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1.  Plausible antioxidant biomechanics and anticonvulsant pharmacological activity of brain-targeted β-carotene nanoparticles 
β-Carotene has been established as a known free radical scavenger with chain-breaking antioxidant properties. It has been documented for the treatment of epileptic convulsions at a 200 mg/kg body weight dose. The reported pathogenesis for epileptic convulsions is oxidative stress. Hence, experimental epileptic convulsions via oxidative stress was induced in albino mice epileptic models (maximal electroshock seizure and pentylenetetrazole [PTZ]). A dose concentration equivalent to 2 mg/kg was efficaciously administered in the form of brain-targeted polysorbate-80-coated poly(d,l-lactide-co-glycolide) nanoparticles. The nanoparticles were prepared by solvent evaporation technique and further characterized for their physical parameters, in-vitro release kinetics, and in-vivo brain release via various standard methods. Normal β-carotene nanoparticles (BCNP) and polysorbate-80-coated β-carotene nanoparticles (P-80-BCNP) of 169.8 ± 4.8 nm and 176.3 ± 3.2 nm in size, respectively, were formulated and characterized. Their zeta potential and polydispersity index were subsequently evaluated after 5 months of storage to confirm stability. In vivo activity results showed that a 2 mg unformulated β-carotene dose was ineffective as an anticonvulsant. However, salutary response was reported from BCNP at the same dose, as the hind limb duration decreased significantly in maximal electroshock seizure to 9.30 ± 0.86 seconds, which further decreased with polysorbate-80 coating to 2.10 ± 1.16 seconds as compared to normal control (15.8 ± 1.49 seconds) and placebo control (16.50 ± 1.43 seconds). In the PTZ model, the duration of general tonic–clonic seizures reduced significantly to 2.90 ± 0.98 seconds by the use of BCNP and was further reduced on P-80-BCNP to 1.20 ± 0.20 seconds as compared to PTZ control and PTZ-placebo control (8.09 ± 0.26 seconds). General tonic–clonic seizures latency was increased significantly to 191.0 ± 9.80 seconds in BCNP and was further increased in P-80-BCNP to 231.0 ± 16.30 seconds, as compared to PTZ (120.10 ± 4.50 seconds) and placebo control (120.30 ± 7.4 seconds). The results of this study demonstrate a plausible novel anticonvulsant activity of β-carotene at a low dose of 2 mg/kg, with brain-targeted nanodelivery, thus increasing its bioavailability and stability.
doi:10.2147/IJN.S34588
PMCID: PMC3419510  PMID: 22915852
anticonvulsant; blood–brain barrier (BBB); targeted brain delivery; polysorbate-80-coated β-carotene nanoparticles (P-80-BCNP); maximal electroshock seizure (MES); pentylenetetrazole (PTZ)
2.  Tissue inhibitor of matrix metalloproteinases-1 loaded poly(lactic-co-glycolic acid) nanoparticles for delivery across the blood–brain barrier 
Aim
The aim of this study was to develop poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for delivery of a protein – tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) – across the blood–brain barrier (BBB) to inhibit deleterious matrix metalloproteinases (MMPs).
Materials and methods
The NPs were formulated by multiple-emulsion solvent-evaporation, and for enhancing BBB penetration, they were coated with polysorbate 80 (Ps80). We compared Ps80-coated and uncoated NPs for their toxicity, binding, and BBB penetration on primary rat brain capillary endothelial cell cultures and the rat brain endothelial 4 cell line. These studies were followed by in vivo studies for brain delivery of these NPs.
Results
Results showed that neither Ps80-coated nor uncoated NPs caused significant opening of the BBB, and essentially they were nontoxic. NPs without Ps80 coating had more binding to endothelial cells compared to Ps80-coated NPs. Penetration studies showed that TIMP-1 NPs + Ps80 had 11.21%±1.35% penetration, whereas TIMP-1 alone and TIMP-1 NPs without Ps80 coating did not cross the endothelial monolayer. In vivo studies indicated BBB penetration of intravenously injected TIMP-1 NPs + Ps80.
Conclusion
The study demonstrated that Ps80 coating of NPs does not cause significant toxic effects to endothelial cells and that it can be used to enhance the delivery of protein across endothelial cell barriers, both in vitro and in vivo.
doi:10.2147/IJN.S54750
PMCID: PMC3901738  PMID: 24531257
PLGA nanoparticles; drug delivery; protein delivery; sustained release; brain delivery; BBB penetration; RBCEC culture
3.  Enhanced brain targeting of temozolomide in polysorbate-80 coated polybutylcyanoacrylate nanoparticles 
Background:
Polybutylcyanoacrylate (PBCA) nanoparticles coated with polysorbate-80 have been extensively proposed for delivering drugs into the animal brain and have shown great potential for therapeutic applications. In this study, we made an attempt to deliver the chemotherapeutic drug, temozolomide, into the brain by using PBCA nanoparticles. The physicochemical characteristics, in vitro release, and brain targeting ability of the drug-loaded nanoparticles were investigated.
Results:
Our results show that a significantly higher concentration of temozolomide in the form of polysorbate-80-coated PBCA nanoparticles was observed in the brain (P < 0.05) in comparison with the free drug.
