Abstract
In the past decades, much attention has been paid to toxicity assessment of nanoparticles prior to clinical and biological applications. While in vitro studies have been increasing constantly, in vivo studies of nanoparticles have not established a unified system until now. Predictive models and validated standard methods are imperative. This review summarizes the current progress in approaches assessing nanotoxicity in main systems, including the hepatic and renal, gastrointestinal, pulmonary, cardiovascular, nervous, and immune systems. Histopathological studies and specific functional examinations in each system are elucidated. Related injury mechanisms are also discussed.
1 Introduction
Nanoparticles (NPs) are particles with the size of 1–100 nm. Current investigation progresses have rendered NP applications in biomedical, bioengineering, and optical fields. Much attention has been drawn to NPs’ toxicology, which poses possible threat both medically and environmentally. From a biomedical perspective, NP toxicology reveals an interaction between the physicochemical characteristics of NPs and their biological effects. Assessments of NP toxicity need a set of design rules. During the past decades, in vitro toxic characterizations of NPs have been well summarized and compared. Marquis et al. [1] reviewed the analytical methods in respect to proliferation, necrosis, apoptosis, DNA damage, and oxidative stress, which are related to the main mechanisms of cytotoxicity. While in vitro studies have been performed extensively [2], the significance of nanotoxicity in vivo studies is being emphasized [3]. Relatively long-term, complicated, and animal-sacrificed in vivo studies come after in vitro assessments and are the inevitable progress before wide-range application. Although many reviews have summarized the methods in both in vitro and in vivo studies in certain nanostructures in different model systems (Table 1), systemic evaluation remains indefinite. Fischer [3] emphasized the importance of developing predictive models of NP toxicity assessment, whereas many researchers have focused on histological changes [25] and pharmacokinetic parameters like exposing [26], biodistribution [27], [28], biochemistry metabolism, and clearance. However, exploration of nanotoxicity remains superficial in sacrificed animals. Based on the in vivo results of NP pharmacokinetics, including homeostasis regulation, systemically evaluating the impact of NPs on the major systems, including the hepatic, renal, digestive, pulmonary, hematological, cardiovascular, nervous, immune systems, may provide profound insight into this field. This review summarizes the recent progress of toxic assessments of NPs from the perspective of single systems.
Assessments of some NPs in medical use.
| Categories | Application | Assessments | References | |
|---|---|---|---|---|
| In vitro | In vivo | |||
| Fe3O4 | Contrast agent (MRI) labeling and tracking | Cytotoxicity | Distribution | [4], [5] |
| Ag | Antimicrobial agent | Genotoxicity, cytotoxicity, cellular uptake | Pulmonary toxicity, hepatotoxicity, immunotoxicity | [6], [7], [8] |
| Au | Biolabel, biosensor, drug carriers | Cytotoxicity | Hepatotoxicity, spleen/lung toxicity | [9], [10], [11] |
| TiO2 | Biomedical ceramic implanted biomaterial sterilization | Cytotoxicity (lung, nervous, hematopoietic, etc.), genotoxicity, microvascular and mitochondrial dysfunction | Skin toxicity | [12], [13] |
| PEG | Drug carriers | Cytotoxicity | Immunotoxicity | [14], [15] |
| CNT | Building blocks | Toxicokinetics | Hepatotoxicity, pulmonary toxicity | [16], [17], [18], [19] |
| PLGA | Drug carriers | Macrophage uptake, phototoxicity | Nephrotoxicity | [20], [21], [22] |
| SLN | Drug carriers | LD50, cytotoxicity, tissue injury | Lung toxicity | [23], [24] |
Fe3O4, Iron oxide; TiO2, Titanium dioxide; PEG, Poly(ethylene glycol); CNT, Carbon nanotube; PLGA, Poly(d, llactideco-glycolide); SLN, solid lipid nanoparticles; LD50, Median lethal dose.
2 Systemic assessment
On a physiological basis, nanotoxicity can be tested from pathological changes, including morphologic changes (gross, microscopic, and ultrastructural changes) and functional damage. The mechanisms underlying NPs’ physiological interactions range from cells to organs and were discussed in the latest review [29]. Additionally, in terms of in vivo studies, the selection of animal models is the initial step. Although many animal models have been built, a standard and predictive model is still underdetermined. Besides the most common experimental mice and rats, zebrafish [30], [31], rabbits [32], and Caenorhabditis elegans [33] were also used in nanotoxicology studies. As the explicitly known genome and developed application in toxicity investigation, mice and rats would be more appropriate models in nanotoxicology studies, which is addressed below (Figure 1).
In vitro toxic characterization has been tested in respect to proliferation, necrosis, apoptosis, DNA damage, and oxidative stress. Mice and rats would be more appropriate models due to their explicit genome for toxicity tests of organs including hepatic and renal, gastrointestinal, pulmonary, hematological, cardiovascular, nervous, reproductive, and immune systems in terms of histopathological changes and functions.
In vivo assessments are divided into two main categories. One involves tissue structure changes [34], [35], apoptosis [36], [37], and inflammation infiltration in main organs (kidney, spleen, lung, brain, and heart). Another one targets certain systems, whose structural specificities are liable to concentrate NPs. For instance, hepatic sinusoid and kupffer cells are the fundamental structures for liver function in metabolism and detoxication, in which NPs are liable to be deposited, as well as in renal filtration membrane. Consequently, combined with the exposing ways (ingestion, injection, transdermal delivery, and inhalation) and applications, appropriate assessment models could be established, especially for the drug delivery of NPs [38].
2.1 Biodistribution
Any single physicochemical property of NPs can influence the distribution, which at a certain extent determines the material toxicity. Size [27], [39], [40], surface charge, constituent [41], [42], and chemistries of the coating could affect NP aggregation and excretion. Elucidating the biodistribution of NPs in organs is useful to guide the adjustment and modification of NPs.
The most common way of exploring the distribution is to remove the main organs [27] or tissues (lung, liver, kidney, heart, spleen, pancreas, brain, fat, and muscle) after animal sacrifice, then track the NPs according to their respective characteristics using physical detection methods. For some metal NPs, their intrinsic properties could be probed by specific instruments. Indeed, gold composite nanodevices in mouse tumor tissues could be explored by instrumental neutron activation analysis [27]. Si and Cd [34] concentrations could be determined by inductively coupled plasma optical emission spectrometry. For other varieties of NPs, some radiolabeled and fluorescent-labeled skills have been extensively applied. [3H]-PLA [42] has served as a marker to show blood concentration and organ distributions of poly(ethylene glycol)-grafted nanocapsules quantitatively. Some fluorescent-labeled particles [43] in tissue homogenates were analyzed by plate reader. In some other materials [44], like quantum dots with heavy metal cores, it was more appropriate to apply multiplexing and multicolor imaging through single-particle Förster resonance energy transfer assays [45]. However, qualitative analysis with light microscope (LM) and electron microscope (EM) failed to show sufficient and significant evidence in current studies. Other imaging techniques, including typical imaging instruments like magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography, optical imaging, and ultrasound, were introduced in the latest reviews [46], [47]. Furthermore, multiscale, real-time, and quantitative technologies were reported lately [48]. As some imaging contrast agents have potential unintentional toxicity, these tracing methods may aggravate the toxicity of NPs. Moreover, the combination of contrast agents may alter the characteristics and consequently change the biodistribution of NPs.
2.2 Hepatic and renal system
Hepatic sinusoid with Kupffer cells and renal glomerular basement membrane, as main metabolism and clearance organs, are fragile to toxic stimuli. Hepatic and renal toxicities are basic biosafety evaluation for drugs, as well as NPs. Oxidative stress can be determined by the index of superoxide dismutase (SOD) and glutathione peroxidase (GPx) [49]. Ultrastructural alterations of the liver and kidney are recommended primarily for morphologic changes [42]. Cationic nanobubbles [50] were visualized in histologic tests by section staining with haptoglobin and H&E. Afterward, tissue apoptosis was observed with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining.
