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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (15 October 2014)

Special Issue Editor

Guest Editor
Prof. Dr. James C. Bonner

Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, USA
Website | E-Mail
Interests: cellular and molecular mechanisms through which toxic environmental agents cause lung diseases; especially pulmonary fibrosis and asthma; lung fibrosis; asthma; nanotoxicology; metals; particles; fibers

Special Issue Information

Dear Colleagues,

The nanotechnology industry is rapidly developing, resulting in the production of a variety of engineered nanomaterials (ENMs) for a variety of applications. These ENMs include carbon nanotubes and metal or metal oxide nanoparticles such as zinc, titanium, cerium and silver that are incorporated into consumer products or encountered in occupational settings. Some of these novel engineered nanostructures represent a potential human health risk, due to the possibility of inhalation exposure and evidence that the lung, as well as other systemic sites, are targets for hazardous effects. Articles in this special issue will address cutting edge research aimed at elucidating the mechanisms through which ENMs cause pulmonary disease in rodents after lung exposure. Inhalation studies in rodents show that ENMs deposit within the distal regions in the lungs and cause inflammation, fibrosis, or alter immune responses. Because novel engineering methodology is resulting in the production of an increasing complexity of ENM structures that vary in toxicological activity, this issue will also address high content screening for the development of structure-activity relationships relevant to inhalation toxicity and safer design of nanoparticles. This will include exploration of factors that mediate toxic effects such as high aspect ratio, durability, and residual metal content. Finally, we will address how susceptibility factors, both genetic and environmental, determine pulmonary and systemic toxicity to ENMs.

Prof. Dr. James C. Bonner
Guest Editor

Submission:

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.

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Keywords

  • nanoparticles
  • lung
  • toxicity
  • asthma
  • fibrosis
  • immunity

Published Papers (13 papers)

