Posts Tagged ‘lung’

Nanotechnology therapy for non-cancerous diseases

Posted in Academic Publishing, Clinical & Translational, Clinical Diagnostics, Curation, Innovations, Materials Science & Engineering, Medical Imaging Technology, Nuclear Medicine, Pharmaceutical Drug Discovery, Pharmacologic toxicities, tagged application in noncancer, lung, nanoparticles, toxicity on October 10, 2015| Leave a Comment »

Nanotechnology therapy for non-cancerous diseases

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Nanotechnology in respiratory medicine

Albert Joachim Omlor¹, Juliane Nguyen², Robert Bals³ and Quoc Thai Dinh¹³

Respiratory Research 2015, 16:64  http://dx.doi.org:/10.1186/s12931-015-0223-5

http://respiratory-research.com/content/16/1/64

Like two sides of the same coin, nanotechnology can be both boon and bane for respiratory medicine. Nanomaterials open new ways in diagnostics and treatment of lung diseases. Nanoparticle based drug delivery systems can help against diseases such as lung cancer, tuberculosis, and pulmonary fibrosis. Moreover, nanoparticles can be loaded with DNA and act as vectors for gene therapy in diseases like cystic fibrosis. Even lung diagnostics with computer tomography (CT) or magnetic resonance imaging (MRI) profits from new nanoparticle based contrast agents. However, the risks of nanotechnology also have to be taken into consideration as engineered nanomaterials resemble natural fine dusts and fibers, which are known to be harmful for the respiratory system in many cases. Recent studies have shown that nanoparticles in the respiratory tract can influence the immune system, can create oxidative stress and even cause genotoxicity. Another important aspect to assess the safety of nanotechnology based products is the absorption of nanoparticles. It was demonstrated that the amount of pulmonary nanoparticle uptake not only depends on physical and chemical nanoparticle characteristics but also on the health status of the organism. The huge diversity in nanotechnology could revolutionize medicine but makes safety assessment a challenging task.

Keywords: Nanoparticles; Lung; Airways; Nanotoxicology; Biodistribution; Nanomedicine

Over the past years nanomaterials have found their way into more and more areas of life. Examples are new coatings and pigments, electronic devices as well as cosmetic products like sunscreens and toothpastes. On top of that, much effort is done to adopt nanotechnology for the treatment of human diseases. The term “Nano” refers to structures in the range of 1 to 100 nm. In contrast to nanoparticles, which have to measure between 1 and 100 nm in all dimensions, nanomaterials may consist of elements bigger than 100 nm but need to be structured in the nanoscale and exhibit characteristic features associated with their nanostructure [1]. In this context, the International Organization for Standardization defined the term nano-object as a material with one, two or three external dimensions in the nanoscale [2] (Fig. 1). Nanomaterials have an extremely high surface area to volume ratio. Therefore, some of them are very reactive or catalytically active. Moreover, in the nanoworld quantum effects become visible and lead to some of the unique properties of nanoparticles. Like viruses and cellular structures, some nanoparticles are able to self-assemble to more complex structures [3]. This makes them interesting candidates for novel drugs. On the other hand it is necessary to redefine toxicology because of nanotechnology. Unlike classical toxicology, where dose and composition matter, in nanotoxicology the focus has to be set on properties like morphology, size, size distribution, surface charge, and agglomeration state as well. Nanotechnology is important for respiratory medicine for several reasons. Firstly, it offers new approaches to treat diseases of the respiratory tract. However, as nanotechnology usage in consumer products, cosmetics, and medicine is continuously increasing, it is also pivotal to understand potentially adverse effects of nanomaterials on the respiratory system. Additionally, studying respiratory effects of manufactured nanomaterials helps to understand the impact of combustion exhaust and ultra-fine dusts on human health. On top of that, the lung is probably the most important gateway of nanoparticles to the human organism. For the assessment of safety in nanotechnology it is therefore also important to elucidate which nanoparticle properties determine pulmonary resorption and biodistribution (Fig. 2).

Fig. 1. Nano-Objects can be divided into nanoparticles, nanofibres and nanoplates depending on the number of external dimensions in the nanoscale

Nano-Objects can be divided into nanoparticles, nanofibres and nanoplates

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Fig. 2. The increasing use of nanotechnology affects respiratory medicine in three main areas. Firstly, nanotechnology enables more sophisticated options in therapy and diagnostics. Secondly, the use of nanomaterials can cause toxic effects in the respiratory system. Health risks associated with the use of nanomaterials are not fully understood and merit further investigation. Moreover, it will be essential to understand the effects of inhaled nanoparticles on extrapulmonary organs

nanotechnology affects respiratory medicine in three main areas

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Applications of nanotechnology in therapeutics and diagnostics

Although clinical application of nanotechnology in therapeutics and diagnostics is still rare, there are multiple promising candidates for future use in the field of respiratory medicine.