Conclusion:
This study indicates that polysorbate-80 coated PBCA nanoparticles could be a feasible carrier for temozolomide delivery to the brain. It is anticipated that the developed formulation may improve on targeted therapy for malignant brain tumors in the future.
doi:10.2147/IJN.S16570
PMCID: PMC3061435  PMID: 21445277
temozolomide; polybutylcyanoacrylate; nanoparticles; polysorbate-80; brain targeting
4.  Pulmonary surfactant is indispensable in order to simulate the in vivo situation 
The article of Gasser et al. [Part Fibre Toxicol. 24; 9:17, 2012] describes the interaction of carbon nanotubes with cells within a complex cell culture model. Besides various toxicity parameters, the influence of coating with pulmonary surfactant was investigated. Pulmonary surfactant covers the entire alveolar region with the main function of decreasing the surface tension in the alveoli to prevent alveolar collapse. Although each inhaled nanoparticle, reaching the alveoli, will come into contact with pulmonary surfactant which will probably lead to a surfactant coating, pulmonary surfactant components are not commonly integrated in in vitro systems. Gasser and co-workers have shown that this surfactant coating is able to influence the further interaction with cellular systems. Hence, each scientist, working with in vitro systems and nanoparticles, should think of integrating pulmonary surfactant structures in order to harmonize the in vitro systems with the in vivo situation. In the present commentary we discuss the most important points of the manuscript of Gasser et al. and discuss where the usage of pulmonary surfactant can be further optimized.
doi:10.1186/1743-8977-10-6
PMCID: PMC3616821  PMID: 23531298
Nanoparticle; Lung; Pulmonary surfactant; Coating
5.  Inhibition of Tissue Factor Expression in Brain Microvascular Endothelial Cells by Nanoparticles Loading NF-κB Decoy Oligonucleotides 
To investigate a nuclear factor-kappa B decoy oligonucleotides strategy on the inhibition of tissue factor (TF) expression in cultured rat brain microvascular endothelial cells (BMECs) by polylactic acid (PLA) nanoparticles delivery system and to evaluate this new vector for in vitro gene therapy. Nanoparticles were formulated using poly D,L-polylactic acid with surface modifying by polysorbates 80. 3-[4,5-Dimethylthiazol-2,5-diphenyl-2H-tetrazolium bromide] (MTT) assays showed that PLA nanoparticles were not toxic to the cultured BMECs.The decoy oligonuceotides (ODNs) loaded within nanoparticles was 6 μg/mg, encapsulation efficacy was (60.5±1.5)%. It was observed by flow cytometry that the cellular uptake of nanoparticles depended on the time of incubation and the concentration of nanoparticles in the medium. And confocal microscopy demonstrated that nanoparticles localized mostly in the BMECs cytoplasm. The released decoy oligonuceotides (ODNs) uptaked by BMECs retained their biologic activity and led to reduced level of tissue factor expression as compared to control cultures. These findings offer a potential therapeutic strategy in the control of TF expression in BMECs in vitro and suggest that PLA nanoparticles may be appropriate as delivery vehicles for decoy strategy in the gene therapy of cerebral thrombosis.
doi:10.3390/ijms9091851
PMCID: PMC2635753  PMID: 19325834
Tissue factor; decoy oligonucleotides; nanoparticles; nuclear factor-kappaB; polylactic acid
6.  Brain Localization and Neurotoxicity Evaluation of Polysorbate 80-Modified Chitosan Nanoparticles in Rats 
PLoS ONE  2015;10(8):e0134722.
The toxicity evaluation of inorganic nanoparticles has been reported by an increasing number of studies, but toxicity studies concerned with biodegradable nanoparticles, especially the neurotoxicity evaluation, are still limited. For example, the potential neurotoxicity of Polysorbate 80-modified chitosan nanoparticles (Tween 80-modified chitosan nanoparticles, TmCS-NPs), one of the most widely used brain targeting vehicles, remains unknown. In the present study, TmCS-NPs with a particle size of 240 nm were firstly prepared by ionic cross-linking of chitosan with tripolyphosphate. Then, these TmCS-NPs were demonstrated to be entered into the brain and specially deposited in the frontal cortex and cerebellum after systemic injection. Moreover, the concentration of TmCS-NPs in these two regions was found to decrease over time. Although no obvious changes were observed for oxidative stress in the in vivo rat model, the body weight was found to remarkably decreased in a dose-dependent manner after exposure to TmCS-NPs for seven days. Besides, apoptosis and necrosis of neurons, slight inflammatory response in the frontal cortex, and decrease of GFAP expression in the cerebellum were also detected in mouse injected with TmCS-NPs. This study is the first report on the sub-brain biodistribution and neurotoxicity studies of TmCS-NPs. Our results provide new insights into the toxicity evaluation of nanoparticles and our findings would help contribute to a better understanding of the neurotoxicity of biodegradable nanomaterials used in pharmaceutics.
doi:10.1371/journal.pone.0134722
PMCID: PMC4527829  PMID: 26248340
7.  Poly(n-butylcyanoacrylate) nanoparticles for oral delivery of quercetin: preparation, characterization, and pharmacokinetics and biodistribution studies in Wistar rats 
Background
Quercetin (QT) is a potential bioflavonol and antioxidant with poor bioavailability and very low distribution in the brain. A new oral delivery system comprising of poly(n-butylcyanoacrylate) nanoparticles (PBCA NPs) was introduced to improve the oral bioavailability of QT and to increase its distribution in the brain. Physicochemical characteristics, in vitro release, stability in simulated gastric fluid and intestinal fluids, and pharmacokinetics and biodistribution studies of QT-PBCA NPs coated with polysorbate-80 (P-80) were investigated.
Objective
This study aimed to investigate the physicochemical characteristics, in vitro release, stability in simulated gastric fluid and intestinal fluids, and pharmacokinetics and biodistribution studies of QT-PBCA NPs coated with polysorbate-80 (P-80).
Results
The results showed that QT-PBCA NPs and QT-PBCA NPs coated with P-80 (QT-PBCA+P-80) had mean particle sizes of 161.1±0.44 nm and 166.6±0.33 nm respectively, and appeared spherical in shape under transmission electron microscopy. The mean entrapment efficiency was 79.86%±0.45% for QT-PBCA NPs and 74.58%±1.44% for QT-PBCA+P-80. The in vitro release of QT-PBCA NPs and QT-PBCA+P-80 showed an initial burst release followed by a sustained release when compared to free QT. The relative bioavailability of QT-PBCA NPs and QT-PBCA+P-80 enhanced QT bioavailability by 2.38- and 4.93-fold respectively, when compared to free QT. The biodistribution study in rats showed that a higher concentration of QT was detected in the brain after the NPs were coated with P-80.
