs could interact with the bacterial cell wall and/or cellular

341

membrane, enhancing the insertion or uptake of the antimicrobial molecules [126].

342

The results described above corroborate the findings of studies on different strategies,

343

confirming that nanoformulation for targeted drug delivery can be used with effective

344

results [27,31]. In this line, the drug delivery MNPs described were efficient against

345

bacteria (MDR), fungi and biofilm of P. aeruginosa and S. aureus [126,127]. These

346

studies elucidate different methods for treatment and prevention of a wide range of

347

infections caused by MDR pathogens. Similar results were achieved against E. coli and

348

Staphylococcus aureus by synthesizing SPION@Au core-shell NPs functionalized with

349

CM, which has a diameter of 12 ± 2 nm, a zeta potential of +24.2 ± 3.5 mV (in PBS),

350

and 0.4 mg of CM per 1 mg of NPs. AMP-NPs have a lower MIC than soluble CM (0.4

351

versus 5 µg/mL), likely due to the synergetic effect of multiple CM peptides on the

352

surface of the NP [122]. It is possible that functionalized nanosystems could be more

353

specific for certain microbial membranes. For example, in this work, the authors

354

showed that soluble peptide interacts strongly with erythrocyte lipid membranes as

355

compared to the AMP-NPs, which indicate an increase in the selectivity for bacterial

356

membranes of the AMP-coated NPs [122]. Nguyen et al. [127] synthetized the POEGA-

357

b-PMAEP and stabilized with IONP. They produced local heating in biofilms on

358

exposure to a magnetic field. The POEGA-b-PMAEP@IONPs showed no toxicity,

359

besides promoting a detachment of biofilm when they heated biofilm cells and elevated

360

the efficiency of planktonic and biofilm cells; these results were compared with

361

gentamicin.

11

362

According to what has been previously described, magnetic fluid hyperthermia could be

363

efficiently used to control some infectious diseases. In this regard, hyperthermia

364

induced by magnetic nanoparticles upon exposure to an alternating magnetic field could

365

induce biofilm detachment, increasing the number of suspended cells and antibiotic

366

efficacy. Also, magnetic nanoparticles have been employed as vehicles for controlled

367

release of different drugs [15]. Indeed, magnetic nanoparticles coated with the

368

antimicrobial molecule ceragenin CSA-13 (MNP-CSA-13) through the imine bond may

369

be used as a pH control system to release it. At lower pH (pH=5), for 1 hour, 25% of

370

CSA-13 was released to the medium. Furthermore, the nanocomposite showed strong

371

antibacterial activity that was more effective than soluble ceragenin in killing the

372

bacteria P. aeruginosa. A significant reduction in CSA-13 hemolytic activity was

373

detected when the antimicrobial molecule was entrapped on the magnetic nanoparticle

374

surface [123]. This approach overcomes a possible functional impairment of the

375

antimicrobial molecules after their conjugation to nanoparticles.

376

In fact,

377

physicochemical properties [3]. Another study using magnetite nanoparticles with a

378

diameter of 39-41 nm coated with chitosan (CS-MNPs) and further loaded with the

379

antibiotic ampicillin corroborates the importance of the strategy mentioned above. The

380

release of ampicillin in this nanocomposite was 100% over 400 min. The antimicrobial

381

effect of the nanocomposite was dependent on the antibiotic since bare nanoparticles

382

were not antimicrobial. The results indicated that the nanocomposite had no bactericidal

383

effect; otherwise, the same nanocomposite exhibited antifungal properties and

384

antimycobacterial effect [128]. This same group also demonstrated antibacterial and

385

antifungal properties with nystatin nanocomposite nanoparticles (Nyst-CS-MNP) by

386

loading nystatin (Nyst) on chitosan (CS)-coated magnetic nanoparticles (MNPs) [129].

387

The results described by Hussein-Al-Ali et al [128] demonstrated that the chitosan-

388

coated particles (CS-MNP) did not have an antimicrobial effect; on the other hand,

389

Hussein-Al-Ali et al [129] demonstrated that the incorporation of nystatin into iron

390

oxide nanoparticles (Nyst-CS-MNP) decreased toxicity and harmful side effects.

391

Another study was designed in order to investigate the fungicidal properties of polyene

392

antibiotics (amphotericin B and nystatin) attached to the surface of aminosilane-coated

393

nanoparticles (MNP@NH2) against clinical isolates of Candida spp, including resistant

394

strains [124]. Synergistic or additive activity was observed with polyene-coated MNPs

the immobilization reactions

can

affect

molecules

with

different

12

395

against all tested Candida strains. Furthermore, functionalized nanoparticles were more

396

potent than unbound agents when tested to prevent Candida biofilm formation.

397

Apparently, disruption of the oxidation-reduction balance mediated by the inactivation

398

of catalase Cat1 is a mechanism leading to inhibition of Candida growth by MNPs.

399

Besides, the authors demonstrated a significant decrease in the toxicity of polyenes

400

against host cells after their conjugation to MNPs.

401

In general, magnetic nanoparticles as a drug delivery platform allow the use of lower

402

amounts of drugs compared to traditional drug therapy, which decreases adverse effects

403

related to drug toxicity. In addition, the majority of the synthesized MNPs show

404

inherent antimicrobial activity, so the combination of antimicrobial molecules with

405

them could imply a synergistic or additive effect in therapies, improving the usefulness

406

of antimicrobial drugs. This effect may be very beneficial in reducing bacterial

407

resistance to traditional antimicrobial therapy.

408

5- MNPs biodistribution and toxicity

409

The expanding applications of MNPs have given rise to many concerns regarding their

410

toxicological properties and long-term impact on human health [30]. The

411

biocompatibility of a drug nanocarrier may be linked to both the immune system

412

response, raised following its administration, and to the intrinsic toxicity of the carrier

413

and/or of its metabolites. Importantly, when associated with a nanocarrier, the toxicity

414

profile of the drug itself may undergo changes as a consequence of forthcoming

415

modification once in the body, due to cell or tissue biodistribution, clearance or

416

metabolization [130].

417

The potential toxicity of MNPs remains an issue of debate. Many in vitro and in vivo

418

experiments have shown apparently contradictory results in this regard, raising more

419

uncertainty [13,30,131]. There is an ongoing need to understand the in vivo

420

biodistribution and potential clearance mechanisms, and hence both their efficacy and

421

safety. H we e , wh

422

influenced by a myriad of factors [132]. In fact, not only the composition of NPs but

423

also their physical size or surface chemistry, among other variables, may affect the

424

physiological response from the patient, determining NP fate [134]. That would depend

425

on whether they would remain in the same nanostructure afterward, or instead become

426

metabolized. In general, MNPs are classified as good candidates for the intravenous

s

q es

ble s h

p

les’ b d s b

s

13

427

administration when they are small in size, that is 10-100 nm, since nanoparticles larger

428

than 200 nm are rapidly cleared by the reticuloendothelial system (RES) from the blood

429

stream, increasing their biodistribution in the liver and the spleen, while nanoparticles

430

lower than 10 nm are more likely removed from the body through renal clearance [13].

431

Recently, Yang et al., [134] studied the size-dependent biodistribution of MNPs of 10,

432

20, 30 and 40 nm in diameter in mice [134]. At the first day post-injection, all MNPs

433

were found primarily in the spleen and liver. Furthermore, size-dependent

434

biodistribution was reported. The smallest NPs (10 nm) were found mainly in the liver,

435

while larger NPs were found in the spleen [134]. Similar distribution patterns have been

436

reported by Jain et al. [135] and Tsuchiya et al. [136] in rats and mice, respectively.