Drug delivery

Nanoparticles can act as vessels for drugs because they are small enough to reach almost any region of the human organism. Drugs can be bound chemically to the nanoparticles by a multitude of different linker molecules or by encapsulation. This allows better control of toxicokinetics. However, the main advantage is the capability of targeted drug delivery. The targeting can be active or passive. In case of tumor diseases, the leaky and immature vasculature of fast growing tumors can be taken advantage of in order to achieve passive targeting of chemotherapeutic loaded nanoparticles. This is called the enhanced permeability and retention (EPR) effect [4]. The first generation nano drug delivery systems rely entirely on the EPR effect. One example is Genoxol-PM, a polymeric paclitaxel loaded poly(lactic acid)-block-poly(ethylene glycol) micelle-formulation [5]. This nanocarrier has recently been tested in a phase II trial in patients with advanced non-small cell lung cancer (NSCLC). 43 patients were treated with four 3-week cycles of Genexol-PM at 230 mg/m² on day 1 combined with gemcitabine 1000 mg/m² on day 1 and day 8. With a response rate of 46.5 %, the therapy showed favorable antitumor activity. Moreover, emetogenicity was low. However, frequent grade 3/4 adverse events like neutropenia and pneumonia were observed [6]. The second generation nanoparticle drug delivery systems possess targeting ligands. These can be antibodies, aptamers, small molecules and proteins (Fig. 3). The attached ligands actively guide the nanoparticles and therefore the drugs to the tumor cells. Tumor specific monoclonal antibodies are already widely used in cancer therapy. Those antibodies can be attached to nanoparticles for active targeting. In a recent study polyglycolic acid nanoparticles, that were conjugated with cetuximab antibodies for targeting and loaded with the drug paclitaxel palmitate, were administered intravenously to mice with A549-luc-C8 lung tumors. The survival rate of these mice increased significantly compared to the control group [7]. Another approach involves aptamers as targeting agents. Aptamers are synthetic oligonucleotides that are capable of binding specific target structures. Their small size, their simple synthesis, and their lack of immunogenicity make them promising ligands for nanoparticles. Moreover, small molecules such as folate can be used for targeting tumor cells that express a high density of folate receptors. In addition, tumors often overexpress receptors for several proteins. Proteins like transferrin therefore are common targeting ligands [8]. These second generation nanocarriers are already used clinically against lung cancer with substances like Aurimmune Cyt-6091 and Bind-014. Aurimmune Cyt-6091 is a drug delivery system based on gold nanoparticles functionalized with polyethylene glycol (PEG) and tumor necrosis factor alpha (TNF-α). It has been used against adenocarcinoma of the lung in a phase I clinical trial. The TNF-α serves both as targeting and therapeutic agent in this case [9]. A phase II clinical trial for non-small cell lung cancer patients has been planned [10]. The nano drug delivery system Bind-014 is currently tested in a phase II clinical trial as second-line therapy for patients with non-small cell lung cancer [11]. Bind-014 nanoparticles consist of a polylactic acid (PLA) core, in which the anti-tumor drug docetaxel is physically entrapped. The particles are surface-decorated with PEG to reduce elimination from the immune system and contain ligands against prostate-specific membrane antigen (PSMA) for targeting. PSMA is expressed in prostate cancer cells and in the neovasculature of nonprostate solid tumors, such as NSCLC [12]. Preliminary data demonstrates, that Bind-014 is clinically active and well tolerated. It also showed promising effects on patients with KRAS mutations, where ordinary anti-tumor agents usually fail. Additionally, adverse effects like anemia, neutropenia and neuropathy were significantly reduced compared to solvent based docetaxel [13].

Four different strategies for active targeting of nanoparticle based drug delivery systems

Fig. 3. Four different strategies for active targeting of nanoparticle based drug delivery systems are shown. The nanoparticles can be conjugated with tumor specific antibodies or aptamers. Additionally, small molecules, such as folate, as well as proteins, such as transferrin, can be used for targeting receptors that are overexpressed on tumors

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Nanoparticle based drug delivery also offers potential in other fields of respiratory medicine. In experiments with tuberculosis infected guinea pigs, it was demonstrated that inhaled alginate nanoparticles encapsulating isoniazid, rifampicin, and pyrazinamide showed better bioavailability and higher efficiency than oral drug medication [14]. Similar results were presented by Pandey et al. with the three antitubercular drugs encapsulated in poly (DL-lactide-co-glycolide) nanoparticles[15]. Moreover, another study demonstrated that pirfenidone loaded nanoparticles have higher anti-fibrotic efficacy in the treatment of mice with bleomycin-induced pulmonary fibrosis than dissolved pirfenidone [16].

Hyperthermia

Nanoparticle induced hyperthermia can be used to locally destroy tumor cells. Heat generation is usually achieved by two approaches, magnetic and photothermal hyperthermia. In magnetic hyperthermia, an extracorporeal coil creates an alternating magnetic field that heats magnetic nanoparticles inside a tumor. This increases the temperature in the tumor without affecting healthy tissue. A recent study assessed the effect of inhalable superparamagnetic iron oxide nanoparticles in a mouse model of NSCLC. Compared to the non-targeted nanoparticles, the epidermal growth factor receptor (EGFR) targeted nanoparticles showed significantly more effective tumor shrinkage after magnetic hyperthermia treatment [17]. The other approach, photothermal therapy uses laser radiation in the visible or near infrared spectrum and photosensitizing nanoparticles such as gold or graphene. A commercial product called auroshell is available for tumor therapy. Auroshell nanoparticles consist of a silica core surrounded by a thin layer of gold. The gold nanoshells are administered intravenously and accumulate in the tumor due to the EPR effect. Upon exposure of the tumor to a near infrared laser, the laser energy is efficiently converted to heat by the gold nanoshells [18]. This therapy, which is called AuroLase, is currently undergoing clinical trial in patients with primary and/or metastatic lung tumors [19] (Fig. 4).

Two different approaches of nanoparticle based hyperthermia therapy

Fig. 4. Two different approaches of nanoparticle based hyperthermia therapy are shown. a In magnetic hyperthermia, magnetic nanoparticles (MNP) are applied intravenously and accumulate inside the tumor. When an oscillating magnetic field is created by an extracorporeal coil the magnetic nanoparticles produce heat inside the tumor. b In photothermal hyperthermia, gold nanoshells (GNS) or similar photosensitizing nanoparticles are applied intravenously and accumulate inside the tumor. Upon exposure of the tumor to near infrared (NIR) laser radiation, the gold nanoshells convert the laser light into heat

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Gene therapy

Like viruses, nanoparticles can be used as vectors for genes. But in contrast to viruses, they are less immunogenic and have higher DNA transport capacity. In a study, DNA loaded polyethylenimine nanoparticles were used in order to treat lipopolysaccharide induced acute lung injury in mice. After intravenous injection of the nanoparticles, the beta2-Adrenic Receptor genes in the nanoparticles led to a short lived transgene expression in alveolar epithelia cells. As a result the 5-day survival rate improved from 28 % to 64 %. The severity of the symptoms measured by alveolar fluid clearance, lung water content, histopathology, bronchioalveolar lavage cellularity, protein concentration, and inflammatory cytokines was also significantly attenuated [20]. DNA loaded nanoparticles are also promising candidates in the treatment of cystic fibrosis. It was shown in a clinical trial that nasal application of DNA nanoparticles is safe and evidently leads to vector gene transfer [21]. One major problem in this context is to overcome the mucus barrier. In a recent study, it was demonstrated that densely PEG-coated DNA nanoparticles can rapidly penetrate extracorporeal human cystic fibrosis and extracorporeal mouse airway mucus. In addition, those particles exhibited better gene transfer after intranasal administration to mice than conventional carriers [22].