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Research

Jump to: Review

Open AccessArticle Comprehensive DNA Adduct Analysis Reveals Pulmonary Inflammatory Response Contributes to Genotoxic Action of Magnetite Nanoparticles
Int. J. Mol. Sci. 2015, 16(2), 3474-3492; doi:10.3390/ijms16023474
Received: 11 October 2014 / Revised: 6 January 2015 / Accepted: 30 January 2015 / Published: 4 February 2015
Cited by 5 | PDF Full-text (963 KB) | HTML Full-text | XML Full-text
Abstract
Nanosized-magnetite (MGT) is widely utilized in medicinal and industrial fields; however, its toxicological properties are not well documented. In our previous report, MGT showed genotoxicity in both in vitro and in vivo assay systems, and it was suggested that inflammatory responses exist behind
[...] Read more.
Nanosized-magnetite (MGT) is widely utilized in medicinal and industrial fields; however, its toxicological properties are not well documented. In our previous report, MGT showed genotoxicity in both in vitro and in vivo assay systems, and it was suggested that inflammatory responses exist behind the genotoxicity. To further clarify mechanisms underlying the genotoxicity, a comprehensive DNA adduct (DNA adductome) analysis was conducted using DNA samples derived from the lungs of mice exposed to MGT. In total, 30 and 42 types of DNA adducts were detected in the vehicle control and MGT-treated groups, respectively. Principal component analysis (PCA) against a subset of DNA adducts was applied and several adducts, which are deduced to be formed by inflammation or oxidative stress, as the case of etheno-deoxycytidine (εdC), revealed higher contributions to MGT exposure. By quantitative-LC-MS/MS analysis, εdC levels were significantly higher in MGT-treated mice than those of the vehicle control. Taken together with our previous data, it is suggested that inflammatory responses might be involved in the genotoxicity induced by MGT in the lungs of mice. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
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Open AccessArticle Effect of Fiber Length on Carbon Nanotube-Induced Fibrogenesis
Int. J. Mol. Sci. 2014, 15(5), 7444-7461; doi:10.3390/ijms15057444
Received: 6 March 2014 / Revised: 11 April 2014 / Accepted: 15 April 2014 / Published: 29 April 2014
Cited by 27 | PDF Full-text (1315 KB) | HTML Full-text | XML Full-text
Abstract
Given their extremely small size and light weight, carbon nanotubes (CNTs) can be readily inhaled by human lungs resulting in increased rates of pulmonary disorders, particularly fibrosis. Although the fibrogenic potential of CNTs is well established, there is a lack of consensus regarding
[...] Read more.
Given their extremely small size and light weight, carbon nanotubes (CNTs) can be readily inhaled by human lungs resulting in increased rates of pulmonary disorders, particularly fibrosis. Although the fibrogenic potential of CNTs is well established, there is a lack of consensus regarding the contribution of physicochemical attributes of CNTs on the underlying fibrotic outcome. We designed an experimentally validated in vitro fibroblast culture model aimed at investigating the effect of fiber length on single-walled CNT (SWCNT)-induced pulmonary fibrosis. The fibrogenic response to short and long SWCNTs was assessed via oxidative stress generation, collagen expression and transforming growth factor-beta (TGF-β) production as potential fibrosis biomarkers. Long SWCNTs were significantly more potent than short SWCNTs in terms of reactive oxygen species (ROS) response, collagen production and TGF-β release. Furthermore, our finding on the length-dependent in vitro fibrogenic response was validated by the in vivo lung fibrosis outcome, thus supporting the predictive value of the in vitro model. Our results also demonstrated the key role of ROS in SWCNT-induced collagen expression and TGF-β activation, indicating the potential mechanisms of length-dependent SWCNT-induced fibrosis. Together, our study provides new evidence for the role of fiber length in SWCNT-induced lung fibrosis and offers a rapid cell-based assay for fibrogenicity testing of nanomaterials with the ability to predict pulmonary fibrogenic response in vivo. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
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Open AccessArticle The Effect of Size on Ag Nanosphere Toxicity in Macrophage Cell Models and Lung Epithelial Cell Lines Is Dependent on Particle Dissolution