2.2.1 Hepatic assessment
Immunohistochemistry was used to detect liver fibrosis and inflammation [50]. Serum enzymology analysis was used for hepatic function evaluation, mainly including alanine aminotransferase, aspartate aminotransferase [51], c-glutamyl transferase, and alkaline phosphatase [52], which indirectly and quantitatively reflect functional changes. Multiple automated hematology analyzer and automated chemistry analyzer are advantageous for the comprehensive analysis if conditions are permitted [53], [54].
2.2.2 Renal assessment
Histopathological study is useful to indicate renal glomerulus degeneration. The different pathologic changes, like glomerulosclerosis and collagenous tubulointerstitial matrix, can be confirmed by immunohistochemistry by detecting fibrotic and mesenchymal markers transforming growth factor-β1, interferon-6, type I collagen, fibronectin, and vimentin [55]. Cell proliferation can be assessed by measuring proliferating cell nuclear antigen [37]. Some kidney special dyeing, including PAS, PASM, and Masson, can be observed under LM [56]. The pathological diagnosis can be also determined by EM. From a functional aspect, kidney indices [57] are commonly measured. Gandhi et al. [58] tested renal variables including total proteins, albumin, and glomerular filtration rate. Urine protein, hematuria, urine albumin, and creatinine ratio [59] were also examined to evaluate the injury degree of the glomerular filtration membrane.
2.3 Gastrointestinal system
Compared with injection, oral administration of drugs or others is considered favorable due to convenience and compliance for patients. Drug bioavailability through oral administration, however, is limited because of physiological barriers of the gastrointestinal tract (GIT). With the improvement of nanocapsule transportation, some new drug delivery systems are gradually being developed, e.g. polymeric NP [60], which prevents biologicals from inactivation and degradation by acid and enzymatic barriers of the GIT. There are a majority of researches that report the benefits of NPs, such as the reversal of nonsteroidal anti-inflammatory drug-induced gastrointestinal injury [61] and radioprotection [62] from cancer radiotherapy. Cerium oxide NPs [63] were also reported to protect gastrointestinal epithelium from reactive oxygen damage. Nevertheless, the hazardous impact from NPs cannot be ignored. Exposure to TiO2 NPs interfered in nutrient absorption of metal contents [64]. Histological assay should be the initial step in which GIT microvilli and epithelial atrophy [65], [66] are observed under EM, and the number of mast cells [64] in the stomach should be counted. Besides, functional tests of GIT were also necessary. Absorption function could be reflected indirectly by the evaluation of metal content and electrolyte. Acid-base unbalance like metabolic alkalosis occurred after the overstock of HCO3−, when certain mental NPs reacted drastically. A novel method quantitatively monitored the digestion of intramolecular-quenched protein under fluorescence spectroscopy in zebrafish [65] and showed digestive malfunction and developmental abnormalities.
2.4 Pulmonary system
Considering environmental issues, the initial researches of pulmonary toxicity were concentrated on inhalable particles [67], [68]. NP, as a new material with targeting and noninvasive characteristics in drug delivery system, is another category related to pulmonary impact. To detect pulmonary accumulation of NPs, MRI [69] was used to visualize antibody-conjugated superparamagnetic iron oxide (SPIO) NPs in a lipopolysaccharide-induced chronic obstructive pulmonary disease mice model. The most common method is intratracheal instillation for long-term [70], [71] and short-term [72] toxicity assessments, in which the bronchoalveolar lavage (BAL) fluid [73] is collected for biochemical analysis, including lactate dehydrogenase (LDH) assay. LDH index is useful to indicate pneumonocyte injury. As a crucial indicator of inflammatory reaction, the number of BAL-recovered neutrophils [74] is counted to indicate the extent of the inflammation. Although tissue studies are less commonly applied, pathology and apoptosis research was occasionally used in these systems. Additionally, lipid peroxidation (LPO) and glutathione production were used to reveal oxidative stress [75].
2.5 Cardiovascular system
For each of the NPs whose exposure is by way of intravenous injection, impact on the cardiovascular system is definite. The biocompatibility of hematology and serum drew lots of attention. Phlebitis is arranged at the first place of the common risk in clinical observation. Venous tolerance was explored in the auricular vein [76], where eye wetness, brachychronic breath, purple lump, blood clot, and edema were recorded. Typical symptoms of phlebitis [77] can be seen through pathological sections. Hemolysis and thrombosis are other common risks. While hemolysis was often tested in vitro [78], the vascular thrombosis model [79] of the carotid artery was applied by platelet aggregation and ATP release in rats. The routine study involving circulation was to count each variation of complete blood, including erythrocytes, total leukocytes, hemoglobin, and hematocrit [36].
As for cardiac injury, serum markers, like troponin-T, creatine kinase-MB, and myoglobin, should be analyzed [80]. Cardiac calcium concentration associated with contraction function and DNA damage also needs to be determined. Although energy-related function damage is concerned, ATP/ADP ratio and concentration of myoglobin in the cardiac cells were calculated less in vivo. Oxidative stress [81] biomarkers should be emphasized, including LPO, reactive oxygen species, and antioxidant enzymes like SOD, GPx, and catalase. Cardiac uptake of NPs was revealed through radioisotope [125I] of iron oxide NPs [82]. An energetics study involving nanocarriers, which needs specific instrumentations, was performed by Vlasova et al. [83] by monitoring the cardiovascular parameters of arterial pressure and heart rate telemetrically, along with an ex vivo study on isolated aorta rings.
2.6 Nervous system
In the nervous system, assessments were focused on the drug delivery of solid lipid NPs (SLNs) in the brain. Especially, brain visualization was improved and drug permeability across the blood-brain barrier was assessed with radiography techniques like PET and PET/CT system [84]. Magnetite-labeled NPs can act as a contrast agent in rat brain MRI [85]. Transportation was further assayed by noninvasive in vivo imaging and ex vivo optical imaging after injection via the carotid artery [86]. The uptake of drug into the brains was determined by the ratio of concentration in the brains (Cbr) to that in the plasma (Cpl) after intravenous injection. The impairment can be reflected by glutamate uptake dysfunction when NPs were translocated to the olfactory bulb [87]. Confocal fluorescence [86] studies were also applied to evaluate the uptake of brain endothelial cells. Meanwhile, acute toxicity was visualized by brain histology examination (LM & TEM) [88] and fluorescence imaging [85].
Nervous injury is mainly assayed by behavioral and electrophysiological studies. Behavioral studies were performed in a well-established animal model [89] with a series of clinical signs of toxicity, including tremors, convulsions, salivation, nausea, vomiting, diarrhea, lethargy, etc. Moreover, spatial learning ability and memory function associated with the hippocampus can be studied by examining the expression of related genes [90]. Electrophysiological investigation with electroencephalogram bands [91] is convenient and reliable. Peripheral electrical stimulus is one common method used in neurophysiology study, in which caudal sensory nerve action potentials [92] (caudal SNAPs) are recorded centrally from the tail. As the high oxidative metabolism in the brain, the function of brain mitochondria, which is easily isolated by differential centrifugation, is a good index to evaluate brain nerve injury [93], [94]. The respiratory chain [95] of the mitochondria provides opportunities for potential mechanism study.
2.7 Immune and reproductive system
The interactions between all new chemical and biological entities of NPs and the immune system need to be clarified prior to application in medicine and biology. Superficial modification of NPs determines their immunogenicity, which may cause immunotoxicity by interacting with the immune system [96]. Due to the complexity of the immune system, the toxicity assessment of NPs relies on overall changes of immune cytokines and molecules, immune organs, hematological system, etc. For instance, the generation and release of ILs and tumor necrosis factors are usually examined upon the use of NPs at high aspect ratio, some metal or certain cationic [97], [98]. Histological changes of major immune organs (e.g. spleen) are preferably observed by H&E dyeing [97], [99].