Diagnostics

Nanoparticles have the potential to improve pulmonary x-ray diagnostics. Folic acid-modified dendrimer-entrapped gold nanoparticles were utilized as imaging probes for targeted CT imaging. In in-vitro and in-vivo tests, the nanoparticles were trapped in the lysosomes of folic acid receptor expressing lung adenocarcinoma cells (SPC-A1). It was possible to detect the tumor cells by micro-CT imaging after nanoparticle uptake. In addition, it was also shown that the particles possess good biocompatibility, with no impact on cell morphology, viability, cell cycle, and apoptosis [23]. Nanoparticles can also be used to enhance MR diagnostics of lung tissue. In experiments with intratracheal administration of Gadolinium-DOTA nanoparticles in mice, signal enhancements in several organs including the lung were measured with ultrashort-echo-time-proton-MRI. The signal change over time in the different organs demonstrated the passage of the nanoparticles from the lung to the blood, then to the kidneys, and finally to the bladder [24].

Toxicological aspects of nanomaterials

Toxic effects of nanoparticles are a major concern in pulmonary medicine. Especially ultrafine particles of low soluble, low toxic materials like titanium dioxide, carbon black, and polystyrene are overall more toxic and inflammatory than fine particles of the same material. This applies to both synthesized nanoparticles and natural dusts [25]. For nano related toxicity multiple mechanisms seem to be important. In the following, the interaction with the immune system, the creation of oxidative stress, and toxic effects on the genome are taken a closer look at. In order to correlate toxic effects with nanoparticle properties, it is necessary to thoroughly characterize the selected nanoparticles prior to administration.

Nanoparticle characterization

The most commonly used methods to characterize nanoparticles for toxicology studies are transmission electron microscopy (TEM) for size, morphology, and agglomeration, dynamic light scattering (DLS) for the size distribution of the particles, zeta potential measurement for nanoparticle surface charge, and x-ray diffraction (XRD) for the particles’ crystal structure. In some cases such as gold and silver nanoparticles, UV-vis spectroscopy can be used to determine size and size distribution due to a special size dependent optical activity [26]. Ideally, nanoparticle characterization is repeated after administration as changes of the nanoparticles during the application process are possible. In in-vitro experiments, nanoparticles are usually applied by mixing with cell culture medium. The dissolved components of the medium, especially the ions, lead to agglomeration and precipitation of many nanoparticles, causing significant changes in their physicochemical properties. Similar effects are to be expected when nanoparticles come into contact with surfactant or other biological fluids. It was shown, that some nanoparticles tend to form protein coronae in biological systems [27].

Effects on immune system and inflammation

Many nanoparticles possess properties that give them the potential to influence the immune system. In this context, nanoparticles’ ability to penetrate cellular boundaries, to escape phagocytation by macrophages, to act as haptens, and even to disturb the Th1/Th2 balance might be essential [28]. For carbon black nanoparticles, a recent study investigated the effects of inhalative exposure on mice with bleomycin-induced pulmonary fibrosis. The analysis of histology as well as cytokine expression suggested that the nanoparticles triggered an inhalation exacerbated lung inflammation. The author concluded that especially for people with pulmonary preconditions inhalation of nanoparticles can lead to serious health problems [29]. In this context, another study found out that PEGylated cationic shell-cross-linked knedel-like (cSCK) nanoparticles produced significantly less airway inflammation than non-PEGylated ones. This was explained by a change in endocytosis. In contrast to the clathrin-dependent endocytosis of non-PEGylated particles, the PEGylated cSCK nanoparticles showed a clathrin-independent route [30]. On the other hand, some nanomaterials exhibit impressive immune modulating activity. As an example, [Gd@C₈₂(OH)₂₂]_n, a fullerene derivate with a gadolinium atom inside showed anticancer activity without being cytotoxic (Fig. 5). In vitro studies demonstrated that [Gd@C₈₂(OH)₂₂]_n activated dendritic cells (DCs) and even induced phenotypic maturation of those cells. Moreover, the [Gd@C₈₂(OH)₂₂]_n treated DCs also stimulated allogenic T cells in a Th1 characteristic. The effect of [Gd@C₈₂(OH)₂₂]_n was comparable, probably even stronger than the effect of lipopolysaccharide (LPS) on DCs. The study also verified that the nanoparticles were free of LPS contamination. In-vivo experiments on ovalbumin (OVA) immunized mice showed enhanced immune responses comparable to the adjuvant effect of Alum on OVA mice. However, whereas Alum lead to a Th2 response pattern with IL-4, IL-5 and IL-10 upregulation, [Gd@C₈₂(OH)₂₂]_n caused a Th1 pattern with upregulation of IFNγ [31]. Similar results were demonstrated in another study using a murine asthma model. OVA sensitized mice that were additionally treated with the nanomaterial graphene oxide during allergen sensitization had stronger airway remodeling and hyperresponsiveness than mice that have only been treated with OVA. The graphene oxide lead to a downregulation of Th2 dependent markers such as IL-4, IL-5, IL-13 IgE and IgG1 but increased Th1-associated IgG2a. Moreover, the graphene oxide increased the macrophage production of mammalian chinitases, chitinase-3-like protein 1 (CHI3L1), and AMCase, which could be the reason for the overall augmentation in airway remodeling and hyperresponsiveness [32]. However, this kind of immune modulation can also be utilized for therapeutic purposes. In a recent study a nanoparticle-based vaccine has been used to treat dust mite allergies in mice. The immune-modulating carriers were generated by loading dust mite allergen Der p2 and the potent Th1 adjuvant unmethylated cytosine-phosphate-guanine (CpG) into biodegradable poly(lactic-co-glycolic acid) (PLGA) polymer particles. Mice treated with those nanoparticles showed significantly lower airway hyperresponsiveness as well as lower IgE antibody levels after a 10 day intranasal Der p2 instillation compared to the control group. The authors conclude that this biodegradable nanoparticle-based vaccination strategy has significant potential for treating HDM allergies [33].