Conclusion
This study indicates that PBCA NPs coated with P-80 can be potential drug carriers for poorly water-soluble drugs. These NPs were observed to improve the drugs’ oral bioavailability and enhance their transport to the brain.
doi:10.2147/IJN.S80706
PMCID: PMC4468990  PMID: 26089668
bioavailability; biodistribution; nanoparticles; pharmacokinetics; poly (n-butylcyanoacrylate); quercetin
8.  Microcalorimetric Method to Assess Phagocytosis: Macrophage-Nanoparticle Interactions 
The AAPS Journal  2010;13(1):20-29.
This study evaluated the use of isothermal microcalorimetry (ITMC) to detect macrophage–nanoparticle interactions. Four different nanoparticle (NP) formulations were prepared: uncoated poly(isobutyl cyanoacrylate) (PIBCA), polysorbate-80-coated PIBCA, gelatin, and mannosylated gelatin NPs. Changes in NP formulations were aimed to either enhance or decrease macrophage–NP interactions via phagocytosis. Alveolar macrophages were cultured on glass slabs and inserted in the ITMC instrument. Thermal activities of the macrophages alone and after titration of 100 μL of NP suspensions were compared. The relative interactive coefficients of macrophage–NP interactions were calculated using the heat exchange observed after NP titration. Control experiments were performed using cytochalasin B (Cyto B), a known phagocytosis inhibitor. The results of NP titration showed that the total thermal activity produced by macrophages changed according to the NP formulation. Mannosylated gelatin NPs were associated with the highest heat exchange, 75.4 ± 7.5 J, and thus the highest relative interactive coefficient, 9,269 ± 630 M-1. Polysorbate-80-coated NPs were associated with the lowest heat exchange, 15.2 ± 3.4 J, and the lowest interactive coefficient, 890 ± 120 M-1. Cyto B inhibited macrophage response to NPs, indicating a connection between the thermal activity recorded and NP phagocytosis. These results are in agreement with flow cytometry results. ITMC is a valuable tool to monitor the biological responses to nano-sized dosage forms such as NPs. Since the thermal activity of macrophage–NP interactions differed according to the type of NPs used, ITMC may provide a method to better understand phagocytosis and further the development of colloidal dosage forms.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-010-9240-y) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-010-9240-y
PMCID: PMC3032094  PMID: 21057907
flow cytometry; isothermal microcalorimetry; macrophages; nanoparticles; phagocytosis
9.  Atomic Layer Deposition Coating of Carbon Nanotubes with Aluminum Oxide Alters Pro-Fibrogenic Cytokine Expression by Human Mononuclear Phagocytes In Vitro and Reduces Lung Fibrosis in Mice In Vivo 
PLoS ONE  2014;9(9):e106870.
Background
Multi-walled carbon nanotubes (MWCNTs) pose a possible human health risk for lung disease as a result of inhalation exposure. Mice exposed to MWCNTs develop pulmonary fibrosis. Lung macrophages engulf MWCNTs and produce pro-fibrogenic cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and osteopontin (OPN). Atomic layer deposition (ALD) is a novel process used to enhance functional properties of MWCNTs, yet the consequence of ALD-modified MWCNTs on macrophage biology and fibrosis is unknown.
Methods
The purpose of this study was to determine whether ALD coating with aluminum oxide (Al2O3) would alter the fibrogenic response to MWCNTs and whether cytokine expression in human macrophage/monocytes exposed to MWCNTs in vitro would predict the severity of lung fibrosis in mice. Uncoated (U)-MWCNTs or ALD-coated (A)-MWCNTs were incubated with THP-1 macrophages or human peripheral blood mononuclear cells (PBMC) and cell supernatants assayed for cytokines by ELISA. C57BL6 mice were exposed to a single dose of A- or U-MWCNTs by oropharyngeal aspiration (4 mg/kg) followed by evaluation of histopathology, lung inflammatory cell counts, and cytokine levels at day 1 and 28 post-exposure.
Results
ALD coating of MWCNTs with Al2O3 enhanced IL-1β secretion by THP-1 and PBMC in vitro, yet reduced protein levels of IL-6, TNF-α, and OPN production by THP-1 cells. Moreover, Al2O3 nanoparticles, but not carbon black NPs, increased IL-1β but decreased OPN and IL-6 in THP-1 and PBMC. Mice exposed to U-MWCNT had increased levels of all four cytokines assayed and developed pulmonary fibrosis by 28 days, whereas ALD-coating significantly reduced fibrosis and cytokine levels at the mRNA or protein level.
Conclusion
These findings indicate that ALD thin film coating of MWCNTs with Al2O3 reduces fibrosis in mice and that in vitro phagocyte expression of IL-6, TNF-α, and OPN, but not IL-1β, predict MWCNT-induced fibrosis in the lungs of mice in vivo.
doi:10.1371/journal.pone.0106870
PMCID: PMC4162563  PMID: 25216247
10.  Pulmonary toxicity following exposure to a tile coating product containing alkylsiloxanes. A clinical and toxicological evaluation 
Context
Coating products are widely used for making surfaces water and dirt repellent. However, on several occasions the use of these products has been associated with lung toxicity.
Objective
In the present study, we evaluated the toxic effects of an aerosolized tile-coating product.
Methods
Thirty-nine persons, who reported respiratory and systemic symptoms following exposure to the tile-coating product, were clinically examined. The product was analysed chemically and furthermore, the exposure scenario was reconstructed using a climate chamber and the toxicological properties of the product were studied using in vivo and by in vitro surfactometry.
Results
The symptoms developed within few hours and included coughing, tachypnoea, chest pain, general malaise and fever. The physical examination revealed perihilar lung infiltrates on chest radiograph and reduced blood oxygen saturation. The acute symptoms resolved gradually within 1–3 days and no delayed symptoms were observed. By means of mass spectrometry and X-ray spectroscopy, it was shown that the product contained non-fluorinated alkylsiloxanes. The exposure conditions in the supermarket were reconstructed under controlled conditions in a climate chamber and particle and gas exposure levels were monitored over time allowing estimation of human exposure levels.