437

Likewise, Weissleder et al. [137] found that, in rats, 82.6% and 6.2% of the injected

438

dose (ID) of ferumoxide, a clinically approved dextran-coated IONP with an overall

439

hydrodynamic diameter of 80 nm, had accumulated in the liver and spleen 1 hour after

440

the intravenous injection. Similarly, Bourrinet et al. [138] compared the biodistribution

441

of ferumoxtran-10, a 30 nm dextran-coated IONP, with the results previously reported

442

for ferumoxide. In rats, ferumoxtran NPs were mainly localized in the spleen (37–46%

443

ID) and lymph nodes (5–11% ID) 24 hours after intravenous injection and had modest

444

distribution in the liver (25% ID), while there was predominant liver uptake of the

445

larger ferumoxides (83% ID at 1-hour post-injection). In the same way, the effect of NP

446

size also influenced their circulation times. Larger particles are more quickly taken up

447

(by the liver and spleen) and have shorter circulation time in the blood compared with

448

the smaller ones [108]. Indeed, ferumoxtran was found to circulate much longer in the

449

blood compared with ferumoxides. While ferumoxtran showed a blood clearance half-

450

life of 97–222 min, depending on the dose used [139], ferumoxides have been reported

451

to have a much shorter plasma clearance half-life of approximately 6 min [138].

452

As mentioned above, surface chemistry is also a determinant in MNP biodistribution.

453

For example, a comparison of different surface charged dextran-coated Fe3O4 NPs,

454

carried out on mice, demonstrated an increase in the liver uptake of cationic (+ 20 mV)

455

(− 30 mV) NPs w h espe

e

l NPs [140]. In connection with this,

456

Veiseh et al. [141] showed that iron oxide nanoparticles (hydrodynamic diameter: 30

457

nm) coated with chitosan and polyethylene glycol (PEG) improve their ability to cross

458

the blood brain barrier [141]. Furthermore, the administration route and the dose are

459

also among the contributing variables which determine the biodistribution and toxicity

14

460

of MNPs [13, 131]. For example, IONPs administrated by via intranasal will eventually

461

enter the lungs, as was demonstrated by Arami et al. [131] in studies carried out in mice.

462

On the other hand, intraperitoneally inoculated SiO2-coated MNPs (50 nm mean

463

diameter) were found distributed at high concentrations in the liver and spleen, followed

464

by other organs such as the kidneys and heart, while a very low accumulation was

465

detected in the lungs [142]. Besides, at high NP concentration, the functions of the liver

466

and spleen of rats are saturated, resorption become slow, and the residual NPs can

467

circulate in the blood for longer times and have more chance of reaching other organs

468

[131].

469

The in vivo interactions of MNPs and biological systems are quite complicated and

470

dynamic. Diverse proteins exist in the blood and specifically bind to nanoparticles.

471

Adsorption of proteins to the NP surface actually promote dramatic changes in its

472

overall physicochemical properties. These interactions may determine NP uptake and

473

degradation. IONPs become enclosed by plasma opsonin proteins by a process known

474

as opsonization, which contributes to the recognition of NPs by macrophages [143].

475

Opsonization is typically pursued by receptor-mediated phagocytosis of the

476

nanoparticles through the innate immune system. In addition, opsonization also

477

enhances the hydrodynamic size of the MNPs, which accelerates their hepatic clearance

478

[131]. Singh et al. [30] confirm that a range of MNPs with different physico-chemical

479

characteristics primarily show low toxicity with dosage of 100 μg.ml-1 or higher [30].

480

In fact, in vitro experiments have associated the exposure of cells to MNPs with

481

important toxic effects like impaired mitochondrial function, DNA damage, cellular

482

membrane leakage, chromosome condensation, cell differentiation and formation of

483

apoptotic bodies [30]. According to this, the effect of MNP surface coating on cellular

484

toxicity has been assessed. For instance, dextran-magnetite NPs are capable of causing

485

cell death and reduced cellular proliferation in a similar way to bare iron oxide NPs

486

[144]. Nevertheless, a recent study conducted in mice and rats evaluated the toxicity of

487

dextran-coated ferrite nanoparticles and showed that these nanoparticles do not cause

488

toxicity mediated by oxidative stress; nor do they interfere with physiological activities

489

or induce pathological lesions [145]. The influence of transferrin-derived MNPs in

490

human fibroblasts has been studied. The derived MNPs were located at the cellular

491

membrane, and the upregulation of different genes, mainly implicated in cell signaling

492

and cytoskeleton formation, was demonstrated [146]. The toxicity described on

15

493

magnetite-dextran NPs is related to rupture of the dextran shell that allows the exposure

494

of the cells to the aggregates of iron oxide [144]. On the other hand, the same research

495

described membrane detachment after exposure to albumin derived MNPs, and this was

496

applied to the communication among albumin and membrane fatty acids and

497

phospholipids, resulting in cytotoxicity (at 50 μg.ml-1), but did not result in cell death

498

[146]. The cytotoxicity value using albumin-derived iron oxide NPs decreased

499

according to the information described above [30]. It is probable that differences in

500

toxicity between in vivo and in vitro experiments are mediated by the fine control of

501

iron homeostasis, which occurs in healthy animals. Therefore, healthy animals are

502

capable of maintaining iron levels and ROS generation within a safe threshold [30]. In

503

fact, in different clinical trials in humans using MNPs, serious toxicity-related problems

504

have not been much focused [130, 145]. Only minor and transitory side effects such as

505

urticaria, diarrhea, and nausea have been documented. Additionally, extensive data

506

about the toxicological effect of MNPs in preclinical studies reinforce the idea that

507

MNPs are biocompatible and non-cytotoxic [134, 135, 142, 145, 149].

508

Concluding Remarks

509

The intrinsic antimicrobial activity of IONPs was demonstrated with different sizes,

510

shapes and surface coatings. IONPs have been engineered to achieve high crystallinity,

511

size distribution and improved magnetic properties, in order to perform better in

512

biomedical applications. In addition, with their low cost of synthesis and high

513

versatility, they are a feasible solution to overcoming infectious diseases. IONPs may

514

provide promising treatments for infectious illnesses by targeting specific and hard-to-

515

reach sites where pathogens are harbored. Besides that, they optimize physicochemical

516

characteristics, allowing the clinical use of new agents or their administration through

517

more convenient routes. However, they also have drawbacks, and we still know very

518

little about the metabolism, clearance, and toxicity of NPs. On the other hand, IONPs

519

promise significant benefits and advances in addressing the key obstacles to treating

520

infectious diseases.

521

Reference

522 523 524 525

[1] M.E. Kruijshaar, J.M. Watson, F. Drobniewski, C. Anderson, T.J. Brown, J.G. Magee, E.G. Smith, A. Story,I. Abubakar, Increasing antituberculosis drug resistance in the United Kingdom: analysis of National Surveillance Data, BMJ. 336 (2008) 1231-4.

16

526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568

[2] N.J. Snell, Examining unmet needs in infectious disease, Drug Discov Today. 8 (2003) 22-30. [3] R.Vries, C.A. Andrade, A.F. Bakuzis, S.M. Mandal, O.L. Franco, Next-generation nanoantibacterial tools developed from peptides, Nanomedicine,Lond. 10 (2015) 164361. [4] J.M. Munita, C.A. Arias, Mechanisms of Antibiotic Resistance, Microbiol Spectr. (2016) 4. [5] C.A. Arias, B.E. Murray, Antibiotic-Resistant Bugs in the 21st Century - A Clinical Super-Challenge, NEnglJMed. 306 (2009) 439-43. [6] N.G. Simoes, A.F. Bettencourt, N. Monge, R. A. Ribeiro, Novel antibacterial agents: An emergent need to win the battle against infections, Mini Rev Med Chem. (2016). [7] A.P. Jallouk, R.U. Palekar, H. Pan, P.H. Schlesinger, S.A.Wickline, Modifications of natural peptides for nanoparticle and drug design, Adv Protein Chem Struct Biol. 98 (2015) 57-91. [8] L. Mohammed, H.G. Gomaa, D. Ragab, J. Zhu, Magnetic nanoparticles for environmental and biomedical applications, Particuology30 (2017) 1–14. [9] H. Zazo, C.I. Colino, J.M. Lanao, Current applications of nanoparticles in infectious diseases, J Control Release 224 (2016) 86-102. [10] P.F. Bonventret, G, Gregoriadis, Killing of intraphagocytic Staphylococcus aureus by dihydrostreptomycin entrapped within liposomes. Antimicrobial Agents and Chemotherapy. (1978)1049-1051. [11] H. Ragelle, F. Danhier, V. Préat, R. Langer, D.G. Anderson,Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field mature.. Expert Opinion on Drug Delivery (2016) 1744-7593. [12] C. Lopez-Abarrategui, A.J. Otero-Gonzalez, A. Alba-Menendez, E. Reguera, O.L. Franco, Nanoparticles as a promise for host defense peptides therapeutics. In: Prokopovich P, (Eds), Biological and Pharmaceutical Applications of Nanomaterials. Boca Raton, USA: CRC Press (2015)129-47. [13] L.H. Reddy, J.L. Arias, J. Nicolas, P. Couvreur, Magnetic Nanoparticles: Design and Characterization, Toxicity and Biocompatibility, Pharmaceutical and Biomedical Applications. Chem Rev. (2012).