Gd@C82(OH)22 consists of a gadolinium atom (green) inside a 2 nm cage of carbon atoms (grey)

Fig. 5. Gd@C₈₂(OH)₂₂ consists of a gadolinium atom (green) inside a 2 nm cage of carbon atoms (grey). The hydroxyl groups (red) outside the cage are responsible for water solubility. In water the molecule forms aggregates [Gd@C₈₂(OH)₂₂]_n with average size of 25 nm

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Oxidative stress and catalysis

Oxidative stress is often brought in context with nanotoxicology. It can be measured directly with dichlorofluorecein or indirectly by the upregulation of reactive oxygen species (ROS) eliminating enzymes like superoxide dismutase [34]. Another approach involves tests whether the nanoparticle dependent toxicity can be reduced by the application of an antioxidant. Widely used semiconductor materials such as lead sulfide nanoparticles may have the potential to generate oxidative stress in the lung. A recent study tested the toxicity of intratracheally applied 30 nm and 60 nm lead sulfide nanoparticles on rats. Oxidative damage was evaluated based on superoxide dismutase, total antioxidant capacity, and concentration of malondialdehyde. In addition to inflammatory responses, both 30 nm and 60 nm groups showed increased oxidative damage compared to control groups. The effect was significantly stronger for the 30 nm lead sulfide compared to the 60 nm nanoparticles [35]. Another nanomaterial which is associated with oxidative stress is nanosized titanium dioxide. Li et al. induced pulmonary injury in mice by daily intranasal instillation of suspended 294 nm TiO₂ nanoparticles for 90 days, demonstrating that the rate of reactive oxygen species (ROS) generation increased with increasing TiO₂ doses. Moreover lipid, protein and DNA peroxidation products were identified in elevated doses, which suggests that ROS dependent lung damage was significant in the nanoparticle treated animals [36]. Furthermore, in vitro tests on BEAS-2B and A549 lung cell lines demonstrated that the commonly used nanoparticles ZnO and Fe₂O₃ are very different in terms of creating oxidative stress. The Fe₂O₃nanoparticles with an average diameter of 39 nm were distributed in the cytoplasm, whereas the 63 nm ZnO nanoparticles were trapped in organelles such as the endosome. In contrast to the Fe₂O₃ nanoparticles the ZnO nanoparticles caused reactive oxygen species production as well as cell cycle arrest, cell apoptosis, mitochondrial dysfunction and glucose metabolism perturbation[37] (Table 1).

Table 1. Oxidative stress induction in respiratory tissue by different nanoparticles

Genotoxicity

Another important type of toxicity caused by nanoparticles is genotoxicity. A common method to quantify genotoxicity is the comet assay, which uses electrophoresis to detect DNA strand breaks. This assay was used in a recent study to check whether intratracheal instilled fullerene C₆₀nanoparticles induced DNA damage in male rats. However, despite inflammatory responses and hemorrhages in the alveoli of the C₆₀ treated rats, there was no significant increase in fractured DNA in their lung cells. Therefore, it was concluded that even at inflammation inducing doses, fullerene C₆₀ nanoparticles have no potential for DNA damage in the lung cells of rats [38]. Similarly, another study demonstrated that intratracheal instillation of anatase TiO₂ nanoparticles on rats did not result in genotoxicity. None of the TiO₂ groups showed an increase in fractured DNA while the positive control with ethyl methanesulfonate exhibited significant increases [39]. In contrast to those results, Kyjovska ZO et al. found that even in low doses, where no inflammation occurs, Printex 90 carbon black nanoparticles induce genotoxicity in mice. There was no inflammation, cell damage and acute phase response, which means that the increased DNA strand breaks are related to direct DNA damage caused by the nanoparticles [40]. On the other hand, a recent study suggests that CeO₂ nanoparticles may be even used as antioxidant and anti-genotoxic agents in the lung. After treatment with the oxidative stress-inducing agent KBrO₃, BEAS-2B cells pretreated with the CeO₂ nanoparticles showed significantly less intracellular ROS as well as a reduction in DNA damage compared to non-pretreated cells [41].

Biodistribution

Nanoparticle detection

Research on the biodistribution of nanoparticles requires tracking of the applied nanoparticles in the test animal. Conventional light microscopy is not able to detect nanoparticles because of Abbe’s law. Therefore, electron microscopic imaging is often required. However, light microscopy can be used to describe the nanoparticle induced changes in the cell morphology without being able to see the nanoparticles themselves. Additionally, nanoparticles can be indirectly made detectable in light microscopy by a method called autometallography. This is a silver staining that can be used to increase the size of several types of nanoparticles like gold, silver, and some metal sulfides and selenides in the histological section [42]. This technique was used to detect silver nanoparticles in the olfactory bulb and lateral brain ventricles of mice that had been intranasally treated with 25 nm silver nanoparticles [43].