The toxicity assessment of the reproductive system is a relatively long-term study. Only a few researches [100], [101], [102], [103], [104] have focused on this kind of chronic study. However, it is a necessary step for the clinical approval of drug products. So far, various in vivo and in vitro models have been developed to study NP-associated toxicity in relative organs of this system (as reviewed in [105]). Different from other systems, the reproductive system is sexually divided into male female and male. Routinely for the male, the testicular tissue structure, the epididymal sperm parameters, the serous sexual hormones (e.g. testosterone), and the concentration of NPs in serum and testis need to be tested [106], [107], [108]. As for the female, sexual hormone (e.g. follicle stimulating hormone, luteinizing hormone, and estradiol) levels in serum need to be measured [105], [109]. Functions of major organs (ovary, uterus, and vaginal tract) also need to be evaluated [110]. The histopathological analysis is supposed to be done. Specifically, organs (testes, uteri, placenta, etc., of parental or offspring generation) with potential resorption of NPs are suggested to be inspected [111], [112], [113], [114]. And last but not the least, reproductive index and offspring development need to be explored as some NPs were reported to penetrate the placenta-blood barrier in rats [115], [116]. Mostly, the teratogenicity of NPs on the fetus is of great concern [115], [117]. Also, the survival, growth, development, and reproduction of the offspring need to be mainly assessed upon prenatal exposure [101], [113], [118].
3 Summary
The application of NPs is increasing along with the development of nanotechnology, including drug delivery system [119], contrast agent of imaging, and engineering. Apart from the undesirable environmental NPs such as nanosilver nano-TiO2 and carbon nanotubes [120], more attention needs to paid to medically applied nanoscale materials in systematical biosafety assessments. While in vitro studies indicate a promising direction, in vivo evaluation, as a closer step to the clinical application, more directly reflects the adaptation and injury of the organism. The present study elaborated the major systems and organ assessments from the aspects of general histopathology and specific function (Table 2). The ultrastructural changes and the relationships between tissues and NPs were clearly revealed through electric microscope. Original and specific pathologic changes were visualized by specific dyeing on paraffin sections. Functional injuries were detected by diverse biomarkers and high-tech equipments. However, in further studies and applications, more attention should be paid to the correlations between internal environment affecting in vivo studies and some single factors controlled in the in vitro studies, although some investigations have indicated that no correlations existed between them [121], [125].
Assessments of NP-related systems.
| Systems | Related NPs | Assessment | References | |
|---|---|---|---|---|
| Histopathology | Function | |||
| Hepatic | All | H&E dyeing, immunohistochemistry, TUNEL | Serum enzymology and hematology analysis | [50], [55] |
| Renal | All | Kidney special dyeing immunohistochemistry | Creatinine ratio | [56], [58], [60] |
| Gastrointestinal | Nanocapsules | GIT microvilli, epithelial atrophy (EM) | Blood metal content and electrolyte test | [67], [68] |
| Respiratory | SPIO | H&E dyeing, TUNEL | Intratracheal instillation | [70], [72], [73], [74], [75] |
| Cardiovascular | Iron oxide | – | Venous tolerance, hemolysis and thrombosis, complete blood count | [36], [79], [80], [83] |
| Neuron | SLN | Brain histology, fluorescence imaging | Location, behavioral studies, electrophysiological investigation, oxidative stress, mitochondria function | [86], [87], [90], [91], [93], [95], [100] |
| Immune | All | H&E dyeing | Rabbit pyrogen test, LNPA, PFCA | [97], [120], [121] |
| Reproduction | All | H&E dyeing, TUNEL | Hematology, serum biochemical investigation, histopathological analysis, offspring development | [101], [111], [122], [123], [124] |
SPIO, Superparamagnetic iron oxide; SLN, Solid lipid nanoparticles; LNPA, Lymph node proliferation assay; PFCA, Plaque-forming cell assay.
Correction note
Correction added after online publication December 15, 2016: Mistakenly this article was previously published online ahead of print containing wrong name for author Xidan Mei: The correct name is: Chaorong Mei.
About the authors
Zhen Qin received her MD from the West China School of Preclinical and Forensic Medicine, Sichuan University, where she is now a PhD candidate. Dr. Qin is studying mechanisms underlying the synergism between Influenza A virus and Streptococcus pneumoniae and recently became strongly interested in the application of nanomaterials in this field.
Wei Zeng is a lecturer in West China School of Preclinical and Forensic Medicine, Sichuan University.
Ting Yang received her bachelor’s degree from West China School of Preclinical and Forensic Medicine, Sichuan University.
Yubin Cao received his bachelor’s degree from West China School of Preclinical and Forensic Medicine, Sichuan University.
Chaorong Mei is a doctor from the Hospital of Chengdu Office of People’s Government of Tibetan autonomous Region.
Yu Kuang received her PhD from West China School of Preclinical and Forensic Medicine, Sichuan University, where she is working at now as a senior experimentalist of the pathogenic biology laboratory.
Acknowledgment
The authors gratefully acknowledge support from the Ability Improve Project (no. J1103604) of the China National Science Talents Cultivation Fund and Department of Microbiology and Experimental Technology Project (1083304121001) of Sichuan University for research support. The authors also thank the Departments of Histology, Embryology, and Neurobiology of Sichuan University for contribution of histological photos.
References
[1] Marquis BJ, Love SA, Braun KL, Haynes CL. Analytical methods to assess nanoparticle toxicity. Analyst. 2009, 134, 425–439.10.1039/b818082bSearch in Google Scholar PubMed
[2] Love SA, Maurer-Jones MA, Thompson JW, Lin Y-S, Haynes CL. Assessing nanoparticle toxicity. Annu. Rev. Anal. Chem. 2012, 5, 181–205.10.1146/annurev-anchem-062011-143134Search in Google Scholar PubMed
[3] Fischer HC, Chan WC. Nanotoxicity: the growing need for in vivo study. Curr. Opin. Biotechnol. 2007, 18, 565–571.10.1016/j.copbio.2007.11.008Search in Google Scholar PubMed