17

569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611

[14] S. Laurent, S. Dutz, U.O. Hafeli, M. Mahmoudi Magnetic fluid hyperthermia: focus on superparamagnetic iron oxide nanoparticles, AdvColloid Interface Sci. 166 (2011) 8-23. [15] C. Lopez-Abarrategui, V. Figueroa-Espi, O. Reyes-Acosta, E. Reguera, A.J. OteroGonzalez, Magnetic nanoparticles: new players in antimicrobial peptide therapeutics, Curr Protein Pept Sci. 14 (2013) 595-606. [16] Borlido L, Azevedo AM, Roque AC, Aires-Barros MR. Magnetic separations in biotechnology. Biotechnol Adv. 31 (2013) 1374-85. [17] V. Figueroa-Espi, A. Alvarez-Paneque, M. Torrens, A.J. Otero-Gonzalez, E. Reguera, Conjugation of manganese ferrite nanoparticles to an anti Sticholysin monoclonal antibody and conjugate applications, Colloids and Surfaces A: Physicochemical and Engineering Aspects. 387 (2011) 118-24. [18] K. Ulbrich, K, Hola, V. Subr, A. Bakandritsos, J. Tucek, R. Zboril, Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies. Chem Rev. 116 (2016) 5338-431. [19] J. Chen, H. Wu, D. Han, C. Xie, Using anti-VEGF McAb and magnetic nanoparticles as double-targeting vector for the radioimmunotherapy of liver cancer, Cancer Lett. 231 (2006) 169-75. [20] A. Natarajan, C. Gruettner, R. Ivkov, G.L. DeNardo, G. Mirick, A. Yuan, A. Foreman, S. J. DeNardo, NanoFerrite particle based radioimmunonanoparticles: binding affinity and in vivo pharmacokinetics, BioconjugChem. 19 (2008) 1211-8. [21] F. Zeinali Sehrig, S. Majidi, S. Asvadi, A. Hsanzadeh, S.H. Rasta, M. Emamverdy, J. Akbarzadeh, S. Jahangiri, S. Farahkhiz, A. Akbarzade, An update on clinical applications of magnetic nanoparticles for increasing the resolution of magnetic resonance imaging, Artif Cells Nanomed Biotechnol. (2015)1-6. [22] A.H. Lu, E.L. Salabas, . S hϋ h, Magnetic Nanoparticles: Synthesis, Protection, Functionalization, and Application, Angew. Chem. Int. Ed. 46 (2007) 1222 – 1244. [23] C. Sun, J.S.H. Lee, M. Zhang, Magnetic nanoparticles in MR imaging and drug delivery, Advanced Drug Delivery Reviews. 60 (2008) 1252–1265. [24] M.J. Hajipour, K.M. Fromm, A.A. Ashkarran, D.J. de Aberasturi, I.R. de Larramendi, T. Rojo, V. Serpooshan, W.J. Parak, M. Mahmoudi, Antibacterial properties of nanoparticles, Trends in Biotechnology. (2012) 30:10.

18

612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628

[25] K.S. Huang, D.B. Shieh, C.S. Yeh, P.C. Wu, F.Y. Cheng, Antimicrobial applications of water-dispersible magnetic nanoparticles in biomedicine, Curr Med Chem. 29 (2014) 3312-22.

629 630

[30] N. Singh, G.J. Jenkins, R. Asadi, S.H. Doak, Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION), Nano Rev. (2010)1.

631 632 633

[31] W. Wu, C.Z. Jiang, V.A. Roy, Designed synthesis and surface engineering strategies of magnetic iron oxide nanoparticles for biomedical applications, Nanoscale.8 (2016) 19421-74,

634 635

[32] W. Wu, Q. He, C. Jiang, Magnetic iron oxide nanoparticles: synthesis and surface functionalization strategies, Nanoscale Res Lett, 3 (2008) 397–415.

636 637 638

[33] C. Han, N. Romero, S. Fischer, J, Dookran, A. Berger, A.L. Doiron, Recent Developments in the use of Nanoparticles for Treatment of Biofilms, Nanotechnol Rev. (2016) 3-46.

639 640 641

[34] G. Kandasamy, D. Maity, Recent advances in superparamagnetic iron oxide nanoparticles (SPIONs) for in vitro and in vivo cancer nanotheranostics, International Journal of Pharmaceutics. 496 (2015) 191–218.

642 643 644 645

[35] J. Salaklang, B. Steitz, A. Finka, C.P. O'Neil, M. Moniatte, A.J. van der Vlies, T.D. Giorgio, H. Hofmann, J.A. Hubbell, A. Petri-Fink, Superparamagnetic nanoparticles as a powerful systems biology characterization tool in the physiological context, Angew Chem Int Ed Engl. 47 (2008) 7857-60.

646 647 648

[36] Y. X. Wáng, J.M. Idée. A comprehensive literatures update of clinical researches of superparamagnetic resonance iron oxide nanoparticles. Magn. Reson. Imaging. 7 (2017) 88–122.

649 650

[37] P.B. Santhosh, N.P. Ulrih, Multifunctional superparamagnetic iron oxide nanoparticles: Promising tools in cancer theranostics, Cancer Lett. (2013) 336-338.

[26] E. Torres-Sangiao, A.M. Holban, M.C. Gestal, Advanced Nanobiomaterials: Vaccines, Diagnosis and Treatment of Infectious Diseases. Molecules. 21 (2016) 867. [27] J. Chomouckaa, J. Drbohlavovaa, D. Huskab, V. Adamb, R. Kizekb, J. Hubaleka, Magnetic nanoparticles and targeted drug delivering. Pharmacological Research. 2010; 62:144–149. [28] J.T. Seil, T.J. Webster, Antimicrobial applications of nanotechnology: methods and literature, Int J Nanomedicine. 7(2012) 2767-81. [29] H. Nosrati, M. Salehiabar, S. Davaran, A. Ramazani, H.K. Manjili, H. Kheiri, H. Danafar, New advances strategies for surface functionalizationof iron oxide magnetic nano particles (IONPs), Chem Intermed. 43 (2017) 7423–7442.