Particle deposition and resorption in the respiratory tract

Most research about biodistribution of nanoparticles in organisms focuses on intravenous injection. However, nanoparticles were shown to be able to pass the blood air barrier of the lung. Whether or not nanoparticles can travel through the lung into the body seems to be size dependent. This was evaluated by injecting neutron activated radioactive gold nanoparticles of 1.4 nm and 18 nm intratracheally to rats. The bigger nanoparticles almost completely retained in the lung while significant amounts of the smaller 1.4 nm particles were found in blood, liver, skin and carcass 24 h after instillation [44]. Choi H. S. et al. applied nanoparticles of different size and charge to mice. The nanoparticles were tracked in different organs through fluorescence labeling. It was demonstrated that nanoparticles rapidly translocated to the mediastinal lymph nodes if they possess a hydrodynamic diameter of 34 nm or less and a neutral or anionic surface. Bigger and positively charged nanoparticles exhibited no significant uptake [45] (Fig. 6). In addition to physical parameters of the applied nanoparticles the health status of the exposed organism also seems to play an important role. A recent study showed that the distribution of oropharyngeal instilled 40 nm gold nanoparticles is influenced by additional LPS treatment. The gold content of organs was measured with inductively coupled plasma mass spectroscopy. BALB/C mice that had been oropharyngeal treated with LPS 24 h prior to the nanoparticle administration exhibited less gold content in their lungs than untreated mice. In both groups gold was detected in different organs. High concentrations were found in heart and thymus in the non LPS group, while the LPS treated mice accumulated most of the gold in the spleen. The author concluded that nanoparticle uptake may depend on medical preconditions [46].

Fig. 6. Pulmonary uptake of nanoparticles depends on size and surface charge. Positively charged nanoparticles and nanoparticles that are bigger than 34 nm cannot pass the epithelial barrier of the lung. Only small and not positively charged nanoparticles can translocate from the lung over blood and lymph system to the organism

Pulmonary uptake of nanoparticles depends on size and surface charge

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Conclusions

Over the last decade, major breakthroughs in nanotechnology have been achieved. It is only a matter of time before new nano based drugs reach respiratory medicine. Especially the fields of targeted drug delivery, gene therapy, and hyperthermia offer great potential for modern drugs. On the other hand the increased use of nanomaterials in all fields of life also bears the risk of exposure through inhalation. It is therefore essential to understand pulmonary toxicology of nanomaterials in all its facets. However, it is still very unclear why the toxic effects of nanoparticles in the respiratory tract are so inhomogeneous and not well predictable. In this context, not only local reactions of lung and airways but also nanoparticle uptake and distribution in the organism are important factors and therefore fields of current research. As only few nanoparticle compositions have been tested, it is questionable whether those results can be easily adapted to other nanoparticles. Because of the continuously increasing diversity of engineered nanoparticles, toxicology can hardly keep pace with the safety assessment of future products. Therefore, more attention should be set on this wide field of research.

Abbreviations

CHI3L1: Chitinase-3-like protein 1

cSCK: Cationic shell-cross-linked knedel-like

CT: Computer tompgraphy

DC: Dendritic cell

DLS: Dynamic light scattering

EGFR: Epidermal growth factor receptor

EPR: Enhanced permeability and retention

LPS: Lipopolysaccharide

MRI: Magnetic resonance imaging

NSCLC: Non-small-cell lung carcinoma

OVA: Ovalbumin

PEG: Polyethylene glycol

PLA: Polylactic acid

PLGA: Poly(lactic-co-glycolic acid)

PSMA: Prostate-specific membrane antigen

ROS: Reactive oxygen species

TEM: Transmission electron microscopy

TNF-α: Tumor necrosis factor alpha

XRD: X-ray diffraction

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Pulmonary applications and toxicity of engineered nanoparticles.

Card JW¹, Zeldin DC, Bonner JC, Nestmann ER.

Am J Physiol Lung Cell Mol Physiol. 2008 Sep;295(3):L400-11.
http://dx.doi.org:/10.1152/ajplung.00041.2008

Because of their unique physicochemical properties, engineered nanoparticles have the potential to significantly impact respiratory research and medicine by means of improving imaging capability and drug delivery, among other applications. These same properties, however, present potential safety concerns, and there is accumulating evidence to suggest that nanoparticles may exert adverse effects on pulmonary structure and function. The respiratory system is susceptible to injury resulting from inhalation of gases, aerosols, and particles, and also from systemic delivery of drugs, chemicals, and other compounds to the lungs via direct cardiac output to the pulmonary arteries. As such, it is a prime target for the possible toxic effects of engineered nanoparticles. The purpose of this article is to provide an overview of the potential usefulness of nanoparticles and nanotechnology in respiratory research and medicine and to highlight important issues and recent data pertaining to nanoparticle-related pulmonary toxicity.

PMID:

18641236

[PubMed – indexed for MEDLINE]

PMCID:

PMC2536798

Free PMC Article

The possibility of nanotechnology dramatically improving the health and quality of life of people throughout the world holds great promise. Predictions of beneficial effects of nanotechnology in numerous industrial, consumer, and medical applications have been promising. By no means an exhaustive list, these applications include those that may lead to more efficient water purification, stronger and lighter building materials, increased computing power and speed, improved generation and conservation of energy, and new tools for the diagnosis and treatment of disease. The optimistic outlook for a future improved by nanotechnology must be tempered, however, by the realization that relatively little is known about the potential adverse effects of nanomaterials on human health and the environment.

The definition of a nanoparticle is generally considered to be a particle with at least one dimension of 100 nm or less. As a result of their small size and unique physicochemical properties, the toxicological profiles of nanoparticles may differ considerably from those of larger particles composed of the same materials (15, 98). Furthermore, nanoparticles of different materials (e.g., gold, silica, titanium, carbon nanotubes, quantum dots) are not expected to interact with and affect biological systems in a similar fashion. As a result, it seems unlikely that the toxic potential and/or mechanisms of nanoparticles can be predicted or explained by any single unifying concept.

The respiratory system represents a unique target for the potential toxicity of nanoparticles due to the fact that in addition to being the portal of entry for inhaled particles, it also receives the entire cardiac output. As such, there is potential for exposure of the lungs to nanoparticles that are introduced to the body via the act of breathing and by any other exposure route that may result in systemic distribution, including dermal and gastrointestinal absorption and direct injection. Interest in the respiratory system as a target for the potential effects, both beneficial and adverse, of nanoparticles is reflected by the steady increase in the number of scientific publications on these subjects during the past decade (Fig. 1).

publications related to the pulmonary toxicity and applications of engineered nanoparticles

Fig. 1.