[4] Soenen SJ, De Cuyper M. Assessing cytotoxicity of (iron oxide – based) nanoparticles: an overview of different methods exemplified with cationic magnetoliposomes. Contrast Media Mol. imaging. 2009, 4, 207–219.10.1002/cmmi.282Search in Google Scholar PubMed
[5] Malvindi MA, De Matteis V, Galeone A, Brunetti V, Anyfantis GC, Athanassiou A, Cingolani R, Pompa PP. Toxicity assessment of silica coated iron oxide nanoparticles and biocompatibility improvement by surface engineering. PLoS One. 2014, 9, e85835.10.1371/journal.pone.0085835Search in Google Scholar PubMed PubMed Central
[6] Rai M, Yadav A, Gade A. Silver nanoparticles as a new generation of antimicrobials. Biotechnol. Adv. 2009, 27, 76–83.10.1016/j.biotechadv.2008.09.002Search in Google Scholar PubMed
[7] Wijnhoven SW, Peijnenburg WJ, Herberts CA, Hagens WI, Oomen AG, Heugens EH, Roszek B, Bisschops J, Gosens I, Van De Meent D. Nano-silver–a review of available data and knowledge gaps in human and environmental risk assessment. Nanotoxicology 2009, 3, 109–138.10.1080/17435390902725914Search in Google Scholar
[8] Johnston HJ, Hutchison G, Christensen FM, Peters S, Hankin S, Stone V. 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. 2010, 40, 328–346.10.3109/10408440903453074Search in Google Scholar PubMed
[9] Daraee H, Eatemadi A, Abbasi E, Fekri Aval S, Kouhi M, Akbarzadeh A. Application of gold nanoparticles in biomedical and drug delivery. Artif. Cells Nanomed. Biotechnol. 2016, 44, 410–422.10.3109/21691401.2014.955107Search in Google Scholar PubMed
[10] Ambwani S, Kandpal D, Arora S, Ambwani TK. Cytotoxic effects of gold nanoparticles exposure employing in vitro animal cell culture system as part of nanobiosafety. In 2ND INTERNATIONAL CONFERENCE ON EMERGING TECHNOLOGIES: MICRO TO NANO 2015 (ETMN-2015): Contributory papers presented in 2nd International Conference on Emerging Technologies: Micro to Nano 2015; AIP Publishing, 2016; pp 020091.10.1063/1.4945211Search in Google Scholar
[11] Lin Z, Monteiro-Riviere NA, Kannan R, Riviere JE. A computational framework for interspecies pharmacokinetics, exposure and toxicity assessment of gold nanoparticles. Nanomedicine 2016, 11, 107–119.10.2217/nnm.15.177Search in Google Scholar PubMed
[12] Iavicoli I, Leso V, Fontana L, Bergamaschi A. Toxicological effects of titanium dioxide nanoparticles: a review of in vitro mammalian studies. Eur. Rev. Med. Pharmacol. Sci. 2011, 15, 481–508.Search in Google Scholar
[13] Yan J, Lin B, Hu C, Zhang H, Lin Z, Xi Z. The combined toxicological effects of titanium dioxide nanoparticles and bisphenol A on zebrafish embryos. Nanoscale Res. Lett. 2014, 9, 1–9.10.1186/1556-276X-9-406Search in Google Scholar PubMed PubMed Central
[14] Rabanel J.-M, Hildgen P, Banquy X. Assessment of PEG on polymeric particles surface, a key step in drug carrier translation. J. Control. Release. 2014, 185, 71–87.10.1016/j.jconrel.2014.04.017Search in Google Scholar PubMed
[15] Liao L, Zhang M, Liu H, Zhang X, Xie Z, Zhang Z, Gong T, Sun X. Subchronic toxicity and immunotoxicity of MeO-PEG-poly (D, L-lactic-co-glycolic acid)-PEG-OMe triblock copolymer nanoparticles delivered intravenously into rats. Nanotechnology 2014, 25, 245705.10.1088/0957-4484/25/24/245705Search in Google Scholar PubMed
[16] Lam C.-w, James JT, McCluskey R, Arepalli S, Hunter RL. A review of carbon nanotube toxicity and assessment of potential occupational and environmental health risks. Crit. Rev. Toxicol. 2006, 36, 189–217.10.1080/10408440600570233Search in Google Scholar PubMed
[17] Du J, Wang S, You H, Zhao X. Understanding the toxicity of carbon nanotubes in the environment is crucial to the control of nanomaterials in producing and processing and the assessment of health risk for human: a review. Environ. Toxicol. Pharmacol. 2013, 36, 451–462.10.1016/j.etap.2013.05.007Search in Google Scholar PubMed
[18] Aschberger K, Johnston HJ, Stone V, Aitken RJ, Hankin SM, Peters SA, Tran CL, Christensen FM. Review of carbon nanotubes toxicity and exposure – appraisal of human health risk assessment based on open literature. Crit. Rev. Toxicol. 2010, 40, 759–790.10.3109/10408444.2010.506638Search in Google Scholar PubMed
[19] Johnston HJ, Hutchison GR, Christensen FM, Peters S, Hankin S, Aschberger K, Stone V. A critical review of the biological mechanisms underlying the in vivo and in vitro toxicity of carbon nanotubes: the contribution of physico-chemical characteristics. Nanotoxicology 2010, 4, 207–246.10.3109/17435390903569639Search in Google Scholar PubMed
[20] Zhang H, Xu J. Enhanced oral bioavailability of salmeterol by loaded PLGA microspheres: preparation, in vitro, and in vivo evaluation. Drug Deliv. 2016, 23, 248–253.10.3109/10717544.2014.909909Search in Google Scholar PubMed
[21] Mody N, Tekade RK, Mehra NK, Chopdey P, Jain NK. Dendrimer, liposomes, carbon nanotubes and PLGA nanoparticles: one platform assessment of drug delivery potential. AAPS PharmSciTech. 2014, 15, 388–399.10.1208/s12249-014-0073-3Search in Google Scholar PubMed PubMed Central
[22] Asthana S, Jaiswal AK, Gupta PK, Dube A, Chourasia MK. Th-1 biased immunomodulation and synergistic antileishmanial activity of stable cationic lipid–polymer hybrid nanoparticle: biodistribution and toxicity assessment of encapsulated amphotericin B. Eur. J. Pharm. Biopharm. 2015, 89, 62–73.10.1016/j.ejpb.2014.11.019Search in Google Scholar
[23] Paranjpe M, Finke J, Richter C, Gothsch T, Kwade A, Büttgenbach S, Müller-Goymann C. Physicochemical characterization of sildenafil-loaded solid lipid nanoparticle dispersions (SLN) for pulmonary application. Int. J. Pharm. 2014, 476, 41–49.10.1016/j.ijpharm.2014.09.031Search in Google Scholar
[24] Paranjpe M, Neuhaus V, Braun A, Mueller Goymann CC. Toxicity testing of sildenafil base loaded liposomes in in vitro and ex vivo models for pulmonary application. Eur. J. Lipid Sci. Technol. 2014, 116, 1129–1136.10.1002/ejlt.201300406Search in Google Scholar
[25] Kim SY, Lee YM, Baik DJ, Kang JS. Toxic characteristics of methoxy poly (ethylene glycol)/poly (ε-caprolactone) nanospheres, in vitro and in vivo studies in the normal mice. Biomaterials. 2003, 24, 55–63.10.1016/S0142-9612(02)00248-XSearch in Google Scholar
[26] Leite-Silva VR, Le Lamer M, Sanchez WY, Liu DC, Sanchez WH, Morrow I, Martin D, Silva HD, Prow TW, Grice JE. The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo. Eur. J. Pharm. Biopharm. 2013, 84, 297–308.10.1016/j.ejpb.2013.01.020Search in Google Scholar PubMed
[27] Balogh L, Nigavekar SS, Nair BM, Lesniak W, Zhang C, Sung LY, Kariapper MS, El-Jawahri A, Llanes M, Bolton B. Significant effect of size on the in vivo biodistribution of gold composite nanodevices in mouse tumor models. Nanomed. Nanotechnol. Biol. Med. 2007, 3, 281–296.10.1016/j.nano.2007.09.001Search in Google Scholar PubMed