Mice exposed to the product developed symptoms of acute pulmonary toxicity in a concentration-and time-dependent manner. The symptoms of acute pulmonary toxicity likely resulted from inhibition of the pulmonary surfactant function as demonstrated by in vitro surfactometry. Among these patients only a partial association between the level of exposure and the degree of respiratory symptoms was observed, which could be because of a high inter-individual difference in sensitivity and time-dependent changes in the chemical composition of the aerosol.
Conclusion
Workers need to cautiously apply surface coating products because the contents can be highly toxic through inhalation, and the aerosols can disperse to locations remote from the worksite and affect bystanders.
doi:10.3109/15563650.2014.915412
PMCID: PMC4086232  PMID: 24815546
Aerosols; Respiratory disorder; Sealing product; Coating product; Occupational exposure
11.  Novel designed polyoxyethylene nonionic surfactant with improved safety and efficiency for anticancer drug delivery 
In order to limit the adverse reactions caused by polysorbate 80 in Taxotere®, a widely used formulation of docetaxel, a safe and effective nanocarrier for this drug has been developed based on micelles formed by a new class of well-defined polyoxyethylene sorbitol oleate (PSO) with sorbitol as the matrix in aqueous solution. The physicochemical properties of the amphiphilic surfactant and the resulting micelles can be easily fine-tuned by the homogeneous sorbitol matrix and pure oleic acid. Composition, critical micelle concentration, and entrapment efficiency were investigated by ultraviolet visible spectroscopy, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorospectrophotometry, and high-performance liquid chromatography. In vitro and in vivo evaluation revealed that PSO had exceptionally low hemolysis and histamine release rates compared with commercial polysorbate 80. Moreover, the tumor targeting delivery of PSO was investigated by in vivo imaging in S180 tumor-bearing mice. The results suggest that this novel delivery system, PSO, provides an acceptable alternative to polysorbate 80 for delivery of docetaxel. Further, due to the hypoallergenic nature of PSO, the mechanism of pseudoallergy caused by the polyoxyethylene nonionic surfactant was investigated. Based on in vitro cell analysis, it was assumed that the initial contact of polyoxyethylene nonionic surfactant with mast cells provoked pseudoallergy via polyamine receptor-mediated endocytosis.
doi:10.2147/IJN.S60667
PMCID: PMC4010632  PMID: 24812509
polyoxyethylene nonionic surfactant; sorbitol; isosorbide; pseudoallergy; docetaxel
12.  Differential pulmonary effects of CoO and La2O3 metal oxide nanoparticle responses during aerosolized inhalation in mice 
Background
Although classified as metal oxides, cobalt monoxide (CoO) and lanthanum oxide (La2O3) nanoparticles, as representative transition and rare earth oxides, exhibit distinct material properties that may result in different hazardous potential in the lung. The current study was undertaken to compare the pulmonary effects of aerosolized whole body inhalation of these nanoparticles in mice.
Results
Mice were exposed to filtered air (control) and 10 or 30 mg/m3 of each particle type for 4 days and then examined at 1 h, 1, 7 and 56 days post-exposure. The whole lung burden 1 h after the 4 day inhalation of CoO nanoparticles was 25 % of that for La2O3 nanoparticles. At 56 days post exposure, < 1 % of CoO nanoparticles remained in the lungs; however, 22–50 % of the La2O3 nanoparticles lung burden 1 h post exposure was retained at 56 days post exposure for low and high exposures. Significant accumulation of La2O3 nanoparticles in the tracheobronchial lymph nodes was noted at 56 days post exposure. When exposed to phagolysosomal simulated fluid, La nanoparticles formed urchin-shaped LaPO4 structures, suggesting that retention of this rare earth oxide nanoparticle may be due to complexation of cellular phosphates within lysosomes. CoO nanoparticles caused greater lactate dehydrogenase release in the bronchoalveolar fluid (BALF) compared to La2O3 nanoparticles at 1 day post exposure, while BAL cell differentials indicate that La2O3 nanoparticles generated more inflammatory cell infiltration at all doses and exposure points. Histopathological analysis showed acute inflammatory changes at 1 day after inhalation of either CoO or La2O3 nanoparticles. Only the 30 mg/m3 La2O3 nanoparticles exposure caused chronic inflammatory changes and minimal fibrosis at day 56 post exposure. This is in agreement with activation of the NRLP3 inflammasome after in vitro exposure of differentiated THP-1 macrophages to La2O3 but not after CoO nanoparticles exposure.
Conclusion
Taken together, the inhalation studies confirmed the trend of our previous sub-acute aspiration study, which reported that CoO nanoparticles induced more acute pulmonary toxicity, while La2O3 nanoparticles caused chronic inflammatory changes and minimal fibrosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12989-016-0155-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12989-016-0155-3
PMCID: PMC4986387  PMID: 27527840
Nanoparticles; Metal oxides; Pulmonary response; In vivo; Mouse
13.  Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy 
The rapid proliferation of many different engineered nanomaterials (defined as materials designed and produced to have structural features with at least one dimension of 100 nanometers or less) presents a dilemma to regulators regarding hazard identification. The International Life Sciences Institute Research Foundation/Risk Science Institute convened an expert working group to develop a screening strategy for the hazard identification of engineered nanomaterials. The working group report presents the elements of a screening strategy rather than a detailed testing protocol. Based on an evaluation of the limited data currently available, the report presents a broad data gathering strategy applicable to this early stage in the development of a risk assessment process for nanomaterials. Oral, dermal, inhalation, and injection routes of exposure are included recognizing that, depending on use patterns, exposure to nanomaterials may occur by any of these routes. The three key elements of the toxicity screening strategy are: Physicochemical Characteristics, In Vitro Assays (cellular and non-cellular), and In Vivo Assays.