Int. J. Mol. Sci. 2014, 15(4), 6815-6830; doi:10.3390/ijms15046815
Received: 20 February 2014 / Revised: 25 March 2014 / Accepted: 9 April 2014 / Published: 22 April 2014
Cited by 16 | PDF Full-text (2346 KB) | HTML Full-text | XML Full-text
Abstract
Silver (Ag) nanomaterials are increasingly used in a variety of commercial applications. This study examined the effect of size (20 and 110 nm) and surface stabilization (citrate and PVP coatings) on toxicity, particle uptake and NLRP3 inflammasome activation in a variety of macrophage
[...] Read more.
Silver (Ag) nanomaterials are increasingly used in a variety of commercial applications. This study examined the effect of size (20 and 110 nm) and surface stabilization (citrate and PVP coatings) on toxicity, particle uptake and NLRP3 inflammasome activation in a variety of macrophage and epithelial cell lines. The results indicated that smaller Ag (20 nm), regardless of coating, were more toxic in both cell types and most active in the THP-1 macrophages. TEM imaging demonstrated that 20 nm Ag nanospheres dissolved more rapidly than 110 nm Ag nanospheres in acidic phagolysosomes consistent with Ag ion mediated toxicity. In addition, there were some significant differences in epithelial cell line in vitro exposure models. The order of the epithelial cell lines’ sensitivity to Ag was LA4 > MLE12 > C10. The macrophage sensitivity to Ag toxicity was C57BL/6 AM > MARCO null AM, which indicated that the MARCO receptor was involved in uptake of the negatively charged Ag particles. These results support the idea that Ag nanosphere toxicity and NLRP3 inflammasome activation are determined by the rate of surface dissolution, which is based on relative surface area. This study highlights the importance of utilizing multiple models for in vitro studies to evaluate nanomaterials. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
Open AccessArticle Comparative Pulmonary Toxicity of Two Ceria Nanoparticles with the Same Primary Size
Int. J. Mol. Sci. 2014, 15(4), 6072-6085; doi:10.3390/ijms15046072
Received: 12 February 2014 / Revised: 25 March 2014 / Accepted: 27 March 2014 / Published: 10 April 2014
Cited by 9 | PDF Full-text (2072 KB) | HTML Full-text | XML Full-text
Abstract
Ceria nanoparticles (nano-ceria) have recently gained a wide range of applications, which might pose unwanted risks to both the environment and human health. The greatest potential for the environmental discharge of nano-ceria appears to be in their use as a diesel fuel additive.
[...] Read more.
Ceria nanoparticles (nano-ceria) have recently gained a wide range of applications, which might pose unwanted risks to both the environment and human health. The greatest potential for the environmental discharge of nano-ceria appears to be in their use as a diesel fuel additive. The present study was designed to explore the pulmonary toxicity of nano-ceria in mice after a single exposure via intratracheal instillation. Two types of nano-ceria with the same distribution of a primary size (3–5 nm), but different redox activity, were used: Ceria-p, synthesized by a precipitation route, and Ceria-h, synthesized by a hydrothermal route. Both Ceria-p and Ceria-h induced oxidative stress, inflammatory responses and cytotoxicity in mice, but their toxicological profiles were quite different. The mean size of Ceria-p agglomerates was much smaller compared to Ceria-h, thereby causing a more potent acute inflammation, due to their higher number concentration of agglomerates and higher deposition rate in the deep lung. Ceria-h had a higher reactivity to catalyzing the generation of reactive oxygen species (ROS), and caused two waves of lung injury: bronchoalveolar lavage (BAL) inflammation and cytotoxicity in the early stage and redox-activity-evoked lipid peroxidation and pro-inflammation in the latter stage. Therefore, the size distribution of ceria-containing agglomerates in the exhaust, as well as their surface chemistry are essential characteristics to assess the potential risks of using nano-ceria as a fuel additive. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
Open AccessArticle Effect of Nanoparticles Exposure on Fractional Exhaled Nitric Oxide (FENO) in Workers Exposed to Nanomaterials
Int. J. Mol. Sci. 2014, 15(1), 878-894; doi:10.3390/ijms15010878