[28] Goel R, Shah N, Visaria R, Paciotti GF, Bischof JC. Biodistribution of TNF-α-coated gold nanoparticles in an in vivo model system. Nanomedicine 2009, 4, 401–410.10.2217/nnm.09.21Search in Google Scholar PubMed PubMed Central
[29] Lane LA, Qian X, Smith AM, Nie S. Physical chemistry of nanomedicine: understanding the complex behaviors of nanoparticles in vivo. Annu. Rev. Phys. Chem. 2015, 66, 521–547.10.1146/annurev-physchem-040513-103718Search in Google Scholar PubMed PubMed Central
[30] Vandhana S, Nithya M, Deepak A. Review on nano toxic effects in living organisms (mice and zebra fish). Int. J. Innov. Res. Sci. Technol. 2015, 1, 134–137.Search in Google Scholar
[31] Fang Q, Shi X, Zhang L, Wang Q, Wang X, Guo Y, Zhou B. Effect of titanium dioxide nanoparticles on the bioavailability metabolism and toxicity of pentachlorophenol in zebrafish larvae. J. Hazard. Mater. 2015, 283, 897–904.10.1016/j.jhazmat.2014.10.039Search in Google Scholar PubMed
[32] Leonardi A, Bucolo C, Drago F, Salomone S, Pignatello R. Cationic solid lipid nanoparticles enhance ocular hypotensive effect of melatonin in rabbit. Int. J. Pharm. 2015, 478, 180–186.10.1016/j.ijpharm.2014.11.032Search in Google Scholar PubMed
[33] Zanni E, De Bellis G, Bracciale MP, Broggi A, Santarelli ML, Sarto MS, Palleschi C, Uccelletti D. Graphite nanoplatelets and Caenorhabditis elegans: insights from an in vivo model. Nano Lett. 2012, 12, 2740–2744.10.1021/nl204388pSearch in Google Scholar PubMed
[34] Guo M, Xu X, Yan X, Wang S, Gao S, Zhu S. In vivo biodistribution and synergistic toxicity of silica nanoparticles and cadmium chloride in mice. J. Hazard. Mater. 2013, 260, 780–788.10.1016/j.jhazmat.2013.06.040Search in Google Scholar PubMed
[35] Sayes CM, Marchione AA, Reed KL, Warheit DB. Comparative pulmonary toxicity assessments of C60 water suspensions in rats: few differences in fullerene toxicity in vivo in contrast to in vitro profiles. Nano Lett. 2007, 7, 2399–2406.10.1021/nl0710710Search in Google Scholar PubMed
[36] Sarhan OMM, Hussein RM. Effects of intraperitoneally injected silver nanoparticles on histological structures and blood parameters in the albino rat. Int. J. Nanomed. 2014, 9, 1505.10.2147/IJN.S56729Search in Google Scholar PubMed PubMed Central
[37] Coccini T, Barni S, Manzo L, Roda E. Apoptosis induction and histological changes in rat kidney following Cd-doped silica nanoparticle exposure: evidence of persisting effects. Toxicol. Mech. Methods. 2013, 23, 566–575.10.3109/15376516.2013.803270Search in Google Scholar PubMed
[38] Gross E, Toste FD, Somorjai GA. Polymer-encapsulated metallic nanoparticles as a bridge between homogeneous and heterogeneous catalysis. Catal. Lett. 2015, 145, 126–138.10.1007/s10562-014-1436-9Search in Google Scholar
[39] De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJ, Geertsma RE. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 2008, 29, 1912–1919.10.1016/j.biomaterials.2007.12.037Search in Google Scholar PubMed
[40] Sonavane G, Tomoda K, Makino K. Biodistribution of colloidal gold nanoparticles after intravenous administration: effect of particle size. Colloids Surf. B. 2008, 66, 274–280.10.1016/j.colsurfb.2008.07.004Search in Google Scholar PubMed
[41] Hsieh C-M, Huang Y-W, Sheu M-T, Ho H-O. Biodistribution profiling of the chemical modified hyaluronic acid derivatives used for oral delivery system. Int. J. Biol. Macromol. 2014, 64, 45–52.10.1016/j.ijbiomac.2013.11.027Search in Google Scholar PubMed
[42] Mosqueira VCF, Legrand P, Morgat J-L, Vert M, Mysiakine E, Gref R, Devissaguet J-P, Barratt G. Biodistribution of long-circulating PEG-grafted nanocapsules in mice: effects of PEG chain length and density. Pharmaceut. Res. 2001, 18, 1411–1419.10.1023/A:1012248721523Search in Google Scholar
[43] Semete B, Booysen L, Lemmer Y, Kalombo L, Katata L, Verschoor J, Swai HS. In vivo evaluation of the biodistribution and safety of PLGA nanoparticles as drug delivery systems. Nanomedicine 2010, 6, 662–671.10.1016/j.nano.2010.02.002Search in Google Scholar PubMed
[44] Li X, Yeh Y-C, Giri K, Mout R, Landis RF, Prakash Y, Rotello VM. Control of nanoparticle penetration into biofilms through surface design. Chem. Comm. 2015, 51, 282–285.10.1039/C4CC07737GSearch in Google Scholar
[45] Massey M, Wu M, Conroy EM, Algar WR. Mind your P’s and Q’s: the coming of age of semiconducting polymer dots and semiconductor quantum dots in biological applications. Curr. Opin. Biotechnol. 2015, 34, 30–40.10.1016/j.copbio.2014.11.006Search in Google Scholar PubMed
[46] Janib SM, Moses AS, MacKay JA. Imaging and drug delivery using theranostic nanoparticles. Adv. Drug Deliver. Rev. 2010, 62, 1052–1063.10.1016/j.addr.2010.08.004Search in Google Scholar PubMed PubMed Central
[47] Park YI, Lee KT, Suh YD, Hyeon T. Upconverting nanoparticles: a versatile platform for wide-field two-photon microscopy and multi-modal in vivo imaging. Chem. Soc. Rev. 2015, 44, 1302–1317.10.1039/C4CS00173GSearch in Google Scholar
[48] Dobrucki LW, Pan D, Smith AM. Multiscale imaging of nanoparticle drug delivery. Curr. Drug Targets. 2015, 16, 560–570.10.2174/1389450116666150202163022Search in Google Scholar PubMed
[49] Orazizadeh M, Fakhredini F, Mansouri E, Khorsandi L. Effect of glycyrrhizic acid on titanium dioxide nanoparticles-induced hepatotoxicity in rats. Chem. Biol. Interact. 2014, 220, 214–221.10.1016/j.cbi.2014.07.001Search in Google Scholar PubMed
[50] Pan T-L, Wang P-W, Al-Suwayeh S A, Huang Y-J, Fang J-Y. Toxicological effects of cationic nanobubbles on the liver and kidneys: biomarkers for predicting the risk. Food Chem. Toxicol. 2012, 50, 3892–3901.10.1016/j.fct.2012.07.005Search in Google Scholar PubMed
[51] Yamagishi Y, Watari A, Hayata Y, Li X, Kondoh M, Tsutsumi Y, Yagi K. Hepatotoxicity of sub-nanosized platinum particles in mice. Pharmazie 2013, 68, 178–182.Search in Google Scholar
[52] Cho W-S, Cho M, Jeong J, Choi M, Cho H-Y, Han BS, Kim SH, Kim HO, Lim YT, Chung BH. Acute toxicity and pharmacokinetics of 13 nm-sized PEG-coated gold nanoparticles. Toxicol. Appl. Pharmacol. 2009, 236, 16–24.10.1016/j.taap.2008.12.023Search in Google Scholar PubMed
[53] Adamcakova-Dodd A, Stebounova LV, Kim JS, Vorrink SU, Ault AP, O’Shaughnessy PT, Grassian VH, Thorne PS. Toxicity assessment of zinc oxide nanoparticles using sub-acute and sub-chronic murine inhalation models. Part. Fibre Toxicol. 2014, 11, 1.10.1186/1743-8977-11-15Search in Google Scholar PubMed PubMed Central