Scientific publications related to the pulmonary toxicity and applications of engineered nanoparticles. The number of articles published in each of the past 10 years was identified by searching the PubMed database

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2536798/bin/zh50090852750001.jpg

he purpose of this article is to complement and expand on previous reviews of the pulmonary effects of nanoparticles (11, 14, 34, 35) by providing an overview of potential applications of nanotechnology in pulmonary research and in diagnosis and treatment of disease. In addition, recent advances regarding the potential pulmonary toxicity of nanoparticles as assessed in human, experimental animal, and in vitro studies are discussed. For the purposes of this article, only intentionally engineered nanoparticles are considered; unintentionally generated (e.g., via combustion engines, grilling, welding) and naturally occurring nanoparticles (e.g., via forest fires or volcanic eruptions) are not included in this discussion.

NANOPARTICLES AND THE LUNG

There are myriad nanoparticles to which the respiratory system may be exposed.

There is the potential for the respiratory system to be exposed to a seemingly countless number of unique nanoparticles, essentially none of which has been sufficiently examined for potential toxicity at this time. A substantial number of nanoparticles are already present in the marketplace in consumer products such as sunscreens, cosmetics, and car wax, and many more are sure to follow (a comprehensive list is maintained and updated by the Project on Emerging Nanotechnologies at the Woodrow Wilson International Center for Scholars: http://www.wilsoncenter.org/nano). Although the toxicity of the majority of nanoparticles may prove to be minimal, the fact that there is any potential for adverse effects to result from exposure suggests that prudence is warranted.

Various types of nanoparticles exist including those that are carbon-based (e.g., nanotubes, nanowires, fullerenes) and metal-based (e.g., gold, silver, quantum dots, metal oxides such as titanium dioxide and zinc oxide) and those that are arguably more biological in nature (e.g., liposomes and viruses designed for gene or drug delivery). To demonstrate the complexity of the situation, it is worthwhile to consider the case of carbon nanotubes as an example. Carbon nanotubes can be: 1) produced and/or cleaned using one of several different methods; 2) produced using one of several different metal catalysts; 3) single- or multi-walled; 4) of various lengths; and 5) subjected to numerous surface modifications. The result of these permutations is that a vast number of unique carbon nanotubes can be derived, all of which fall under one broad category, namely the carbon nanotube. Dividing these into single-walled and multi-walled forms reduces the ambiguity only so much, and we are still left with potentially thousands of each type. Furthermore, as has been demonstrated in recent in vitro experiments (37), the potential for nanotube agglomeration or for adhesion of nanotubes to biological molecules and the resultant alteration of their reactivity must be considered. Needless to say, the variations in nanoparticle form and functionality, not only for carbon nanotubes but also for nanoparticles in general, present significant challenges in the assessment of their potential usefulness and toxicity.

Nanoparticle accumulation within the lung.

Nanoparticles may reach the lung via inhalation or systemic delivery and do so by incidental/accidental or intentional means. Intentional pulmonary administration is being examined as a means of nanoparticle delivery for imaging and therapeutic purposes and is discussed separately below. Incidental or accidental inhalation exposure to nanoparticles can be envisioned most likely to occur as a result of exposure to occupational aerosols during the production or packaging of nanoparticles or nanostructured materials (89). In addition to pulmonary effects resulting from such exposures, translocation and subsequent systemic exposure and accumulation are also possible and are being investigated. It should be noted that nanoparticles naturally tend to agglomerate into larger particles that can be microns in size, thereby reducing the likelihood of free nanoparticles being respired. However, surface modifications designed to limit particle-particle interactions and protein binding may reduce the tendency for nanoparticle agglomeration and increase the potential for inhalation and deposition within the lungs (131).

Incidental pulmonary exposure as a result of systemic delivery is likely inherent for any nanoparticle that is injected or that might be absorbed following dermal application or ingestion. Although no published human data pertaining to pulmonary accumulation of nanoparticles following systemic exposure were identified, several animal studies have demonstrated pulmonary accumulation of nanoparticles (or of drug-conjugated nanoparticles) by means of determining their quantity in total lung homogenate preparations following their ingestion or intravenous or subcutaneous injection (43, 71, 109, 138, 142, 155). None of these studies investigated whether systemically administered nanoparticles traversed the blood-air barrier to gain access to the interstitium or lung epithelium; however, this is not necessarily a requirement for beneficial (or detrimental) effects to ensue. Although the levels and duration of accumulation appear to vary for the different nanoparticles examined, these data highlight the potential for exposure of the lungs to nanoparticles via the systemic route.

PULMONARY APPLICATIONS OF NANOPARTICLES

Imaging and diagnostic applications.

Many improvements in imaging capabilities that will benefit basic and clinical pulmonary research and disease diagnosis can be envisioned through the application of nanotechnology. Advances that include the delivery of nanoparticle imaging agents to specific cells or tissues of interest, the development of nanoprobes for molecular imaging of disease pathways, and the development of better contrast agents are forthcoming (21, 22, 115). Quantum dots are one type of nanoparticle that is proving to be particularly useful for imaging and diagnostic purposes. These semiconductor nanocrystals have broad absorption spectra and narrow emission spectra, and as their fluorescence is dependent on their chemical composition and size, multiple quantum dots (each with a unique color emission) can be detected simultaneously. Moreover, their relatively large surface area provides the opportunity for attachment of peptides or antibodies that precisely target cell types or tissues for imaging, thereby increasing specificity and decreasing background. In this regard, Akerman et al. (2) demonstrated that quantum dots coated with a peptide that binds to membrane dipeptidase on pulmonary endothelial cells were detected in the lung but not in brain or kidney 5 min after intravenous administration in BALB/c mice. Furthermore, in a study using quantum dots conjugated to monoclonal antibodies, rapid and specific detection of respiratory syncytial virus infection was demonstrated in vitro and in the lungs of BALB/c mice in vivo (137). Quantum dots have also been used to study tumor cell extravasation into lung tissue in C57BL/6 mice (140), highlighting the utility of these nanoparticles in the study of tumor metastasis.