Received: 11 December 2013 / Revised: 26 December 2013 / Accepted: 3 January 2014 / Published: 9 January 2014
Cited by 10 | PDF Full-text (320 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Fractional exhaled nitric oxide (FENO) measurement is a useful diagnostic test of airway inflammation. However, there have been few studies of FENO in workers exposed to nanomaterials. The purpose of this study was to examine the effect of nanoparticle (NP) exposure on FENO
[...] Read more.
Fractional exhaled nitric oxide (FENO) measurement is a useful diagnostic test of airway inflammation. However, there have been few studies of FENO in workers exposed to nanomaterials. The purpose of this study was to examine the effect of nanoparticle (NP) exposure on FENO and to assess whether the FENO is increased in workers exposed to nanomaterials (NM). In this study, both exposed workers and non-exposed controls were recruited from NM handling plants in Taiwan. A total of 437 subjects (exposed group = 241, non-exposed group = 196) completed the FENO and spirometric measurements from 2009–2011. The authors used a control-banding (CB) matrix to categorize the risk level of each participant. In a multivariate linear regression analysis, this study found a significant association between risk level 2 of NP exposure and FENO. Furthermore, asthma, allergic rhinitis, peak expiratory flow rate (PEFR), and NF-κB were also significantly associated with FENO. When the multivariate logistic regression model was adjusted for confounders, nano-TiO2 in all of the NM exposed categories had a significantly increased risk in FENO > 35 ppb. This study found associations between the risk level of NP exposure and FENO (particularly noteworthy for Nano-TiO2). Monitoring FENO in the lung could open up a window into the role nitric oxide (NO) may play in pathogenesis. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
Open AccessArticle Carbon Nanotube-Induced Pulmonary Granulomatous Disease: Twist1 and Alveolar Macrophage M1 Activation
Int. J. Mol. Sci. 2013, 14(12), 23858-23871; doi:10.3390/ijms141223858
Received: 10 October 2013 / Revised: 14 November 2013 / Accepted: 15 November 2013 / Published: 6 December 2013
Cited by 6 | PDF Full-text (324 KB) | HTML Full-text | XML Full-text
Abstract
Sarcoidosis, a chronic granulomatous disease of unknown cause, has been linked to several environmental risk factors, among which are some that may favor carbon nanotube formation. Using gene array data, we initially observed that bronchoalveolar lavage (BAL) cells from sarcoidosis patients displayed elevated
[...] Read more.
Sarcoidosis, a chronic granulomatous disease of unknown cause, has been linked to several environmental risk factors, among which are some that may favor carbon nanotube formation. Using gene array data, we initially observed that bronchoalveolar lavage (BAL) cells from sarcoidosis patients displayed elevated mRNA of the transcription factor, Twist1, among many M1-associated genes compared to healthy controls. Based on this observation we hypothesized that Twist1 mRNA and protein expression might become elevated in alveolar macrophages from animals bearing granulomas induced by carbon nanotube instillation. To address this hypothesis, wild-type and macrophage-specific peroxisome proliferator-activated receptor gamma (PPARγ) knock out mice were given oropharyngeal instillation of multiwall carbon nanotubes (MWCNT). BAL cells obtained 60 days later exhibited significantly elevated Twist1 mRNA expression in granuloma-bearing wild-type or PPARγ knock out alveolar macrophages compared to sham controls. Overall, Twist1 expression levels in PPARγ knock out mice were higher than those of wild-type. Concurrently, BAL cells obtained from sarcoidosis patients and healthy controls validated gene array data: qPCR and protein analysis showed significantly elevated Twist1 in sarcoidosis compared to healthy controls. In vitro studies of alveolar macrophages from healthy controls indicated that Twist1 was inducible by classical (M1) macrophage activation stimuli (LPS, TNFα) but not by IL-4, an inducer of alternative (M2) macrophage activation. Findings suggest that Twist1 represents a PPARγ-sensitive alveolar macrophage M1 biomarker which is induced by inflammatory granulomatous disease in the MWCNT model and in human sarcoidosis. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
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Review