[54] Carneiro MLB, Peixoto RC, Joanitti GA, Oliveira RG, Telles LA, Miranda-Vilela AL, Bocca AL, Vianna LM, da Silva IC, de Souza AR. Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer. J. Nanobiotechnology. 2013, 11, 1.10.1186/1477-3155-11-4Search in Google Scholar PubMed PubMed Central
[55] Coccini T, Barni S, Mustarelli P, Locatelli C, Roda E. One-month persistence of inflammation and alteration of fibrotic marker and cytoskeletal proteins in rat kidney after Cd-doped silica nanoparticle instillation. Toxicol. Lett. 2015, 232, 449–457.10.1016/j.toxlet.2014.11.021Search in Google Scholar PubMed
[56] Yanardağ R, Bolkent Ş, Özsoy‐Saçan Ö, Karabulut‐Bulan Ö. The effects of chard (Beta vulgaris L. var. cicla) extract on the kidney tissue serum urea and creatinine levels of diabetic rats. Phytother. Res. 2002, 16, 758–761.10.1002/ptr.1041Search in Google Scholar PubMed
[57] Gui S, Li B, Zhao X, Sheng L, Hong J, Yu X, Sang X, Sun Q, Ze Y, Wang L. Renal injury and Nrf2 modulation in mouse kidney following chronic exposure to TiO2 nanoparticles. J. Agric. Food Chem. 2013, 61, 8959–8968.10.1021/jf402387eSearch in Google Scholar PubMed
[58] Gandhi S, Srinivasan B, Akarte AS. An experimental assessment of toxic potential of nanoparticle preparation of heavy metals in streptozotocin induced diabetes. Exp. Toxicol. Pathol. 2013, 65, 1127–1135.10.1016/j.etp.2013.05.004Search in Google Scholar PubMed
[59] Petrica L, Vlad A, Gluhovschi G, Zamfir A, Popescu C, Gadalean F, Dumitrascu V, Vlad D, Popescu R, Velciov S. Glycated peptides are associated with proximal tubule dysfunction in type 2 diabetes mellitus. Int. J. Clin. Exp. Med. 2015, 8, 2516.Search in Google Scholar
[60] Pridgen EM, Alexis F, Farokhzad OC. Polymeric nanoparticle technologies for oral drug delivery. Clin. Gastroenterol. Hepatol. 2014, 12, 1605–1610.10.1016/j.cgh.2014.06.018Search in Google Scholar PubMed PubMed Central
[61] Fricker G, Kromp T, Wendel A, Blume A, Zirkel J, Rebmann H, Setzer C, Quinkert R-O, Martin F, Müller-Goymann C. Phospholipids and lipid-based formulations in oral drug delivery. Pharmaceut. Res. 2010, 27, 1469–1486.10.1007/s11095-010-0130-xSearch in Google Scholar PubMed
[62] Pamujula S, Kishore V, Rider B, Agrawal KC, Mandal TK. Radioprotection in mice following oral administration of WR-1065/PLGA nanoparticles. Int. J. Radiat. Biol. 2008, 84, 900–908.10.1080/09553000802460198Search in Google Scholar PubMed
[63] Colon J, Hsieh N, Ferguson A, Kupelian P, Seal S, Jenkins DW, Baker CH. Cerium oxide nanoparticles protect gastrointestinal epithelium from radiation-induced damage by reduction of reactive oxygen species and upregulation of superoxide dismutase 2. Nanomedicine 2010, 6, 698–705.10.1016/j.nano.2010.01.010Search in Google Scholar PubMed
[64] Wang Y, Chen Z, Ba T, Pu J, Chen T, Song Y, Gu Y, Qian Q, Xu Y, Xiang K. Susceptibility of young and adult rats to the oral toxicity of titanium dioxide nanoparticles. Small 2013, 9, 1742–1752.10.1002/smll.201201185Search in Google Scholar PubMed
[65] Lin S, Wang X, Ji Z, Chang CH, Dong Y, Meng H, Liao Y-P, Wang M, Song T-B, Kohan S. Aspect ratio plays a role in the hazard potential of CeO2 nanoparticles in mouse lung and zebrafish gastrointestinal tract. ACS Nano. 2014, 8, 4450–4464.10.1021/nn5012754Search in Google Scholar PubMed PubMed Central
[66] Han X-Y, Du W-L, Huang Q-C, Xu Z-R, Wang Y-Z. Changes in small intestinal morphology and digestive enzyme activity with oral administration of copper-loaded chitosan nanoparticles in rats. Biol. Trace. Elem. Res. 2012, 145, 355–360.10.1007/s12011-011-9191-xSearch in Google Scholar PubMed
[67] Wickramasinghe A, Karunaratne D, Sivakanesan R. PM 10-bound polycyclic aromatic hydrocarbons: biological indicators lung cancer risk of realistic receptors and ‘source-exposure-effect relationship’ under different source scenarios. Chemosphere 2012, 87, 1381–1387.10.1016/j.chemosphere.2012.02.044Search in Google Scholar PubMed
[68] Xia Z, Duan X, Tao S, Qiu W, Liu D, Wang Y, Wei S, Wang B, Jiang Q, Lu B. Pollution level inhalation exposure and lung cancer risk of ambient atmospheric polycyclic aromatic hydrocarbons (PAHs) in Taiyuan China. Environ. Pollut. 2013, 173, 150–156.10.1016/j.envpol.2012.10.009Search in Google Scholar PubMed
[69] Al Faraj A, Shaik AS, Afzal S, Al Sayed B, Halwani R. MR imaging and targeting of a specific alveolar macrophage subpopulation in LPS-induced COPD animal model using antibody-conjugated magnetic nanoparticles. Int. J. Nanomed. 2014, 9, 1491.10.2147/IJN.S59394Search in Google Scholar PubMed PubMed Central
[70] Bermudez E, Mangum JB, Wong BA, Asgharian B, Hext PM, Warheit DB, Everitt JI. Pulmonary responses of mice rats and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol. Sci. 2004, 77, 347–357.10.1093/toxsci/kfh019Search in Google Scholar PubMed
[71] Bermudez E, Mangum JB, Asgharian B, Wong BA, Reverdy EE, Janszen DB, Hext PM, Warheit DB, Everitt JI. Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles. Toxicol. Sci. 2002, 70, 86–97.10.1093/toxsci/70.1.86Search in Google Scholar PubMed
[72] Ma-Hock L, Burkhardt S, Strauss V, Gamer AO, Wiench K, van Ravenzwaay B, Landsiedel R. Development of a short-term inhalation test in the rat using nano-titanium dioxide as a model substance. Inhal. Toxicol. 2009, 21, 102–118.10.1080/08958370802361057Search in Google Scholar PubMed
[73] Paranjpe M, Müller-Goymann CC. Nanoparticle-mediated pulmonary drug delivery: a review. Int. J. Mol. Sci. 2014, 15, 5852–5873.10.3390/ijms15045852Search in Google Scholar PubMed PubMed Central
[74] Zhang DD, Hartsky MA, Warheit DB. Time course of quartz and TiO2 particle-induced pulmonary inflammation and neutrophil apoptotic responses in rats. Exp. Lung Res. 2002, 28, 641–670.10.1080/01902140260426742Search in Google Scholar PubMed
[75] Braakhuis HM, Gosens I, Krystek P, Boere JA, Cassee FR, Fokkens PH, Post JA, van Loveren H, Park MV. Particle size dependent deposition and pulmonary inflammation after short-term inhalation of silver nanoparticles. Part. Fibre Toxicol. 2014, 11, 1.10.1186/s12989-014-0049-1Search in Google Scholar
[76] Zhang W, Wang G, See E, Shaw JP, Baguley BC, Liu J, Amirapu S, Wu Z. Post-insertion of poloxamer 188 strengthened liposomal membrane and reduced drug irritancy and in vivo precipitation superior to PEGylation. J. Control. Release. 2015, 203, 161–169.10.1016/j.jconrel.2015.02.026Search in Google Scholar
[77] Laverman P, Dams ETM, Storm G, Hafmans TG, Croes HJ, Oyen WJ, Corstens FH, Boerman OC. Microscopic localization of PEG-liposomes in a rat model of focal infection. J. Control. Release. 2001, 75, 347–355.10.1016/S0168-3659(01)00402-3Search in Google Scholar