Other nanoprobes for pulmonary imaging and diagnostics are also being examined experimentally. A recent study by le Masne de Chermont et al. (78) demonstrated that inorganic luminescent nanoparticles can be optically excited before injection into mice to provide long-lasting imaging of the lung. This was particularly evident for the positively charged nanoparticles that were studied, as noninvasive external detection revealed significant pulmonary accumulation of these nanoparticles up to 1 h following intravenous injection (78).

Therapeutic applications.

The potential therapeutic applications of nanoparticles in respiratory and systemic diseases are numerous (20, 21, 112,115, 133). A considerable thrust of recent research has been focused on determining the suitability of nanoparticles of various types to serve as vectors for the pulmonary delivery of drugs or genes via inhalation or systemic administration, whereas other efforts have been directed toward developing and delivering nano-sized drug particles to the lung (Table 1). The majority of the studies reported to date have focused on the utility of these strategies for the treatment of pulmonary infection. As an example, gene transfer using intranasal administration of chitosan-DNA nanospheres was shown to prophylactically inhibit respiratory syncytial virus infection and to reduce allergic airway inflammation in mice when given prophylactically or therapeutically (74, 75). Moreover, nanoparticle-mediated intranasal delivery of short interfering RNA (siRNA) targeted against a specific viral gene, NS1, has also been shown to inhibit respiratory syncytial virus infection in mice and rats (72, 161).

Table 1.

The usefulness of nano-sized drug particles as treatment modalities in models of pulmonary infection has also been investigated. Inhalation of aerosolized nano-sized itraconazole resulted in significantly higher lung concentrations in mice than did oral administration (138) and was found to prophylactically inhibit invasive pulmonary aspergillosis and reduce infection-related deaths in mice, whereas oral drug administration did not (4, 59). In addition, Pandey et al. (110) demonstrated that a single inhalation of aerosolized poly (DL-lactide-co-glycolide) nanoparticles loaded with antitubercular drugs (isoniazid, rifampicin, or pyrazinamide) resulted in therapeutic plasma drug levels for up to 6 days in guinea pigs and found that repeated inhalations were as effective as more frequent oral administrations of free drug in treating experimental tuberculosis. A subsequent study revealed that a single subcutaneous injection of these antitubercular drug-containing nanoparticles in mice resulted in therapeutic plasma drug levels for up to 32 days and was more effective at reducing bacterial counts in the lungs and spleen than was daily oral administration of free drug (109). Finally, Zahoor et al. (158) reported that the same antitubercular drugs were more effective than free oral drugs when they were encapsulated in alginate nanoparticles and administered via inhalation to guinea pigs.

Other studies relevant to the potential utility of nano-sized drugs in disease treatment have examined siRNA-mediated suppression of target mRNA levels following intranasal administration of chitosan-based nanoparticles in mice (61) and the pharmacokinetics of lipid-coated nanoparticles of 5-fluorouracil in hamsters (58). Moreover, allergic airway inflammation in mice has been shown to be reduced by intravenous administration of polymer nanoparticles coated with a P-selectin inhibitor (67) and by intranasal administration of chitosan nanoparticles carrying theophylline (79). Importantly, Dames et al. (30) recently reported on the ability to externally direct inhaled magnetically charged iron oxide nanoparticles to specific areas of the lungs of mice without adversely affecting respiratory mechanics, demonstrating for the first time that targeted aerosol delivery to the lungs is achievable. Such an approach could prove to be beneficial in the treatment of localized lung infections or tumors.

Although the majority of the toxicity studies that are discussed below focused on nonbiodegradable nanoparticles such as metals and carbon nanotubes, nanoparticles designed for clinical pulmonary drug delivery will likely be biodegradable (133). In this regard, Dailey et al. (29) reported that intratracheal administration of biodegradable polymeric nanoparticles to BALB/c mice did not induce pulmonary inflammation (measured as bronchoalveolar lavage fluid neutrophil influx, protein content, and lactate dehydrogenase activity), whereas nonbiodegradable polystyrene nanoparticles did. In addition to the treatment of lung diseases, the inhalation route is being explored for the systemic delivery of drugs to treat a variety of nonpulmonary ailments. This is due in part to the large surface area of the lungs and the relatively high bioavailability of many small molecules when administered by this route (113). As discussed below, human studies have not demonstrated systemic translocation of nanoparticles following inhalation, although some animal studies suggest that it is possible. Indeed, experimental animal data demonstrating achievement of therapeutic plasma drug levels following inhalation of nanoparticle-encapsulated antitubercular drugs (109, 110, 158) indicate that this approach may be feasible. Efforts to develop safe and effective nanoparticles for aerosol delivery are ongoing (33, 41, 52, 53, 124, 130) and will undoubtedly lead to significant advances in the treatment of respiratory and systemic diseases.

A simplified depiction of potential factors that may influence the effects of engineered nanoparticles on the respiratory system.

Fig. 2. From: Pulmonary applications and toxicity of engineered nanoparticles.

A simplified depiction of potential factors that may influence the effects of engineered nanoparticles on the respiratory system.

Jeffrey W. Card, et al. Am J Physiol Lung Cell Mol Physiol. 2008 September;295(3):L400-L411.

…. more….

Studies in humans.

As summarized elsewhere (7, 107), inhaled particles of different sizes exhibit different fractional depositions within the human respiratory tract. Although inhaled ultrafine particles (<100 nm) deposit in all regions, tracheobronchial deposition is highest for particles <10 nm in size, whereas alveolar deposition is highest for particles approximately 10–20 nm in size (7, 107). Particles <20 nm in size also efficiently deposit in the nasopharyngeal-laryngeal region. Human studies of potential adverse pulmonary effects resulting from exposure to engineered nanoparticles appear to be limited, although a number of investigations into pulmonary deposition patterns of inhaled nanoparticles in the healthy and diseased lung have been conducted (5, 24, 28, 93). Computational models predict increased deposition of inhaled nanoparticles in diseased or constricted airways (44), and, consistent with this prediction, obstructive lung disease and asthma have both been demonstrated to increase their pulmonary retention (5, 24). Nonetheless, Pietropaoli et al. (114) did not observe differences between healthy and asthmatic subjects in respiratory parameters assessed up to 45 h after a 2-h inhalation of ultrafine carbon particles (up to 25 μg/m²), nor was airway inflammation observed in either group (measured as exhaled nitric oxide). Moreover, the same study reported that exposure of healthy subjects to a higher concentration of ultrafine carbon particles (50 μg/m² for 2 h) resulted in decreased midexpiratory flow rate and carbon monoxide diffusing capacity 21 h after exposure, albeit still in the absence of airway inflammation (114). Thus nanoparticles may influence respiratory function and gas exchange without a concomitant induction of inflammation.