There is a strong likelihood that biological activity of nanoparticles will depend on physicochemical parameters not routinely considered in toxicity screening studies. Physicochemical properties that may be important in understanding the toxic effects of test materials include particle size and size distribution, agglomeration state, shape, crystal structure, chemical composition, surface area, surface chemistry, surface charge, and porosity.
In vitro techniques allow specific biological and mechanistic pathways to be isolated and tested under controlled conditions, in ways that are not feasible in in vivo tests. Tests are suggested for portal-of-entry toxicity for lungs, skin, and the mucosal membranes, and target organ toxicity for endothelium, blood, spleen, liver, nervous system, heart, and kidney. Non-cellular assessment of nanoparticle durability, protein interactions, complement activation, and pro-oxidant activity is also considered.
Tier 1 in vivo assays are proposed for pulmonary, oral, skin and injection exposures, and Tier 2 evaluations for pulmonary exposures are also proposed. Tier 1 evaluations include markers of inflammation, oxidant stress, and cell proliferation in portal-of-entry and selected remote organs and tissues. Tier 2 evaluations for pulmonary exposures could include deposition, translocation, and toxicokinetics and biopersistence studies; effects of multiple exposures; potential effects on the reproductive system, placenta, and fetus; alternative animal models; and mechanistic studies.
doi:10.1186/1743-8977-2-8
PMCID: PMC1260029  PMID: 16209704
14.  Different biokinetics of nanomedicines linking to their toxicity; an overview 
In spite of the extreme rise to the knowledge of nanotechnology in pharmaceutical sciences, there are currently limited experimental works studying the interactions between nanoparticles (NPs) and the biological system. Adjustment of size and surface area plays the main role in the reaction between NPs and cells leading to their increased entrance into cells through skin, gastrointestinal and respiratory system. Moreover, change in physicochemical reactivity of NPs causes them to interact with circulatory and cellular proteins differentially leading to the altered parameters of their biokinetics, including adsorption, distribution, translocation, transformation, and elimination. A direct relationship between the surface area, reactive oxygen species generating capability, and proinflammatory effects of NPs have been found in respiratory tract toxicity. Additionally, complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanodrugs have been well defined. Inhalation studies of some NPs have confirmed the translocation of inhaled materials to extra pulmonary organs such as central nervous system (CNS) via olfactory neurons and induction of inflammatory response. Injectable uncoated NPs have a tendency to remain on the injection site while the poly ethanol glycol (PEG)-coated NPs can be notably drained from the injection site to get as far as the lymph nodes where they accumulate. This confirms the existence of channels within the extracellular matrix for NPs to move along. Furthermore, induction of DNA strand breaks and formation of micronuclei have been recorded for exposure to some NPs such as single-walled carbon nanotubes.
In the recent years, most of the studies have simply outlined better efficacy of nanodrugs, but few discussed their possible toxic reactions specially if used chronically. Therefore, we emphasize that this part of the nanoscience must not be undermined and toxicologists must be sensitive to set up suitable in vivo or in vitro toxicity models. A system for collecting data about the relationships between NPs’ structure-size-efficacy-toxicity (SSET) should be specified with special regard to portal of entry and target organ.
doi:10.1186/2008-2231-21-14
PMCID: PMC3586357  PMID: 23432813
Nanomedicine; Biokinetics; Nanotoxicology; Review
15.  Physicochemical characteristics of nanomaterials that affect pulmonary inflammation 
The increasing manufacture and use of products based on nanotechnology raises concerns for both workers and consumers. Various studies report induction of pulmonary inflammation after inhalation exposure to nanoparticles, which can vary in aspects such as size, shape, charge, crystallinity, chemical composition, and dissolution rate. Each of these aspects can affect their toxicity, although it is largely unknown to what extent. The aim of the current review is to analyse published data on inhalation of nanoparticles to identify and evaluate the contribution of their physicochemical characteristics to the onset and development of pulmonary inflammation. Many physicochemical characteristics of nanoparticles affect their lung deposition, clearance, and pulmonary response that, in combination, ultimately determine whether pulmonary inflammation will occur and to what extent. Lung deposition is mainly determined by the physical properties of the aerosol (size, density, shape, hygroscopicity) in relation to airflow and the anatomy of the respiratory system, whereas clearance and translocation of nanoparticles are mainly determined by their geometry and surface characteristics. Besides size and chemical composition, other physicochemical characteristics influence the induction of pulmonary inflammation after inhalation. As some nanoparticles dissolve, they can release toxic ions that can damage the lung tissue, making dissolution rate an important characteristic that affects lung inflammation. Fibre-shaped materials are more toxic to the lungs compared to spherical shaped nanoparticles of the same chemical composition. In general, cationic nanoparticles are more cytotoxic than neutral or anionic nanoparticles. Finally, surface reactivity correlates well with observed pulmonary inflammation. With all these characteristics affecting different stages of the events leading to pulmonary inflammation, no unifying dose metric could be identified to describe pulmonary inflammation for all nanomaterials, although surface reactivity might be a useful measure. To determine the extent to which the various characteristics influence the induction of pulmonary inflammation, the effect of these characteristics on lung deposition, clearance, and pulmonary response should be systematically evaluated. The results can then be used to facilitate risk assessment by categorizing nanoparticles according to their characteristics.
doi:10.1186/1743-8977-11-18
PMCID: PMC3996135  PMID: 24725891
Nanoparticles; Inhalation exposure; Pulmonary toxicity; Particle characteristics; Surface reactivity; Risk assessment
16.  Toxicity assessment of zinc oxide nanoparticles using sub-acute and sub-chronic murine inhalation models 
Background
Although ZnO nanoparticles (NPs) are used in many commercial products and the potential for human exposure is increasing, few in vivo studies have addressed their possible toxic effects after inhalation. We sought to determine whether ZnO NPs induce pulmonary toxicity in mice following sub-acute or sub-chronic inhalation exposure to realistic exposure doses.