[78] Fornaguera C, Calderó G, Mitjans M, Vinardell MP, Solans C, Vauthier C. Interactions of PLGA nanoparticles with blood components: protein adsorption coagulation activation of the complement system and hemolysis studies. Nanoscale 2015, 7, 6045–6058.10.1039/C5NR00733JSearch in Google Scholar
[79] Radomski A, Jurasz P, Alonso‐Escolano D, Drews M, Morandi M, Malinski T, Radomski MW. Nanoparticle‐induced platelet aggregation and vascular thrombosis. Br. J. Pharmacol. 2005, 146, 882–893.10.1038/sj.bjp.0706386Search in Google Scholar PubMed PubMed Central
[80] Baky N, Faddah L, Al-Rasheed N, Fatani A. Induction of inflammation DNA damage and apoptosis in rat heart after oral exposure to zinc oxide nanoparticles and the cardioprotective role of α-lipoic acid and vitamin E. Drug Res. 2013, 63, 228–236.10.1055/s-0033-1334923Search in Google Scholar PubMed
[81] Shafiee H, Mohammadi H, Rezayat SM, Hosseini A, Baeeri M, Hassani S, Mohammadirad A, Bayrami Z, Abdollahi M. Prevention of malathion-induced depletion of cardiac cells mitochondrial energy and free radical damage by a magnetic magnesium-carrying nanoparticle. Toxicol. Mech. Method. 2010, 20, 538–543.10.3109/15376516.2010.518173Search in Google Scholar PubMed
[82] de Barros ALB, Chacko A-M, Mikitsh JL, Al Zaki A, Salavati A, Saboury B, Tsourkas A, Alavi A. Assessment of global cardiac uptake of radiolabeled iron oxide nanoparticles in apolipoprotein-E-deficient mice: implications for imaging cardiovascular inflammation. Mol. Imaging Biol. 2014, 16, 330–339.10.1007/s11307-013-0709-9Search in Google Scholar PubMed PubMed Central
[83] Vlasova MA, Tarasova OS, Riikonen J, Raula J, Lobach AS, Borzykh AA, Smirin BV, Kauppinen EI, Eletskii AV, Herzig K-H. Injected nanoparticles: the combination of experimental systems to assess cardiovascular adverse effects. Eur. J. Pharm. Biopharm. 2014, 87, 64–72.10.1016/j.ejpb.2014.02.001Search in Google Scholar PubMed
[84] Frigell J, García I, Gómez-Vallejo V, Llop J, Penadés S. 68Ga-labeled gold glyconanoparticles for exploring blood-brain barrier permeability: preparation biodistribution studies and improved brain uptake via neuropeptide conjugation. J. Am. Chem. Soc. 2013, 136, 449–457.10.1021/ja411096mSearch in Google Scholar PubMed
[85] Vera NPM, Schmidt R, Langer K, Zlatev I, Wronski R, Auer E, Havas D, Windisch M, von Briesen H, Wagner S. Tracking of magnetite labeled nanoparticles in the rat brain using MRI. PLoS One 2014, 9, e92068.10.1371/journal.pone.0092068Search in Google Scholar PubMed PubMed Central
[86] Liu D, Lin B, Shao W, Zhu Z, Ji T, Yang C. In vitro and in vivo studies on the transport of PEGylated silica nanoparticles across the blood-brain barrier. ACS Appl. Mater. Interfaces 2014, 6, 2131–2136.10.1021/am405219uSearch in Google Scholar PubMed
[87] Win-Shwe T-T, Fujimaki H. Nanoparticles and neurotoxicity. Int. J. Mol. Sci. 2011, 12, 6267–6280.10.3390/ijms12096267Search in Google Scholar PubMed PubMed Central
[88] Blasi P, Schoubben A, Traina G, Manfroni G, Barberini L, Alberti PF, Cirotto C, Ricci M. Lipid nanoparticles for brain targeting III. Long-term stability and in vivo toxicity. Int. J. Pharm. 2013, 454, 316–323.10.1016/j.ijpharm.2013.06.037Search in Google Scholar PubMed
[89] Pradhan S, Patra P, Mitra S, Dey KK, Jain S, Sarkar S, Roy S, Palit P, Goswami A. Manganese nanoparticles: impact on non-modulated plant as a potent enhancer in nitrogen metabolism and toxicity study both in vivo and in vitro. J. Agr. Food Chem. 2014, 62, 8777–8785.10.1021/jf502716cSearch in Google Scholar PubMed
[90] Win-Shwe T-T, Yamamoto S, Fujitani Y, Hirano S, Fujimaki H. Spatial learning and memory function-related gene expression in the hippocampus of mouse exposed to nanoparticle-rich diesel exhaust. Neurotoxicology 2008, 29, 940–947.10.1016/j.neuro.2008.09.007Search in Google Scholar PubMed
[91] Horváth E, Oszlánczi G, Máté Z, Szabó A, Kozma G, Sápi A, Kónya Z, Paulik E, Nagymajtényi L, Papp A. Nervous system effects of dissolved and nanoparticulate cadmium in rats in subacute exposure. J. Appl. Toxicol. 2011, 31, 471–476.10.1002/jat.1664Search in Google Scholar PubMed
[92] Negishi T, Koizumi F, Uchino H, Kuroda J, Kawaguchi T, Naito S, Matsumura Y. NK105 a paclitaxel-incorporating micellar nanoparticle is a more potent radiosensitising agent compared to free paclitaxel. Br. J. Cancer. 2006, 95, 601–606.10.1038/sj.bjc.6603311Search in Google Scholar PubMed PubMed Central
[93] Akopova O, Kolchinskaya L, Nosar V, Bouryi V, Mankovska I, Sagach V. Effect of potential-dependent potassium uptake on production of reactive oxygen species in rat brain mitochondria. Biochemistry (Mosc). 2014, 79, 44–53.10.1134/S0006297914010076Search in Google Scholar PubMed
[94] Long TC, Saleh N, Tilton RD, Lowry GV, Veronesi B. Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity. Environ. Sci. Technol. 2006, 40, 4346–4352.10.1021/es060589nSearch in Google Scholar PubMed
[95] Bhagavan HN, Chopra RK. Coenzyme: absorption tissue uptake metabolism and pharmacokinetics. Free Radic. Res. 2006, 40, 445–453.10.1080/10715760600617843Search in Google Scholar PubMed
[96] Dobrovolskaia MA, Shurin M, Shvedova AA. Current understanding of interactions between nanoparticles and the immune system. Toxicol. Appl. Pharm. 2016, 299, 78–89.10.1201/b22372-5Search in Google Scholar
[97] Wang X, Tian J, Yong K-T, Zhu X, Lin MC-M, Jiang W, Li J, Huang Q, Lin G. Immunotoxicity assessment of CdSe/ZnS quantum dots in macrophages lymphocytes and BALB/c mice. J. Nanobiotechnology. 2016, 14, 1.10.1186/s12951-016-0162-4Search in Google Scholar PubMed PubMed Central
[98] Baron L, Gombault A, Fanny M, Villeret B, Savigny F, Guillou N, Panek C, Le Bert M, Lagente V, Rassendren F. The NLRP3 inflammasome is activated by nanoparticles through ATP ADP and adenosine. Cell Death Dis. 2015, 6, e1629.10.1038/cddis.2014.576Search in Google Scholar PubMed PubMed Central
[99] Silva AH, Locatelli C, Filippin-Monteiro FB, Martin P, Liptrott NJ, Zanetti-Ramos BG, Benetti LC, Nazari EM, Albuquerque CA, Pasa AA. Toxicity and inflammatory response in Swiss albino mice after intraperitoneal and oral administration of polyurethane nanoparticles. Toxicol. Lett. 2016, 246, 17–27.10.1016/j.toxlet.2016.01.018Search in Google Scholar PubMed
[100] Wang Z, Chen Z, Zuo Q, Song F, Wu D, Cheng W, Fan W. Reproductive toxicity in adult male rats following intra-articular injection of cobalt–chromium nanoparticles. J. Orthop. Sci. 2013, 18, 1020–1026.10.1007/s00776-013-0458-2Search in Google Scholar PubMed