19

651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694

[38] J.K. Xu, F.F. Zhang, J.J. Sun, J. Sheng, F. Wang, M. Sun, Bio and nanomaterials based on Fe3O4, Molecules. 19 (2014) 21506-28. [39] S. Wu, A. Sun, F. Zhai, J. Wang, W. Xu, Q. Zhang, A.A. Volinsky, Fe3O4 magnetic nanoparticles synthesis from tailings by ultrasonic chemical co-precipitation, Materials Letters. 65 (2011) 1882-4. [40] A. Tavakoli, M. Sohrabi, A. Kargari, A review of methods for synthesis of nanostructured metals with emphasis on iron compounds. Chemical Papers. 61 (2007) 61:151-70. [41] F. Chen, Q, Gao, G. Hong, J. Ni, Synthesis and characterization of magnetite dodecahedron nanostructure by hydrothermal method, Journal of Magnetism and Magnetic Materials. 320 (2008) 1775-80. [42] O. Crisan, K. von Haeften, A.M. Ellis, C. Binns, Novel gas-stabilized iron clusters: synthesis, structure and magnetic behaviour, Nanotechnology. 19 (2008) 505602. [43] S.A. Rishton, Y. Lu, R.A. Altman, A.C. Marley, X.P. Bian, C. Jahnes, et al. ,Magnetic tunnel junctions fabricated at tenth-micron dimensions by electron beam lithography, Microelectronic Engineering. 35 (1997) 249-52. [44] E. Ahmadzadeh, F.T. Rowshan, M. Hosseini, A biological method for in-situ synthesis of hydroxyapatite-coated magnetite nanoparticles using Enterobacter aerogenes: Characterization and acute toxicity assessments, Materials Science and Engineering C. 73 (2017) 220–224. [45] K.B. Narayanan, N. Sakthivel, Biological synthesis of metal nanoparticles by microbes, Adv Colloid Interface Sci, (2010)156:1-13. [46] M. Bloemen, W. Brullot, T.T. Luong, N. Geukens, A. Gils, T. Verbiest, Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications, J Nanopart Res. 14 (2012) 1100. [47] M. Racuciu, D.E. Creanga, A. Airinei, Citric-acid-coated magnetite nanoparticles for biological applications, EurPhysJESoftMatter. 21 (2006) 117-21. [48] Z. Huang, F. Tang, Preparation, structure, and magnetic properties of polystyrene coated by Fe3O4 nanoparticles, JColloid Interface Sci. 275 (2004) 142-7. [49] M. Barrow, A. Taylor, P. Murray, M.J. Rosseinsky, D.J. Adams, Design considerations for the synthesis of polymer coated iron oxide nanoparticles for stem cell labelling and tracking using MRI, Chem Soc Rev. 44 (2015) 6733-48.

20

695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722

[50] G.G. Utkan, F. Sayar, P. Batat, S. Ide, M. Kriechbaum, E. Piskin, Synthesis and characterization of nanomagnetite particles and their polymer coated forms, JColloid Interface Sci. 353 (2011) 372-9.

723 724 725 726

[57] Y. Li, R. Lin, L. Wang, J. Huang, H. Wu, G. Cheng, Z. Zhou, T. MacDonald, L. Yang, H. Mao, PEG-β-AGE Polymer Coated Magnetic Nanoparticle Probes with Facile Functionalization and Anti-fouling Properties for Reducing Non-specific Uptake and Improving Biomarker Targeting, J Mater Chem B Mater Biol Med. 3 (2015) 3591-603.

727 728

[58] I. Liakos, A.M. Grumezescu, A.M. Holban, Magnetite nanostructures as novel strategies for anti-infectious therapy, Molecules. 19 (2014) 12710-26.

729 730 731

[59] S.M. Häffner, M. Malmsten, Membrane interactions and antimicrobial effects of inorganic nanoparticles, Advances in Colloid and Interface Science. 248(2017) 105– 128.

732 733 734

[60] A. Majid, W. Ahmed, Y. Patil-Sen, T. Sen, Synthesis and characterisation of magnetic nanoparticles in medicine. In: Jackson M., Ahmed W. (Eds) Micro and Nanomanufacturing Volume II. Springer, Cham. 2018.

[51] C. Fang, Z. Xiong, H.Qin, G. Huang, J. Liu, M. Ye, S. Feng, H. Zou, One-pot synthesis of magnetic colloidal nanocrystal clusters coated with chitosan for selective enrichment of glycopeptides, Anal Chim Acta. 841 (2014) 99-105. [52] J. Xie, J. Wang, G. Niu, J. Huang, K. Chen, X. Li, X. Chen, Human serum albumin coated iron oxide nanoparticles for efficient cell labeling, ChemCommun(Camb). 46(2010) 433-5. [53] M. Barrow, A. Taylor, J. Garcia Carrion, P. Mandal, B.K. Park, H. Poptani, P. Murray, M.J. Rosseinsky, D.J. Adams, Co-precipitation of DEAE-dextran coated SPIONs: how synthesis conditions affect particle properties, stem cell labelling and MR contrast, Contrast Media Mol Imaging. 11 (2016) 362-70. [54] M. Khalkhali, S. Sadighian, K. Rostamizadeh, F. Khoeini, M. Naghibi, N. Bayat, M. Habibizadeh, M. Hamidi, Synthesis and characterization of dextran coated magnetite nanoparticles for diagnostics and therapy, Bioimpacts. 5 (2015) 141-50. [55] E. Amstad, T. Gillich, I. Bilecka, M. Textor, E. Reimhult, Ultrastable iron oxide nanoparticle colloidal suspensions using dispersants with catechol-derived anchor groups, Nano Lett. 9 (2009) 4042–4048. [56] Z. Xu, Y. Hou, Y Sun, Magnetic core/shell Fe3O4/Au and Fe3O4/Au/Ag nanoparticles with tunable plasmonic properties, J. Am. Chem. Soc. 129 (2007) 86988699.

21

735 736

[61] M. Saeed, W. Ren, A. Wu, Therapeutic applications of iron oxide based nanoparticles in cancer: basic concepts and recent advances, Biomater Sci. (2018) 1-37.

737 738 739

[62] A. Akbarzadeh, M. Samiei, S. Davaran, Magnetic nanoparticles: preparation, physical properties, and applications in biomedicine, Nanoscale Research Letters. (2012) 7-144.

740 741 742

[63] R. Prucek, J. Tucek, M. Kilianova, A. Panacek, L. Kvitek, J. Filip, M. K l ř, K. T m k , R. Zb ř l, The targeted antibacterial and antifungal properties of magnetic nanocomposite of iron oxide and silver nanoparticles, Biomaterials. 32 (2011) 4704-13.

743 744 745

[64] N. Duran, M. Duran, M.B. de Jesus, A.B. Seabra, W.J. Favaro, G. Nakazato, Silver nanoparticles: A new view on mechanistic aspects on antimicrobial activity, Nanomedicine. 2016;12: 789-99.

746 747 748

[65] S.S. Behera, J.K. Patra, K. Pramanik, N. Panda, H. Thatoi, Characterization and Evaluation of Antibacterial Activities of Chemically Synthesized Iron Oxide Nanoparticles, World Journal of Nano Science and Engineering. 2 (2012) 196-200.

749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775

[66] J.S. Kim, E. Kuk, K.N. Yu, Antimicrobial effects of silver nanoparticles. Nanomedicine: Nanotechnology, Biology and Medicine. 1 (2007) 95-101. [67] L. Zhang, Y. Jiang, Y. Ding M. Povey, D. York, Investigation into the antibacterial behaviour of suspensions of ZnO nanoparticles (ZnO Nanofluids), Journal of Nanoparticle Research. 3 (2007) 479- 489. [68] S. Makhluf, R. Dror, Y. Nitzan, Y. Abramovich, R. Jelinek, A. Gedanken, Microwave-assisted synthesis of nanocrystalline mgo and its use as a bacteriocide, Advanced Functional Materials. 10 (2005) 1708-1715. [69] C. Lee, J.Y. Kim, W.I. Lee, K.L. Nelson, J. Yoon, D.L. Sedlak, Bactericidal effect of zero-valent iron nanoparticles on Escherichia coli, Environmental Science & Technology. 13 (2008) 4927-4933. [70] Q. Yao, Y. Gao, T. Gao, Y. Zhang, C. Harnoode, A. Dong, Y. Liu, L. Xiao, Surface arming magnetic nanoparticles with amine N-halamines as recyclable antibacterial agents: Construction and evaluation, Colloids Surf B Biointerfaces. 144 (2016) 319-26. [71] M. Thukkaram, S. Sitaram, S.K. Kannaiyan, G. Subbiahdoss, Antibacterial Efficacy of Iron-Oxide Nanoparticles against Biofilms on Different Biomaterial Surfaces. Int J Biomater. (2014) 7160-80. [72] P.K. Taylor, A.T. Yeung, R.E. Hancock, Antibiotic resistance in Pseudomonas aeruginosa biofilms: towards the development of novel anti-biofilm therapies, J Biotechnol. 191 (2014) 121-30.