Methods
Mice (C57Bl/6) were exposed to well-characterized ZnO NPs (3.5 mg/m3, 4 hr/day) for 2 (sub-acute) or 13 (sub-chronic) weeks and necropsied immediately (0 wk) or 3 weeks (3 wks) post exposure. Toxicity was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase activity and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid as well as measurements of pulmonary mechanics. Generation of reactive oxygen species was assessed in the lungs. Lungs were evaluated for histopathologic changes and Zn content. Zn concentration in blood, liver, kidney, spleen, heart, brain and BAL fluid was measured.
Results
An elevated concentration of Zn2+ was detected in BAL fluid immediately after exposures, but returned to baseline levels 3 wks post exposure. Dissolution studies showed that ZnO NPs readily dissolved in artificial lysosomal fluid (pH 4.5), but formed aggregates and precipitates in artificial interstitial fluid (pH 7.4). Sub-acute exposure to ZnO NPs caused an increase of macrophages in BAL fluid and a moderate increase in IL-12(p40) and MIP-1α, but no other inflammatory or toxic responses were observed. Following both sub-acute and sub-chronic exposures, pulmonary mechanics were no different than sham-exposed animals.
Conclusions
Our ZnO NP inhalation studies showed minimal pulmonary inflammation, cytotoxicity or lung histopathologic changes. An elevated concentration of Zn in the lung and BAL fluid indicates dissolution of ZnO NPs in the respiratory system after inhalation. Exposure concentration, exposure mode and time post exposure played an important role in the toxicity of ZnO NPs. Exposure for 13 wks with a cumulative dose of 10.9 mg/kg yielded increased lung cellularity, but other markers of toxicity did not differ from sham-exposed animals, leading to the conclusion that ZnO NPs have low sub-chronic toxicity by the inhalation route.
doi:10.1186/1743-8977-11-15
PMCID: PMC3994238  PMID: 24684892
Zinc oxide nanoparticles; Dissolution; Inhalation; Murine model; Pulmonary response; Toxicity
17.  Nanosilver induces minimal lung toxicity or inflammation in a subacute murine inhalation model 
Background
There is increasing interest in the environmental and health consequences of silver nanoparticles as the use of this material becomes widespread. Although human exposure to nanosilver is increasing, only a few studies address possible toxic effect of inhaled nanosilver. The objective of this study was to determine whether very small commercially available nanosilver induces pulmonary toxicity in mice following inhalation exposure.
Results
In this study, mice were exposed sub-acutely by inhalation to well-characterized nanosilver (3.3 mg/m3, 4 hours/day, 10 days, 5 ± 2 nm primary size). Toxicity was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase activity and inflammatory cytokines in bronchoalveolar lavage fluid. Lungs were evaluated for histopathologic changes and the presence of silver. In contrast to published in vitro studies, minimal inflammatory response or toxicity was found following exposure to nanosilver in our in vivo study. The median retained dose of nanosilver in the lungs measured by inductively coupled plasma - optical emission spectroscopy (ICP-OES) was 31 μg/g lung (dry weight) immediately after the final exposure, 10 μg/g following exposure and a 3-wk rest period and zero in sham-exposed controls. Dissolution studies showed that nanosilver did not dissolve in solutions mimicking the intracellular or extracellular milieu.
Conclusions
Mice exposed to nanosilver showed minimal pulmonary inflammation or cytotoxicity following sub-acute exposures. However, longer term exposures with higher lung burdens of nanosilver are needed to ensure that there are no chronic effects and to evaluate possible translocation to other organs.
doi:10.1186/1743-8977-8-5
PMCID: PMC3040688  PMID: 21266073
18.  Duloxetine HCl Lipid Nanoparticles: Preparation, Characterization, and Dosage Form Design 
AAPS PharmSciTech  2011;13(1):125-133.
Solid lipid nanoparticles (SLNs) of duloxetine hydrochloride (DLX) were prepared to circumvent the problems of DLX, which include acid labile nature, high first-pass metabolism, and high-dosing frequency. The DLX-SLNs were prepared by using two different techniques, viz. solvent diffusion method and ultrasound dispersion method, and evaluated for particle size, zeta potential, entrapment efficiency, physical characteristics, and chemical stability. Best results were obtained when SLNs were prepared by ultrasound dispersion method using glyceryl mono stearate as solid lipid and DLX in ratio of 1:20 and mixture of polysorbate 80 and poloxamer 188 as surfactant in concentration of 3%. The mean particle size of formulation and entrapment efficiency was 91.7 nm and 87%, respectively, and had excellent stability in acidic medium. Differential scanning calorimetry and X-ray diffraction data showed complete amorphization of DLX in lipid. In vitro drug release from SLNs was observed for 48 h and was in accordance with Higuchi kinetics. In vivo antidepressant activity was evaluated in mice by forced swim test. DLX-SLNs showed significant enhancement in antidepressant activity at 24 h when administered orally in comparison to drug solution. These results confirm the potential of SLNs in enhancing chemical stability and improving the efficacy of DLX via oral route. The SLN dispersion was converted into solid granules by adsorbing on colloidal silicon dioxide and characterized for particle size after redispersion, morphology, and flow properties. Results indicated that nanoparticles were successfully adsorbed on the carrier and released SLNs when dispersed in water.
doi:10.1208/s12249-011-9727-6
PMCID: PMC3299448  PMID: 22167415
acid labile; adsorption; duloxetine HCl; lymphatic absorption; solid lipid nanoparticles
19.  Deducing in Vivo Toxicity of Combustion-Derived Nanoparticles from a Cell-Free Oxidative Potency Assay and Metabolic Activation of Organic Compounds 
Background
The inhalation of combustion-derived nanoparticles (CDNPs) is believed to cause an oxidative stress response, which in turn may lead to pulmonary or even systemic inflammation.
Objective and Methods
In this study we assessed whether the in vivo inflammatory response—which is generally referred to as particle toxicity—of mice to CDNPs can be predicted in vitro by a cell-free ascorbate test for the surface reactivity or, more precisely, oxidative potency (OxPot) of particles.