[101] Di Bona KR, Xu Y, Gray M, Fair D, Hayles H, Milad L, Montes A, Sherwood J, Bao Y, Rasco JF. Short-and long-term effects of prenatal exposure to iron oxide nanoparticles: influence of surface charge and dose on developmental and reproductive toxicity. Int. J. Mol. Sci. 2015, 16, 30251–30268.10.3390/ijms161226231Search in Google Scholar PubMed PubMed Central
[102] Hong J-S, Kim S, Lee SH, Jo E, Lee B, Yoon J, Eom I-C, Kim H-M, Kim P, Choi K. Combined repeated-dose toxicity study of silver nanoparticles with the reproduction/developmental toxicity screening test. Nanotoxicology 2014, 8, 349–362.10.3109/17435390.2013.780108Search in Google Scholar PubMed
[103] Kong L, Tang M, Zhang T, Wang D, Hu K, Lu W, Wei C, Liang G, Pu Y. Nickel nanoparticles exposure and reproductive toxicity in healthy adult rats. Int. J. Mol. Sci. 2014, 15, 21253–21269.10.3390/ijms151121253Search in Google Scholar PubMed PubMed Central
[104] Roychoudhury S, Nath S, Massanyi P, Stawarz R, Kacaniova M, Kolesarova A. Copper-induced changes in reproductive functions: in vivo and in vitro effects. Physiol. Res. 2016, 65, 11.10.33549/physiolres.933063Search in Google Scholar PubMed
[105] Saunders M, Hutchison G, Carreira SC. Reproductive toxicity of nanomaterials. Therapy 2015, 40, 44.Search in Google Scholar
[106] Li X, Yang X, Yuwen L, Yang W, Weng L, Teng Z, Wang L. Evaluation of toxic effects of CdTe quantum dots on the reproductive system in adult male mice. Biomaterials 2016, 96, 24–32.10.1016/j.biomaterials.2016.04.014Search in Google Scholar PubMed
[107] Layali E, Tahmasbpour E, Jorsaraei S. The effects of silver nanoparticles on oxidative stress and sperm parameters quality in male rats. J. Babol Univ. Med. Sci. 2016, 18, 48–55.Search in Google Scholar
[108] Ren L, Zhang J, Zou Y, Zhang L, Wei J, Shi Z, Li Y, Guo C, Sun Z, Zhou X. Silica nanoparticles induce reversible damage of spermatogenic cells via RIPK1 signal pathways in C57 mice. Int. J. Nanomed. 2016, 11, 2251.10.2147/IJN.S102268Search in Google Scholar PubMed PubMed Central
[109] Chattopadhyay A, Sarkar M, Sengupta R, Roychowdhury G, Biswas NM. Antitesticular effect of copper chloride in albino rats. J. Toxicol. Sci. 1999, 24, 393–397.10.2131/jts.24.5_393Search in Google Scholar PubMed
[110] Babaei H, Roshangar L, Sakhaee E, Abshenas J, Kheirandish R, Dehghani R. Ultrastructural and morphometrical changes of mice ovaries following experimentally induced copper poisoning. Iran. Red Crescent Med. J. 2012, 14, 558.Search in Google Scholar
[111] Mozaffari Z, Parivar K, Roodbari NH, Irani S. Histopathological evaluation of the toxic effects of zinc oxide (ZnO) nanoparticles on testicular tissue of NMRI adult mice. Adv. Stud. Biol. 2015, 7, 275–291.10.12988/asb.2015.5425Search in Google Scholar
[112] Bai Y, Zhang Y, Zhang J, Mu Q, Zhang W, Butch ER, Snyder SE, Yan B. Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility. Nat. Nanotechnol. 2010, 5, 683–689.10.1038/nnano.2010.153Search in Google Scholar PubMed PubMed Central
[113] Kubo-Irie M, Shinkai Y, Matsuzawa S, Uchida H, Suzuki K, Niki R, Oshio S, Takeda K. Prenatal exposure to rutile-type alumina-coated titanium dioxide nanoparticles impairs mouse spermatogenesis. Fund. Toxicol. Sci. 2016, 3, 67–74.10.2131/fts.3.67Search in Google Scholar
[114] Qi W, Bi J, Zhang X, Wang J, Wang J, Liu P, Li Z, Wu W. Damaging effects of multi-walled carbon nanotubes on pregnant mice with different pregnancy times. Sci. Rep. 2014, 4, 4352.10.1038/srep04352Search in Google Scholar PubMed PubMed Central
[115] Zhang W, Yang L, Kuang H, Yang P, Aguilar ZP, Wang A, Fu F, Xu H. Acute toxicity of quantum dots on late pregnancy mice: effects of nanoscale size and surface coating. J. Hazard. Mater. 2016, 318, 61–69.10.1016/j.jhazmat.2016.06.048Search in Google Scholar PubMed
[116] Shimizu M, Tainaka H, Oba T, Mizuo K, Umezawa M, Takeda K. Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse. Part. Fibre Toxicol. 2009, 6, 1.10.1186/1743-8977-6-20Search in Google Scholar PubMed PubMed Central
[117] Lim J-H, Kim S-H, Lee I-C, Moon C, Kim S-H, Shin D-H, Kim H-C, Kim J-C. Evaluation of maternal toxicity in rats exposed to multi-wall carbon nanotubes during pregnancy. Environ. Health Toxicol. 2011, 26, e2011006.10.5620/eht.2011.26.e2011006Search in Google Scholar PubMed PubMed Central
[118] Huang X, Zhang F, Sun X, Choi K-Y, Niu G, Zhang G, Guo J, Lee S, Chen X. The genotype-dependent influence of functionalized multiwalled carbon nanotubes on fetal development. Biomaterials 2014, 35, 856–865.10.1016/j.biomaterials.2013.10.027Search in Google Scholar PubMed PubMed Central
[119] Gelperina S, Kisich K, Iseman MD, Heifets L. The potential advantages of nanoparticle drug delivery systems in chemotherapy of tuberculosis. Am. J. Respir. Crit. Care Med. 2005, 172, 1487–1490.10.1164/rccm.200504-613PPSearch in Google Scholar PubMed PubMed Central
[120] Hendren CO, Lowry M, Grieger KD, Money ES, Johnston JM, Wiesner MR, Beaulieu SM. Modeling approaches for characterizing and evaluating environmental exposure to engineered nanomaterials in support of risk-based decision making. Environ. Sci. Technol. 2013, 47, 1190–1205.10.1021/es302749uSearch in Google Scholar PubMed
[121] Nyk M, Kumar R, Ohulchanskyy TY, Bergey EJ, Prasad PN. High contrast in vitro and in vivo photoluminescence bioimaging using near infrared to near infrared up-conversion in Tm3+ and Yb3+ doped fluoride nanophosphors. Nano Lett. 2008, 8, 3834–3838.10.1021/nl802223fSearch in Google Scholar PubMed PubMed Central
[122] Watson C, Ge J, Cohen J, Pyrgiotakis G, Engelward BP, Demokritou P. High throughput screening platform for engineered nanoparticle-mediated genotoxicity using CometChip technology. ACS Nano. 2014, 8, 2118–2133.10.1021/nn404871pSearch in Google Scholar PubMed PubMed Central
[123] Nel A, Xia T, Meng H, Wang X, Lin S, Ji Z, Zhang H. Nanomaterial toxicity testing in the 21st century: use of a predictive toxicological approach and high-throughput screening. Acc. Chem. Res. 2012, 46, 607–621.10.1021/ar300022hSearch in Google Scholar PubMed PubMed Central
[124] Lai DY. Toward toxicity testing of nanomaterials in the 21st century: a paradigm for moving forward. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2012, 4, 1–15.10.1002/wnan.162Search in Google Scholar PubMed
[125] Das J, Das S, Paul A, Samadder A, Bhattacharyya SS, Khuda-Bukhsh AR. Assessment of drug delivery and anticancer potentials of nanoparticles-loaded siRNA targeting STAT3 in lung cancer in vitro and in vivo. Toxicol. Lett. 2014, 225, 454–466.10.1016/j.toxlet.2014.01.009Search in Google Scholar PubMed
©2016, Chaorong Mei, Yu Kuang et al., published by De Gruyter, Berlin/Boston
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