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Open AccessReview The Role of Autophagy as a Mechanism of Toxicity Induced by Multi-Walled Carbon Nanotubes in Human Lung Cells
Int. J. Mol. Sci. 2015, 16(1), 40-48; doi:10.3390/ijms16010040
Received: 14 October 2014 / Accepted: 15 December 2014 / Published: 23 December 2014
Cited by 2 | PDF Full-text (877 KB) | HTML Full-text | XML Full-text
Abstract
Carbon nanotubes (CNTs) are promising nanomaterials having unique physical and chemical properties, with applications in a variety of fields. In this review, we briefly summarize the intrinsic properties of highly purified multi-walled CNTs (MWCNTs, HTT2800) and their potential hazardous effects on intracellular and
[...] Read more.
Carbon nanotubes (CNTs) are promising nanomaterials having unique physical and chemical properties, with applications in a variety of fields. In this review, we briefly summarize the intrinsic properties of highly purified multi-walled CNTs (MWCNTs, HTT2800) and their potential hazardous effects on intracellular and extracellular pathways, which alter cellular signaling and impact major cell functions such as differentiation, reactive oxygen species (ROS) production, apoptosis, and autophagy. A recent study suggested that the induction of autophagy by CNTs causes nanotoxicity. Autophagy was recently recognized as a critical cell death pathway, and autophagosome accumulation has been found to be associated with exposure to CNTs. Although autophagy is considered as a cytoprotective process, it is often observed in association with cell death, and the relationship between autophagy and cell death remains unclear. Our recent study suggests that the levels of autophagy-related genes (LC3B) and autophagosome formation are clearly up-regulated, along with an increase in numbers of autophagosome vacuoles. This review highlights the importance of autophagy as an emerging mechanism of CNT toxicity. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
Open AccessReview Inhalation of Silver Nanomaterials—Seeing the Risks
Int. J. Mol. Sci. 2014, 15(12), 23936-23974; doi:10.3390/ijms151223936
Received: 15 October 2014 / Revised: 26 November 2014 / Accepted: 15 December 2014 / Published: 22 December 2014
Cited by 9 | PDF Full-text (4802 KB) | HTML Full-text | XML Full-text
Abstract
Demand for silver engineered nanomaterials (ENMs) is increasing rapidly in optoelectronic and in health and medical applications due to their antibacterial, thermal, electrical conductive, and other properties. The continued commercial up-scaling of ENM production and application needs to be accompanied by an understanding
[...] Read more.
Demand for silver engineered nanomaterials (ENMs) is increasing rapidly in optoelectronic and in health and medical applications due to their antibacterial, thermal, electrical conductive, and other properties. The continued commercial up-scaling of ENM production and application needs to be accompanied by an understanding of the occupational health, public safety and environmental implications of these materials. There have been numerous in vitro studies and some in vivo studies of ENM toxicity but their results are frequently inconclusive. Some of the variability between studies has arisen due to a lack of consistency between experimental models, since small differences between test materials can markedly alter their behaviour. In addition, the propensity for the physicochemistry of silver ENMs to alter, sometimes quite radically, depending on the environment they encounter, can profoundly alter their bioreactivity. Consequently, it is important to accurately characterise the materials before use, at the point of exposure and at the nanomaterial-tissue, or “nanobio”, interface, to be able to appreciate their environmental impact. This paper reviews current literature on the pulmonary effects of silver nanomaterials. We focus our review on describing whether, and by which mechanisms, the chemistry and structure of these materials can be linked to their bioreactivity in the respiratory system. In particular, the mechanisms by which the physicochemical properties (e.g., aggregation state, morphology and chemistry) of silver nanomaterials change in various biological milieu (i.e., relevant proteins, lipids and other molecules, and biofluids, such as lung surfactant) and affect subsequent interactions with and within cells will be discussed, in the context not only of what is measured but also of what can be visualized. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
Open AccessReview Lung Injury Induced by TiO2 Nanoparticles Depends on Their Structural Features: Size, Shape, Crystal Phases, and Surface Coating
Int. J. Mol. Sci. 2014, 15(12), 22258-22278; doi:10.3390/ijms151222258
Received: 20 September 2014 / Revised: 31 October 2014 / Accepted: 24 November 2014 / Published: 3 December 2014
Cited by 22 | PDF Full-text (728 KB) | HTML Full-text | XML Full-text
Abstract
With the rapid development of nanotechnology, a variety of engineered nanoparticles (NPs) are being produced. Nanotoxicology has become a hot topic in many fields, as researchers attempt to elucidate the potential adverse health effects of NPs. The biological activity of NPs strongly depends
[...] Read more.
With the rapid development of nanotechnology, a variety of engineered nanoparticles (NPs) are being produced. Nanotoxicology has become a hot topic in many fields, as researchers attempt to elucidate the potential adverse health effects of NPs. The biological activity of NPs strongly depends on physicochemical parameters but these are not routinely considered in toxicity screening, such as dose metrics. In this work, nanoscale titanium dioxide (TiO2), one of the most commonly produced and widely used NPs, is put forth as a representative. The correlation between the lung toxicity and pulmonary cell impairment related to TiO2 NPs and its unusual structural features, including size, shape, crystal phases, and surface coating, is reviewed in detail. The reactive oxygen species (ROS) production in pulmonary inflammation in response to the properties of TiO2 NPs is also briefly described. To fully understand the potential biological effects of NPs in toxicity screening, we highly recommend that the size, crystal phase, dispersion and agglomeration status, surface coating, and chemical composition should be most appropriately characterized. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
Open AccessReview Right or Left: The Role of Nanoparticles in Pulmonary Diseases
Int. J. Mol. Sci. 2014, 15(10), 17577-17600; doi:10.3390/ijms151017577
Received: 21 February 2014 / Revised: 25 August 2014 / Accepted: 25 August 2014 / Published: 29 September 2014
Cited by 6 | PDF Full-text (3462 KB) | HTML Full-text | XML Full-text
Abstract
Due to the rapid development of the nanotechnology industry in the last decade, nanoparticles (NPs) are omnipresent in our everyday life today. Many nanomaterials have been engineered for medical purposes. These purposes include therapy for pulmonary diseases. On other hand, people are endeavoring