22

776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819

[73] A.M. Grumezescu, R. Cristescu, MC Chifiriuc, Dorcioman G, Socol G, Mihailescu IN, et al. Fabrication of magnetite-based core-shell coated nanoparticles with antibacterial properties. Biofabrication. 2015;7:015014. [74] T. Javanbakht, S. Laurent, D. Stanicki, K.J. Wilkinson, Relating the Surface Properties of Superparamagnetic Iron Oxide Nanoparticles (SPIONs) to Their Bactericidal Effect towards a Biofilm of Streptococcus mutans, PLoS One. 11 (2016) e0154445. [75] M. Agarwala, B. Choudhury, R.N. Yadav, Comparative study of antibiofilm activity of copper oxide and iron oxide nanoparticles against multidrug resistant biofilm forming uropathogens, Indian J Microbiol. 2014;54:365-8. [76] C. Haney, J. Rowe, J. Robinson, Spions Increase Biofilm Formation by Pseudomonas aeruginosa, Journal of Biomaterials and Nanobiotechnology. 3 (2012) 508-18. [77] J. Borcherding, J. Baltrusaitis, H. Chen, L. Stebounova, C.M. Wu, G. Rubasinghege, I. A. Mudunkotuwa, J.C. Caraballo, J. Zabner, V. H. Grassian, A.P. Comellas, Iron oxide nanoparticles induce growth, induce biofilm formation, and inhibit antimicrobial peptide function, Environ Sci Nano. 1 (2014) 123-32. [78] A. Amirnasr, G. Emtiazi, S. Abasi, M. Yaaghoobi, Adsorption of hemoglobin, fatty acid and glucose to iron nanoparticles as a mean for drug delivery, J Biochem Tech. 3 (2011) 280-3. [79] Z. Vardanyan, A. Trchounian, Fe(III) and Fe(II) ions different effects on Enterococcus hirae cell growth and membrane-associated ATPase activity, Biochem Biophys Res Commun. 417(2012) 541-5. [80] L. Gao, Y. Liu, D. Kim,Y. Li, G. Hwang, P.C. Naha, D.P. Cormode, H. Koo, Nanocatalysts promote Streptococcus mutans biofilm matrix degradation and enhance bacterial killing to suppress dental caries in vivo. Biomaterials. 101(2016) 272-84. [81] Y. Liu, P.C. Naha, G. Hwang, D. Kim, Y. Huang, A. Simon-Soro, H.I. Jung, Z. Ren, Y. Li, S. Gubara, F. Alawi, D. Zero, A.T. Hara, D.P. Cormode, H. Koo. Topical ferumoxytol nanoparticles disrupt biofilms and prevent tooth decay in vivo via intrinsic catalytic activity. Nat Commun. 2018 31;9(1):2920. [82] I.A. Wani, T. Ahmad, N. Manzoor, Size and shape dependant antifungal activity of gold nanoparticles: a case study of Candida. Colloids Surf. B: Biointerfaces.101 (2013) 162–170. 23

820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863

[83] P. Szweda, K. Gucwa, E. Kurzyk, E. Romanowska, K. Dzierzanowska-Fangrat, A. Zielinska Jurek, P.M. Kus, S. Milewski, Essential oils, silver nanoparticles and propolis as alternative agents against fluconazole resistant Candida albicans, Candida glabrata and Candida krusei clinical isolates, Indian J. Microbiol. 55 (2015) 175–183. [84] K. Gold, B.Slay, M. Knackstedt, A. K. Gaharwar, Antimicrobial Activity of Metal and Metal-Oxide Based Adv. Therap. 2018 [85] S.J. Park, Hye H. Park, S.Y. Kim, S.J. Kim, K. Woo, G.P. Ko, Antiviral Properties of Silver Nanoparticles on a Magnetic Hybrid Colloid. Appl. Environ. Microbiol. 80 (2014), (8) 2343-2350. [86] N. Durán, M. Durán, M.B. de Jesus, A.B. Seabra, W.J. Fávaro, G. Nakazato, Silver nanoparticles: A new view on mechanistic aspects on antimicrobial activity. Nanomedicine: Nanotechnology, Biology, and Medicine. 12 (2016) 789–799. [87] D. Paredes, C. Ortiz, R. Torres, Synthesis, characterization, and evaluation of antibacterial effect of Ag nanoparticles against Escherichia coli O157:H7 and methicillinresistant Staphylococcus aureus (MRSA).Int. J. Nanomedicine. 9 (2014) 1717–1729. [88] N.K. Palanisamy, N. Ferina, A.N. Amirulhusni, Z. Mohd-Zain, J. Hussaini, L.J. Ping, R. Durairaj, Antibiofilm properties of chemically synthesized silver nanoparticles found against Pseudomonas aeruginosa. J. Nanobiotechnology.12 (2014) 12-22. [89] M. Ahamed, H.A. Alhadlaq, M.M. Khan, P. Karuppiah, N.A. Aldhabi, Synthesis, characterization and antimicrobial activity of copper oxide nanoparticles. J. Nanomater. (2014) 1–4. [90] T. Kruk, K. Szczepanowicz, J. Stefanska, R.P. Socha, P. Warszynski, Synthesis and antimicrobial activity of monodisperse copper nanoparticles. Colloids Surf. B: Biointerfaces. 128 (2015) 17–22. [91] J. Vidic, S. Stankic, F. Haque, D. Ciric, R. Le Goffic, A. Vidy, J. Jupille, B. Delmas, Selective antibacterial effects of mixed ZnMgO nanoparticles, J. Nanoparticle Res. 15 (2013) 1–10. [92] A. Sellik, T. Pollet, L. Ouvry, S. Briançon, H. Fessi, D. J. Hartmann, F.N.R. Renaud, Degradation of paraoxon (VX chemical agent simulant) and bacteria by magnesium oxide depends on the crystalline structure of magnesium oxide. Chem.-Biol. Interact. 267 (2017) 67-73. [93] V. Dhapte, S. Kadam, V. Pokharkar, P.K. Khanna, V. Dhapte. Versatile SiO2 Nanopar-ticles Polymer Composites with Pragmatic Properties. ISRN Inorg. Chem. (2014)1–8. 24