Results
For six types of CDNPs with widely varying particle diameter (10–50 nm), organic content (OC; 1–20%), and specific Brunauer, Emmett, and Teller (BET) surface area (43–800 m2/g), OxPot correlated strongly with the in vivo inflammatory response (pulmonary polymorphonuclear neutrophil influx 24 hr after intratracheal particle instillation). However, for CDNPs with high organic content, OxPot could not explain the observed inflammatory response, possibly due to shielding of the OxPot of the carbon core of CDNPs by an organic coating. On the other hand, a pathway-specific gene expression screen indicated that, for particles rich in polycyclic aromatic hydrocarbon (PAHs), cytochrome P450 1A1 (CYP1A1) enzyme-mediated biotransformation of bio-available organics may generate oxidative stress and thus enhance the in vivo inflammatory response.
Conclusion
The compensatory nature of both effects (shielding of carbon core and biotransformation of PAHs) results in a good correlation between inflammatory response and BET surface area for all CDNPs. Hence, the in vivo inflammatory response can either be predicted by BET surface area or by a simple quantitative model, based on in vitro OxPot and Cyp1a1 induction.
doi:10.1289/ehp.11370
PMCID: PMC2627865  PMID: 19165387
air pollution; BET; biotransformation; carbonaceous particles; Cyp1a1; dose response; nanoparticles; nanotoxicity; organic compounds; oxidative stress; particle toxicity; soot particles; specific surface area; surface toxicity; ultrafine particles
20.  Comparison of the Pulmonary Oxidative Stress Caused by Intratracheal Instillation and Inhalation of NiO Nanoparticles when Equivalent Amounts of NiO Are Retained in the Lung 
Antioxidants  2016;5(1):4.
NiO nanoparticles were administered to rat lungs via intratracheal instillation or inhalation. During pulmonary toxicity caused by NiO nanoparticles, the induction of oxidative stress is a major factor. Both intratracheal instillation and inhalation of NiO nanoparticles induced pulmonary oxidative stress. The oxidative stress response protein, heme oxygenase-1 (HO-1), was induced by the administration of NiO nanoparticles at both the protein and gene expression level. Additionally, certain oxidative-stress markers in the lung, such as 8-iso-prostaglandin F2α, thioredoxin, and inducible nitric oxide synthase were increased. Furthermore, the concentration of myeloperoxidase (MPO) in the lung was also increased by the administration of NiO nanoparticles. When the amount of NiO in the lung is similar, the responses against pulmonary oxidative stress of intratracheal instillation and inhalation are also similar. However, the state of pulmonary oxidative stress in the early phase was different between intratracheal instillation and inhalation, even if the amount of NiO in the lung was similar. Inhalation causes milder oxidative stress than that caused by intratracheal instillation. On evaluation of the nanoparticle-induced pulmonary oxidative stress in the early phase, we should understand the different states of oxidative stress induced by intratracheal instillation and inhalation.
doi:10.3390/antiox5010004
PMCID: PMC4808753  PMID: 26797643
oxidative stress; nanoparticle; nickel oxide; inhalation; intratracheal instillation
21.  Distribution of β-carotene-encapsulated polysorbate 80-coated poly(D, L-lactide-co-glycolide) nanoparticles in rodent tissues following intravenous administration 
Purpose
Biodegradable nanoparticles (NPs) composed of poly(D, L-lactide-co-glycolide) (PLGA) have attracted considerable attention as delivery systems of drugs and antioxidative compounds, such as β-carotene (BC). Intravenous (IV) administration of BC-containing PLGA-NPs (BC-PLGA-NPs) coated with polysorbate 80 (PS80) has been shown to effectively deliver BC to the brain. However, the whole-body distribution profile of BC is still not clear. Therefore, we investigated the accumulation of BC in various organs, including the brain, following IV administration of PS80-coated BC-PLGA-NPs in rats.
Methods
PS80-coated and uncoated BC-PLGA-NPs were prepared by solvent evaporation, and administered intravenously to Sprague Dawley rats at a BC dose of 8.5 mg/rat. Accumulation of BC in various organs (brain, heart, liver, lungs, and spleen) and blood plasma was evaluated by high performance liquid chromatography with ultraviolet (UV) detection, 1 hour after administration.
Results
We prepared PS80-coated BC-PLGA-NPs with an entrapment efficiency of 14%, a particle size of 260 nm, and a zeta potential of −26 mV. Coating with PS80 was found to result in significant accumulation of BC in the lungs, rather than in the brain and other tissues. Further, plasma levels of BC in the PS80-coated BC-PLGA-NP group were much lower than those of the uncoated BC-PLGA-NP group.
Conclusion
Following IV administration, PS80-coated BC-PLGA-NPs are quickly transferred from plasma circulation to the lungs, rather than the brain. Significant accumulation of BC in the lungs may be useful for health-related applications.
doi:10.2147/IJN.S94336
PMCID: PMC4669931  PMID: 26664113
β-carotene; intravenous administration; nanoparticles; poly(D, L-lactide-co-glycolide) (PLGA); polysorbate 80 (PS80); tissue distribution
22.  An in vivo and in vitro toxicological characterization of realistic nanoscale CeO2 inhalation exposures 
Nanotoxicology  2012;7(8):1338-1350.