[...] Read more.
Due to the rapid development of the nanotechnology industry in the last decade, nanoparticles (NPs) are omnipresent in our everyday life today. Many nanomaterials have been engineered for medical purposes. These purposes include therapy for pulmonary diseases. On other hand, people are endeavoring to develop nanomaterials for improvement or replacement of traditional therapies. On the other hand, nanoparticles, as foreign material in human bodies, are reported to have potential adverse effects on the lung, including oxidase stress, inflammation, fibrosis and genotoxicity. Further, these damages could induce pulmonary diseases and even injuries in other tissues. It seems that nanoparticles may exert two-sided effects. Toxic effects of nanomaterials should be considered when their use is developed for therapies. Hence this review will attempt to summarize the two-side roles of nanoparticles in both therapies for pulmonary diseases and initiation of lung diseases and even secondary diseases caused by lung injuries. Determinants of these effects such as physicochemical properties of nanoparticles will also be discussed. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
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Open AccessReview Nanoinformatics: Emerging Databases and Available Tools
Int. J. Mol. Sci. 2014, 15(5), 7158-7182; doi:10.3390/ijms15057158
Received: 17 February 2014 / Revised: 28 March 2014 / Accepted: 9 April 2014 / Published: 25 April 2014
Cited by 13 | PDF Full-text (851 KB) | HTML Full-text | XML Full-text
Abstract
Nanotechnology has arisen as a key player in the field of nanomedicine. Although the use of engineered nanoparticles is rapidly increasing, safety assessment is also important for the beneficial use of new nanomaterials. Considering that the experimental assessment of new nanomaterials is costly
[...] Read more.
Nanotechnology has arisen as a key player in the field of nanomedicine. Although the use of engineered nanoparticles is rapidly increasing, safety assessment is also important for the beneficial use of new nanomaterials. Considering that the experimental assessment of new nanomaterials is costly and laborious, in silico approaches hold promise. Several major challenges in nanotechnology indicate a need for nanoinformatics. New database initiatives such as ISA-TAB-Nano, caNanoLab, and Nanomaterial Registry will help in data sharing and developing data standards, and, as the amount of nanomaterials data grows, will provide a way to develop methods and tools specific to the nanolevel. In this review, we describe emerging databases and tools that should aid in the progress of nanotechnology research. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
Open AccessReview Nanoparticle-Mediated Pulmonary Drug Delivery: A Review
Int. J. Mol. Sci. 2014, 15(4), 5852-5873; doi:10.3390/ijms15045852
Received: 22 January 2014 / Revised: 28 March 2014 / Accepted: 28 March 2014 / Published: 8 April 2014
Cited by 42 | PDF Full-text (377 KB) | HTML Full-text | XML Full-text
Abstract
Colloidal drug delivery systems have been extensively investigated as drug carriers for the application of different drugs via different routes of administration. Systems, such as solid lipid nanoparticles, polymeric nanoparticles and liposomes, have been investigated for a long time for the treatment of
[...] Read more.
Colloidal drug delivery systems have been extensively investigated as drug carriers for the application of different drugs via different routes of administration. Systems, such as solid lipid nanoparticles, polymeric nanoparticles and liposomes, have been investigated for a long time for the treatment of various lung diseases. The pulmonary route, owing to a noninvasive method of drug administration, for both local and systemic delivery of an active pharmaceutical ingredient (API) forms an ideal environment for APIs acting on pulmonary diseases and disorders. Additionally, this route offers many advantages, such as a high surface area with rapid absorption due to high vascularization and circumvention of the first pass effect. Aerosolization or inhalation of colloidal systems is currently being extensively studied and has huge potential for targeted drug delivery in the treatment of various diseases. Furthermore, the surfactant-associated proteins present at the interface enhance the effect of these formulations by decreasing the surface tension and allowing the maximum effect. The most challenging part of developing a colloidal system for nebulization is to maintain the critical physicochemical parameters for successful inhalation. The following review focuses on the current status of different colloidal systems available for the treatment of various lung disorders along with their characterization. Additionally, different in vitro, ex vivo and in vivo cell models developed for the testing of these systems with studies involving cell culture analysis are also discussed. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)
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Open AccessReview Toxicological Assessment of Inhaled Nanoparticles: Role of in Vivo, ex Vivo, in Vitro, and in Silico Studies
Int. J. Mol. Sci. 2014, 15(3), 4795-4822; doi:10.3390/ijms15034795
Received: 3 December 2013 / Revised: 24 February 2014 / Accepted: 3 March 2014 / Published: 18 March 2014
Cited by 26 | PDF Full-text (1176 KB) | HTML Full-text | XML Full-text
Abstract
The alveolar epithelium of the lung is by far the most permeable epithelial barrier of the human body. The risk for adverse effects by inhaled nanoparticles (NPs) depends on their hazard (negative action on cells and organism) and on exposure (concentration in the
[...] Read more.
The alveolar epithelium of the lung is by far the most permeable epithelial barrier of the human body. The risk for adverse effects by inhaled nanoparticles (NPs) depends on their hazard (negative action on cells and organism) and on exposure (concentration in the inhaled air and pattern of deposition in the lung). With the development of advanced in vitro models, not only in vivo, but also cellular studies can be used for toxicological testing. Advanced in vitro studies use combinations of cells cultured in the air-liquid interface. These cultures are useful for particle uptake and mechanistic studies. Whole-body, nose-only, and lung-only exposures of animals could help to determine retention of NPs in the body. Both approaches also have their limitations; cellular studies cannot mimic the entire organism and data obtained by inhalation exposure of rodents have limitations due to differences in the respiratory system from that of humans. Simulation programs for lung deposition in humans could help to determine the relevance of the biological findings. Combination of biological data generated in different biological models and in silico modeling appears suitable for a realistic estimation of potential risks by inhalation exposure to NPs. Full article
(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)

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