864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906

[94] S.M. Dizaj, F.Lotfipour, M. Barzegar-Jalali, M. H. Zarrintan, K. Adibkia, Antimicrobial activity of the metals and metal oxide nanoparticles. Materials Science and Engineering C. 44 (2014) 278–284. 5 K. Z w d k , . K s elewsk , . P w sk , K. K d , . el k, S. R lsk , N. Wronska, K. Lisowska, Mechanisms of antibacterial activity and stability of silver nanoparticles grown on magnetron sputtered TiO2 coatings. Bull Mater Sci. 39 (2016) 57–68. . , E. Hamon, S. Ennahar, M. Estner, M.C. Lett, P. Horvatovich, J.-P. Gies, V. Keller, N. Keller, P. Andre, TiO2 photocatalysis damages lipids and proteins in Escherichia coli. Appl. Environ. Microbiol. 80 (2014) 2573–2581. [97] Q. Liu, M. Zhang, Z.x. Fang, X.h. Rong, Effects of ZnO nanoparticles and microwaveheating on the sterilization and product quality of vacuum packaged Caixi. J. Sci. Food Agric. 94 (2014) 2547–2554. [98] S. Chakraborti, A.K. Mandal, S. Sarwar, P. Singh, R. Chakraborty, P. Chakrabarti, Bactericidal effect of polyethyleneimine capped ZnO nanoparticles on multiple antibiotic resistant bacteria harboring genes of high-pathogenicity island. Colloids Surf. B: Biointerfaces. 121 (2014) 44–53. [99] K. Zheng, M. I. Setyawati, D. T. Leong, J. Xie, Antimicrobial Gold Nanoclusters. ACS Nano 11 (2017) 6904–6910. [100] A. Abdal Dayem, M.K. Hossain, S.B. Lee, K. Kim, S.K. Saha, G.M. Yang, H.Y. Choi, S.G. Cho, The Role of Reactive Oxygen Species (ROS) in the Biological Activities of Metallic Nanoparticles, Int J Mol Sci. (2017)18. [101] C. Lopez-Abarrategui, V. Figueroa-Espi, M.B. Lugo-Alvarez, C.D. Pereira, H. Garay, J.A. Barbosa, R. Falcão, L. Jiménez-Hernández,O. Estévez-Hernández, E. Reguera, O.L. Franco, S.C. Dias, A. J. Otero-Gonzalez, The intrinsic antimicrobial activity of citric acid-coated manganese ferrite nanoparticles is enhanced after conjugation with the antifungal peptide Cm-p5, Int J Nanomedicine. 11(2016) 3849-57. [102] S. Chatterjee, A. Bandyopadhyay, K. Sarkar, Effect of iron oxide and gold nanoparticles on bacterial growth leading towards biological application, J Nanobiotechnology.(2011) 9:34. [103] S. He, Y. Feng, N. Gu, Y. Zhang, X. Lin, The effect of gamma-Fe2O3 nanoparticles on Escherichia coli genome, EnvironPollut. 159 (2011) 3468-73.

25

907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949

[104] M. Arakha, S. Pal, D. Samantarrai, T.K. Panigrahi, B.C. Mallick, K. Pramanik, B. Mallick, S. Jhaa, Antimicrobial activity of iron oxide nanoparticle upon modulation of nanoparticle-bacteria interface, Sci Rep. 5 (2015) 14813. [105] H. Wu, J.J. Yin, W.G. Wamer, M. Zeng, Y.M. Lo, Reactive oxygen speciesrelated activities of nano-iron metal and nano-iron oxides, Journal of Food and Drug Analysis. 22 (2014) 86-94. [106] E. Hoseinzadeh, P. Makhdoumi, P. Taha, J. Stelling, H. Hossini, M. A. Kamal, G. Md. Ashraf, A review on nano-antimicrobials: metal nanoparticles, methods, and mechanisms, Curr Drug Metab. (2016). [107] L. Gao, J. Zhuang, L. Nie, J. Zhang, Y. Zhang, N. Gu, T. Wang, J. Feng, D. Yang, S. Perrett, X. Yan, Intrinsic peroxidase-like activity of ferromagnetic nanoparticles, NatNanotechnol. 2 (2007) 577-83. [108] J.A. Guivar, E.G. Fernandes, V. Zucolotto, A peroxidase biomimetic system based on Fe3O4 nanoparticles in non-enzymatic sensors, Talanta. 141 (2015) 307-14. [109] S. Liu, F. Lu, R. Xing, J.J. Zhu, Structural effects of Fe3O4 nanocrystals on peroxidase-like activity, Chemistry. 17 (2011) 620-5. [110] Y. Shi, P. Su, Y. Wang, Y.Yang, Fe3O4 peroxidase mimetics as a general strategy for the fluorescent detection of H2O2-involved systems, Talanta. 130 (2014) 259-64. [111] L. Su, W. Qin, H. Zhang, Z.U. Rahman, C. Ren, S. Ma, X. Chen, The peroxidase/catalase-like activities of MFe(2)O(4) (M=Mg, Ni, Cu) MNPs and their application in colorimetric biosensing of glucose, Biosens Bioelectron. 63 (2015) 38491. [112] M. Yang, Y. Guan, Y. Yang, T. Xia, W. Xiong, N. Wang, C. Guo, Peroxidaselike activity of amino-functionalized magnetic nanoparticles and their applications in immunoassay, J Colloid Interface Sci. (405) 2013 291-5. [113] P.P. Fu, Q. Xia, H-M. Hwang, P.C. Ray, H. Yu, Mechanisms of nanotoxicity: Generation of reactive oxygen species, Journal of Food and Drug Analysis. 22 (2014) 64-75. [114] E.J. Park, H.N.Umh, D.H. Choi, M.H. Cho, W. Choi, S.W. Kim, Y. Kim, J.H. Kim, Magnetite- and maghemite-induced different toxicity in murine alveolar macrophage cells. Archives of Toxicology, 88 (2014) 1607-18. [115] B. Wang, J.J. Yin, X. Zhou, I. Kurash, Z. Chai, Y. Zhao, F.Weiyue, Physicochemical Origin for Free Radical Generation of Iron Oxide Nanoparticles in

26

950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992

Biomicroenvironment: Catalytic Activities Mediated by Surface Chemical States, The Journal of Physical Chemistry C. 117 (2013) 383-92. [116] A. Konwar, S. Kalita, J. Kotoky, D. Chowdhury, Chitosan-Iron Oxide Coated Graphene Oxide Nanocomposite Hydrogel: A Robust and Soft Antimicrobial Biofilm, ACS Appl Mater Interfaces. 8 (2016) 20625-34. [117] I. Anghel, A.M.Grumezescu, A.M. Holban, A. Ficai, A.G. Anghel, M.C. Chifiriuc, Biohybrid Nanostructured Iron Oxide Nanoparticles and Satureja hortensis to Prevent Fungal Biofilm Development, Int J Mol Sci. 14 (2013) 18110-23. [118] C. Chifiriuc, V. Grumezescu, A.M. Grumezescu, C. Saviuc, V. Lazar, E. Andronescu, Hybrid magnetite nanoparticles/Rosmarinus officinalis essential oil nanobiosystem with antibiofilm activity, Nanoscale Res Lett. 7 (2012) 209. [119] A.M. Grumezescu, M.C. Chifiriuc, C.S. aviuc, V. Grumezescu, R. Hristu, D.E. Mihaiescu, G. A. Stanciu, E. Andronescu, Hybrid nanomaterial for stabilizing the antibiofilm activity of Eugenia carryophyllata essential oil, IEEE Trans Nanobioscience. 11 (2012)360-5. [120] B. Chudzik, A. Miaskowski, Z. Surowiec, G. Czernel, T. Duluk, A .Marczuk, M. g ś, Effectiveness of magnetic fluid hyperthermia against Candida albicans cells, Int J Hyperthermia. 32 (2016) 842-57. [121] R. Nordstrom, M. Malmsten, Delivery systems for antimicrobial peptides, Adv Colloid Interface Sci. (2017). [122] M.M. Masadeh, G.A. Karasneh, M.A. Al-Akhras, B.A. Albiss, K.M. Aljarah, S.I. Al-azzam, K.H. Alzoubi, Cerium oxide and iron oxide nanoparticles abolish the antibacterial activity of ciprofloxacin against gram positive and gram negative biofilm bacteria, Cytotechnology. 67 (2015) 427-35. [123] H. Maleki, A. Rai, S. Pinto, M. Evangelista, R.M. Cardoso, C. Paulo, T. Carvalheiro, A. Paiva, M. Imani, A. Simchi, L. Durães, A. Portugal, L. Ferreira, High Antimicrobial Activity and Low Human Cell Cytotoxicity of Core-Shell Magnetic Nanoparticles Functionalized with an Antimicrobial Peptide, ACS Appl Mater Interfaces. 8 (2016) 11366-78. [124] K. Niemirowicz, B. Durnas, G. Tokajuk, K. Gluszek, A.Z. Wilczewska, I. M s lewsk , . M h l k, . S d , M. W ek, B. K ew , S. źdź, S. s ek, R. Bucki, Magnetic nanoparticles as a drug delivery system that enhance fungicidal activity of polyene antibiotics, Nanomedicine. 12 (2016) 2395-404.