Nanoscale CeO2 is increasingly used for industrial and commercial applications, including catalysis, UV-shielding, and as an additive in various nanocomposites. Because of its increasing potential for consumer and occupational exposures, a comprehensive toxicological characterization of this nanomaterial is needed. Preliminary results from intratracheal instillation studies in rats point to cytoxicity and inflammation, though these studies may not accurately use realistic nanoscale exposure profiles. In contrast, published in vitro cellular studies have reported limited toxicological outcomes for the case of nano-ceria. Here, we present an integrative study evaluating the toxicity of nanoscale CeO2 both in vitro, using the A549 lung epithelial cell line, and in vivo using an intact rat model. Realistic nano-ceria exposure atmospheres were generated using the Harvard Versatile Engineered Nanomaterial Generation System (VENGES), and rats were exposed via inhalation. Finally, the use of a nanothin amorphous SiO2 encapsulation coating as a means of mitigating CeO2 toxicity was assessed. Results from the inhalation experiments show lung injury and inflammation with increased PMN and LDH levels in the bronchoalveolar lavage fluid of the CeO2 exposed rats. Moreover, exposure to SiO2-coated CeO2 did not induce any pulmonary toxicity to the animals, representing clear evidence for the safe by design SiO2-encapsualtion concept.
doi:10.3109/17435390.2012.739665
PMCID: PMC4438163  PMID: 23061914
Engineered nanomaterials; CeO2; in vivo inhalation studies; in vitro toxicological studies; safe by design ENMs
23.  Pulmonary Response to Surface-Coated Nanotitanium Dioxide Particles Includes Induction of Acute Phase Response Genes, Inflammatory Cascades, and Changes in MicroRNAs: A Toxicogenomic Study 
Titanium dioxide nanoparticles (nanoTiO2) are used in various applications including in paints. NanoTiO2 inhalation may induce pulmonary toxicity and systemic effects. However, the underlying molecular mechanisms are poorly understood. In this study, the effects of inhaled surface-coated nanoTiO2 on pulmonary global messenger RNA (mRNA) and microRNA (miRNA) expression in mouse were characterized to provide insight into the molecular response. Female C57BL/6BomTac mice were exposed for 1 hr daily to 42.4 ± 2.9 (SEM) mg surface-coated nanoTiO2/m3 for 11 consecutive days by inhalation and were sacrificed 5 days following the last exposure. Physicochemical properties of the particles were determined. Pulmonary response to nanoTiO2 was characterized using DNA microarrays and pathway-specific PCR arrays and related to data on pulmonary inflammation from bronchial lavages. NanoTiO2 exposure resulted in increased levels of mRNA for acute phase markers serum amyloid A-1 (Saa1) and serum amyloid A-3 (Saa3), several C-X-C and C-C motif chemokines, and cytokine tumor necrosis factor genes. Protein analysis of Saa1 and 3 showed selective upregulation of Saa3 in lung tissues. Sixteen miRNAs were induced by more than 1.2-fold (adjusted P-value < 0.05) following exposure. Real time polymerase chain reaction confirmed the upregulation of miR-1, miR-449a and revealed dramatic induction of miR-135b (60-fold). Thus, inhalation of surface-coated nanoTiO2 results in changes in the expression of genes associated with acute phase, inflammation and immune response 5 days post exposure with concomitant changes in several miRNAs. The role of these miRNAs in pulmonary response to inhaled particles is unknown and warrants further research. Environ. Mol. Mutagen., 2011. © 2011 Wiley-Liss, Inc.†
doi:10.1002/em.20639
PMCID: PMC3210826  PMID: 21259345
nanotitanium dioxide; gene expression; microRNA; inflammation
24.  Albumin nanoparticles coated with polysorbate 80 as a novel drug carrier for the delivery of antiretroviral drug—Efavirenz 
Purpose of the study:
The antiretroviral therapy (ART) has dramatically improved human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) treatment, prevention and also has been found to increase the lifespan of HIV/AIDS patients by providing durable control of the HIV replication in patients. Efavirenz is a non-nucleoside reverse transcriptase inhibitor of HIV-1. The purpose of this study is to formulate efavirenz-loaded bovine serum albumin nanoparticles to improve efavirenz delivery into various organs.
Materials and Methods:
Nanoparticles were prepared by desolvation technique and coated with polysorbate 80. Ethanol, glutaraldehyde, and mannitol were used as desolvating, cross linking agent, and cryoprotectant, respectively. Drug to polymer ratio was chosen at five levels from 1:2, 1:3, 1:4, 1:5, and 1:6 (by weight). The formulated nanoparticles were characterized for Fourier Transform Infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) studies, entrapment efficiency, particle size, surface charge, surface morphology, in vitro drug release, release kinetics, stability studies, and biodistribution studies.
Results and Major Conclusion:
The particle size of the prepared formulations was found below 250nm with narrow size distribution, spherical in shape and showed good entrapment efficiency (45.62-72.49%). The in vitro drug release indicated biphasic release and its data were fitted to release kinetics models and release pattern was Fickian diffusion controlled release profile. The prepared nanoparticles increased efavirenz delivery into various organs by several fold in comparison with the free drug.
doi:10.4103/2230-973X.138348
PMCID: PMC4131386  PMID: 25126528
Albumin nanoparticles; animal testing; desolvation technique; Efavirenz (NNRTIs); polysorbate 80
25.  Validation of an in vitro exposure system for toxicity assessment of air-delivered nanomaterials 
To overcome the limitations of in vitro exposure of submerged lung cells to nanoparticles (NPs), we validated an integrated low flow system capable of generating and depositing airborne NPs directly onto cells at an air–liquid interface (ALI). The in vitro exposure system was shown to provide uniform and controlled dosing of particles with 70.3% efficiency to epithelial cells grown on transwells. This system delivered a continuous airborne exposure of NPs to lung cells without loss of cell viability in repeated 4 h exposure periods. We sequentially exposed cells to air-delivered copper (Cu) NPs in vitro to compare toxicity results to our prior in vivo inhalation studies. The evaluation of cellular dosimetry indicated that a large amount of Cu was taken up, dissolved and released into the basolateral medium (62% of total mass). Exposure to Cu NPs decreased cell viability to 73% (p < 0.01) and significantly (p < 0.05) elevated levels of lactate dehydrogenase, intracellular reactive oxygen species and interleukin-8 that mirrored our findings from subacute in vivo inhalation studies in mice. Our results show that this exposure system is useful for screening of NP toxicity in a manner that represents cellular responses of the pulmonary epithelium in vivo.
doi:10.1016/j.tiv.2012.08.030
PMCID: PMC3950355  PMID: 22981796
Nanoparticles; Lung cells; Air–liquid interface; Deposition efficiency; Spatial uniformity; Cellular dose

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