27

993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036

[125] W. Zhang, X. Shi, J. Huang, Y. Zhang, Z. Wu, Y. Xian, Bacitracin-conjugated superparamagnetic iron oxide nanoparticles: synthesis, characterization and antibacterial activity, Chemphyschem : a European journal of chemical physics and physical chemistry. 13 (2012) 3388-96. [126] K. Niemirowicz, E. Piktel, A.Z. Wilczewska, K.H. Markiewicz, B. Durnas, M W ek, . P s k , M. W blewsk , W. N kl sk , P. B. Savage, R. Bucki, Core-shell magnetic nanoparticles display synergistic antibacterial effects against Pseudomonas aeruginosa and Staphylococcus aureus when combined with cathelicidin LL-37 or selected ceragenins, Int J Nanomedicine. 11 (2016) 5443-55. [127] T.K. Nguyen, H.T. Duong, R. Selvanayagam, C. Boyer, N. Barraud, Iron oxide nanoparticle-mediated hyperthermia stimulates dispersal in bacterial biofilms and enhances antibiotic efficacy, Sci Rep. 5 (2015) 18385. [128] S.H. Hussein-Al-Ali, M.E. El Zowalaty, M.Z. Hussein, B.M. Geilich, T.J. Webster, Synthesis, characterization, and antimicrobial activity of an ampicillinconjugated magnetic nanoantibiotic for medical applications, Int J Nanomedicine. 9 (2014) 3801-14. [129] S.H. Hussein-Al-Ali, M.E. El Zowalaty, A.U. Kura, B. Geilich, S. Fakurazi, T.J. Webster, M.Z. Hussein, Antimicrobial and controlled release studies of a novel nystatin conjugated iron oxide nanocomposite, Biomed Res Int.(2014) 651831. [130] Y. Anzai, C.W. Piccoli, E.K. Outwater, W. Stanford, D.A. Bluemke, P. Nurenberg, S. Saini, K.R. Maravilla, D.E. Feldman, U.P. Schmiedl, J.A. Brunberg, I.R. Francis, S.E. Harms, P.M. Som, C.M. Tempany, Evaluation of neck and body metastases to nodes with ferumoxtran 10-enhanced MR imaging: phase III safety and efficacy study, Radiology. 228 (2003) 777-88. [131] H. Arami, A. Khandhar, D. Liggitt, K.M. Krishnan, In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide nanoparticles, Chem Soc Rev. 44 (2015) 8576-607. [132] B.S. Zolnik, N. Sadrieh, Regulatory perspective on the importance of ADME assessment of nanoscale material containing drugs, Adv Drug Deliv Rev. 61 (2009) 422-7. [133] J.P. Almeida, A.L. Chen, A. Foster, R. Drezek, In vivo biodistribution of nanoparticles, Nanomedicine (Lond). 6 (2011) 815-35. [134] L. Yang, H. Kuang, W. Zhang, Z.P. Aguilar, Y. Xiong, W. Lai, H. Xu, H. Wei, Size dependent biodistribution and toxicokinetics of iron oxide magnetic nanoparticles in mice, Nanoscale. 7 (2015) 625-36.

28

1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078

[135] T.K. Jain, M.K. Reddy, M.A. Morales, D.L. Leslie-Pelecky, V. Labhasetwar, Biodistribution, clearance, and biocompatibility of iron oxide magnetic nanoparticles in rats. Mol Pharm. 5 (2008) 316-27. [136] K. Tsuchiya, N. Nitta, A. Sonoda, A. Nitta-Seko, S. Ohta, H. Otani, M. Takahashi, K. Murata, K. Murase, S. Nohara, K. Mukaisho, Histological study of the biodynamics of iron oxide nanoparticles with different diameters, Int J Nanomedicine. 6 (2011) 1587-94. [137] R. Weissleder, D.D. Stark, B.L. Engelstad, B.R. Bacon, C.C. Compton, D.L. White, P. Jacobs, J. Lewis, Superparamagnetic iron oxide: pharmacokinetics and toxicity, AJR Am J Roentgenol. 152 (1989) 167-73. [138] P. Bourrinet, H.H. Bengele, B. Bonnemain, A. Dencausse, J.M. Idee, P.M. Jacobs, J.M. Lewis, Preclinical safety and pharmacokinetic profile of ferumoxtran-10, an ultrasmall superparamagnetic iron oxide magnetic resonance contrast agent, Invest Radiol. 41 (2006) 313-24. [139] S. Majumdar, S.S. Zoghbi, J.C. Gore Pharmacokinetics of superparamagnetic iron-oxide MR contrast agents in the rat, Invest Radiol. 25 (1990) 771-7. [140] C. Chouly, D. Pouliquen, I. Lucet, J.J. Jeune, P. Jallet, Development of superparamagnetic nanoparticles for MRI: effect of particle size, charge and surface nature on biodistribution, JMicroencapsul. 13 (1996) 245-55. [141] O. Veiseh, C. Sun, C. Fang, N. Bhattarai, J. Gunn, F. Kievit, K. Du, B. Pullar, D. Lee, R.G. Ellenbogen, J. Olson, M. Zhang, Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood-brain barrier, Cancer Res. 69 (2009) 6200-7. [142] J.S. Kim, T.J. Yoon, K.N. Yu, B.G. Kim, S.J. Park, H.W. Kim, K.H. Lee, S.B. Park, J.K. Lee, M.H. Cho,Toxicity and tissue distribution of magnetic nanoparticles in mice, ToxicolSci. 89 (2006) 338-47. [143] D.E. Owens, N.A. Peppas, Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles, Int J Pharm. 307 (2006) 93-102. [144] C.C. Berry, S. Wells, S. Charles, A.S. Curtis, Dextran and albumin derivatised iron oxide nanoparticles: influence on fibroblasts in vitro, Biomaterials. 24 (2003) 45517.

29

1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100

[145] N.S. Remya, S. Syama, A. Sabareeswaran, P.V. Mohanan, Toxicity, toxicokinetics and biodistribution of dextran stabilized Iron oxide Nanoparticles for biomedical applications, Int J Pharm. 511 (2016) 586-98.

1101

Fig. 1. (A) Schematic representation of Fe3O4; (B) Magnetization properties of

1102 1103 1104

Ferromagnetic and Superparamagnetic NPs with and without the influence of external magnetic field. Modified from Ref. [36] [37]. Fig. 2. Description of different strategies to obtain IONPs.

1105 1106 1107 1108

Fig. 3. Representation of different nanoparticles: (A) Core-Shell structure; I) Spherical structure with single core, II) Core–satellite, III) Mesoporus, IV) Lipossome, (B) Matrix-dispersed structure -Inorganic matrix, I) aggregated cores, II) multiple cores; (C) Hollow structure, I) Mesoporous hollow.

1109 1110

Fig. 4. Mechanisms of antimicrobial activity of the IONPs and ROS. The Nanoparticle is represented by magnetite (Fe3O4) in blue, the surface coating in green and therapeutic

1111 1112 1113 1114

drug in orange. Table 1: Commercially available nanoparticle-based drug delivery systems in USA and EU. Table 2. Magnetic Nanoparticle (MNP) and their antimicrobial activity.

[146] C.C. Berry, S. Charles, S. Wells, M.J. Dalby, A.S. Curtis, The influence of transferrin stabilised magnetic nanoparticles on human dermal fibroblasts in culture, IntJPharm. 269 (2004) 211-25. [147] H.S. Kim, Y. Choi, I.C. Song, W.K. Moon, Magnetic resonance imaging and biological properties of pancreatic islets labeled with iron oxide nanoparticles NMR, Biomed. 22 (2009) 852-6. [148] H.C. Thoeny, M. Triantafyllou, F.D. Birkhaeuser, J.M. Froehlich, D.W. Tshering, T. Binser, A. Fleischmann, P. Vermathen, U.E. Studer, Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging reliably detect pelvic lymph node metastases in normal-sized nodes of bladder and prostate cancer patients, EurUrol. 55 (2009) 761-9. [149] D. Edge, C.M. Shortt, O.L. Gobbo, S. Teughels, A. Prina-Mello, Y. Volkov, P. MacEneaney, M.W. Radomski, F. Markos, Pharmacokinetics and bio-distribution of novel super paramagnetic iron oxide nanoparticles (SPIONs) in the anaesthetized pig, Clin Exp Pharmacol Physiol. 43 (2016) 319-26.

1115

30

1116 1117

31

1118 1119

32

1120 1121

33

1122 1123

34

Delivery system

Name

Active molecule

Indication

Administrati on

Year of approv al

Abraxane

Paclitaxel

Metastatic Breast Cancer, Advanced NonSmall Cell Lung Cancer and Metastatic Adenocarcinoma of the Pancreas

I.V.

2005

Liposomes

AmBisome

Amphoteri cin B

I.V.

1997

Liposomes

DaunoXom e

Fungal infections, Cryptococcal meningitis, visceral leishmaniasis, Daunorubic AIDS-related in Kaposi's sarcoma citrate

I.V.

1996

Liposomes DepoCyt

DepoCyt

Cytarabine

Lymphomatous meningitis

Lumbar puncture

1999

Liposomes PEGylated Liposomes

DepoDur Doxil/Cael yx/ LipoDox

Morphine Doxorubici n (generic)

Pain relief Ovarian cancer, AIDS-related Kaposi's sarcoma, Multiple myeloma

Epidural I.V.

2004 1995 2013 (USA)

Liposomes

Exparel

Bupivacain e

Post-surgical analgesia

Local/ Depofoam

2011 (USA)

Liposomes

Marqibo

Vincristine

Philadelphia chromosomenega tive acute lymphoblastic leukemia

I.V.

2012 (USA)

Proteinbased delivery systems Albuminbound paclitaxel nanoparticle s (Nab®technology)

Lipidbased delivery systems

35

1124 1125 1126

Liposomes

Mepact

Mifamurtid e

Osteosarcoma

I.V.

2009 (EU)

Liposomes

Myocet

Doxorubici n citrate

Metastatic Breast Cancer

I.V.

2000 (EU)

Liposomes

Visudyne

Verteporfin

Photodynamic therapy used in eye neovascularizatio n

I.V.

2002

Liposomes

MM-398

Iritonecan

I.V.

2015 (USA)

Lipid nanoparticle s Lipid nanoparticle s

Abelcet

Amphoteri cin B

Metastatic Adenocarcinoma of the Pancreas with 5fluorouracil and leucovorin Fungal infections

I.V.

1995

Amphotec

Amphoteri cin B

Fungal infections, Cryptococcal meningitis, visceral leishmaniasis,

I.V.

1996

Nanoemulsi on Nanoemulsi on

Diprivan

Propofol

I.V.

1989

Durezol

Diflupredn ate

Ocular

2008 (USA)

Nanoemulsi on

Restasis

Cyclospori ne

General anesthesia Eye inflammation, uveitis A Dry eye syndrome

Ocular

2003 (USA)

Nanoemulsi on Metalbased delivery systems SPION coated with a carbohydrat e

Ikervis

Cyclospori ne

A Dry eye syndrome

Ocular

2015 (EU)

Feraheme

Ferumoxyt ol

Iron deficiency anemia associated with chronic kidney diseases

I.V.

2009 (USA)

* When not specified, the drug is approved in both the USA and the EU. Approval in only one jurisdiction is indicated in parentheses following year of approval. I.V- intravenous. Ragelle et al.(11).

36

1127 1128 1129

Table 02. Magnetic Nanoparticle (MNP) and their antimicrobial activity.

37

1130

MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus; Nanoparticle

Size (nm)

Synthesis

Characterization

Microorganism

Ou

Au

1.625nm

Ultrasonic; Turkevich; Colloidal, Chemical

UV-Vis; TEM

Candida albicans; C. albicans, Candida glabrata; E. coli, Salmonella typhi, S. aureus, S. epidermidis, P. aeruginosa.

Gold nanoparti excellent antifu activity; Au N positive and ne

Ag

680

Polyvinylpyrrolidone (PVP); Sol-gel

X-ray diffraction; UV–Vis, TEM

Silver nanopa antimicrobial induces gaps membrane, ion metabolic pro damages.

Cu

5100

Biopreparation, Microwave; Green synthesis (Aloe vera);(Pterocarpus marsupium)

UV-Vis, FTIR, TEM XRD, SEM-EDS,

Fe3O4

2200

Co-precipitation, Chemical

UV-Vis spectroscopy, XRD SEM, BET

E. coli, Candida albicans, Klebsiella pneumoniae, S. aureus, B. subtilis, P. aeruginosa, Enterobacter cloacae, Aeromonas sp. SH10 and Corynebacterium sp. SH09, S. aureus (MRSA), Staphylococcus aureus (VRSA). E. aerogenes, S. aureus, Shigella dysenteriae, Vibrio cholerae non.0139(L4), S. pneumoniae,E. coli MRSA, MRSE, VRE, K pneumoniae, Pseudomonas spp Proteus mirabilis. S. aureus, Shigella flexneri, Bacillus licheniformis, Brevibacillus brevis, V. cholerae, P. aeruginosa, S. aureus, S. epidermis, B. subtilis and E. coli MRSA, MRSE, VRE, K pneumoniae, Pseudomonas spp. and P. mirabilia.

Strongly dimini forming urop and E. coli). Th bacterial cell interrupt enzym

Showed antibac disrupt the cell

Table 02. Size (nm) Nanoparticle Mg

11130

Ti

760

Zn

12200

Synthesis

Characterization

Microorganism

Ou

Co-precipitation

XRD, XPS, HR-SEM, FTIR, PL, DTA, TGA

E. coli, B. subtilis, S. aureus.

Antibacterial damages in formation of RO

Sol-gel

XRD, TEM, UV-Vis, PL, FTIR, PSA, SEM

E. coli, S. aureus, K. pneumoniae, MRSA.

Showed effici activity, The Ti integrity, and fo

ZnO using albumen as biotemplate, Sol-gel, Chemical, Wet chemical

XRD, TEM, AFM, DLS, PCCS, FTIR, SEM

E. coli, S. aureus, Proteus vulgaris, Salmonella typhimurium, Shigella flexneri, B. cereus, MSSA, Salmonella sp,.

Demonstrated antibacterial generation, deteriorated; a internalization

38

1131

VRE, vancomycin-resistant entero- cocci; MRSE, methicillin-resistant Staphylococcus epidermidis;

1132 1133 1134 1135 1136 1137

The characterization abbreviated in this column are as follows: AFM, atomic force spectroscopy; BET, Brunauer–Emmett–Teller anal- ysis; DLS, dynamic light scattering; DTA, differential thermal analysis; FTIR, Fourier transform infrared spectroscopy; HR, high-resolution; PCCS, photon cross correlation spectroscopy; PL, photoluminescence; PSA, particle size analyser; SEM, scanning electron microscopy; TEM, transmission electron microscopy; UV-Vis, ultraviolet–visible spectroscopy; XPS, X-ray photoelectron spectroscopy; XRD, X-ray diffraction.

1138 1139 1140 1141

39

1142

Declaration of interests

1143 1144 1145

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

1146 1147 1148 1149

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

1150 1151 1152 1153 1154

40

1155

Graphical abstract

1156 1157 1158

Highlights

1159 1160

1- Introduction

1161 1162 1163

2- Magnetic nanoparticles (MNPs) synthesis and functionalization

1164 1165

3- Antimicrobial activity of MNPs

1166 1167

4- Antimicrobial drug delivery by MNPs

1168 1169

5- MNPs biodistribution and toxicity

1170 1171

41