Several studies have also examined the potential for inhaled manufactured ultrafine particles (i.e., ^99mtechnetium-labeled carbon nanoparticles) to translocate from the lungs to the systemic circulation in humans. This is an important issue to consider as inhaled engineered nanoparticles may exert adverse cardiovascular effects, similar to the proposed mechanism for the nanoparticulate fraction of urban air pollution (15, 40). All but one of the studies reported to date indicate that inhaled ^99mtechnetium-labeled carbon nanoparticles are not detected outside of the lungs in appreciable quantities after inhalation (17, 91, 93, 100, 150, 151). However, as alluded to by Mills et al. (91), these findings do not indicate that other nanoparticles will behave in the same manner, nor do they rule out the possibility that nanoparticles may interact with and influence the vasculature. Moreover, the studies conducted to date have used a single inhalation exposure protocol, and it is possible that repeated exposures may result in greater pulmonary accumulation and translocation of significant quantities of nanoparticles to the circulation.

Studies in experimental animals.

Pulmonary effects resulting from airway administration of nanoparticles have been examined in a number of experimental animal studies, a summary of which is presented in Table 2. Although the primary outcomes of interest in the majority of these studies have been pulmonary inflammation and fibrosis, several have investigated distribution patterns within the lung and the potential translocation and systemic distribution of nanoparticles following pulmonary administration; these are summarized in Table 3. In addition to the endpoints listed in Tables 2 and ​and3,3, carcinogenic effects of inhaled nanoparticles (ultrafine particles) have, in some instances, been found to be more severe than those of larger size analogs. This is thought to result primarily from lung particle overload due to the inability of alveolar macrophages to recognize and/or clear particles of this size, leading to particle build up, chronic inflammation, fibrosis, and tumorigenesis. These effects are discussed in detail elsewhere (14, 101) and will not be covered here.

…..more…

Improvements in the diagnosis and treatment of respiratory diseases as a result of the application of nanotechnology are anticipated, and experimental evidence indicates that engineered nanoparticles have unique properties that may render them beneficial in visualizing disease processes earlier and in delivering therapeutics to the lung, possibly even to specific areas within the lung. Using the lungs as a portal of entry for nanoparticles in the treatment of systemic diseases is also being explored and holds tremendous promise. However, nanotechnology is not without its limitations, and of foremost concern is the current lack of knowledge regarding the potential toxicity of engineered nanoparticles. As has been summarized here, a considerable amount of data from in vitro and in vivo studies indicates that nanoparticles have the capacity to exert adverse pulmonary effects, although not all nanoparticles are equivalent in this regard. In addition, in vitro toxicities are not always predictive of in vivo effects or potencies and vice versa, underscoring the need for the continued development and refinement of a suitable testing strategy for assessing the pulmonary effects of nanoparticles. It is anticipated that continued investigation into the mechanisms underlying the adverse in vitro and in vivo effects summarized in this review and their relevance to human lung physiology and disease will lead to a better understanding of the potential hazards associated with nanoparticle exposure and to the development of safe and effective respiratory medical applications and therapeutics based on nanotechnology.

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Can Resolvins Suppress Acute Lung Injury?

Posted in Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Pharmaceutical Industry Competitive Intelligence, Systemic Inflammatory Response Related Disorders, tagged Acute lung injury, Aspirin, Harvard Medical School, inflammation, lung, Omega-3 fatty acid, Resolvins, University of Southern California on March 6, 2013| 1 Comment »

Can Resolvins Suppress Acute Lung Injury?

Reporter: Larry H Bernstein, MD, FCAP

Putting the brakes on acute lung injury: can resolvins suppress acute lung injury?

Cox RR Jr., Phillips O,and Kolliputi N

http://www.frontiersin.org Front.Physio. 2012;3:445.        http://dx.doi.org/10.3389/fphys.2012.00445
http://www.FrontPhysiol.com/putting_the_brakes_on_acute_lung_injury_can_resolvins_suppress_acute_lung_injury?/

The presence of resolvins, proresolving lipid mediators: their role in the resolution of ALI
Eickmeier et al.,
Mucosal Immunity 2012

conversion of DHA to RvD1 by

• activation of RvD1 Receptor (ALX/FPR2) in pulmonary mucosa alleviates effects of inflammation in APALI

endogenous attenuation of inflammation in APALI
http://www.MucosalImmunity.com/Eikmeier/The_presence_of_resolvins:_their_role_in_the_resolution_of_ALI

 Putting the brakes on acute lung injury: can resolvins suppress acute lung injury?
Ruan R. Cox Jr., Oluwakemi Phillips and Narasaiah Kolliputi*
Front Physiol. 2012;3:445.   doi: 10.3389/fphys.2012.00445. Epub 2012 Nov 29.       http://dx.doi.org/10.3389/fphys.2012.00445
http://fphys.com/Putting the brakes on acute lung injury: can resolvins suppress acute lung injury?

A commentary on

Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury

by Eickmeier, O., Seki, H., Haworth, O., Hilberath, J. N., Gao, F., Uddin, M., et al. (2012). Mucosal Immunol. doi: 10.1038/mi.2012.66

Acute lung injury (ALI), a syndrome of respiratory failure, is a major clinical problem in the United States. With a high incidence rate, affecting nearly 200,000 annually and a significant morbidity and mortality rate, ALI represents a significant source of health care expenditure with a cost of 3.5–6 billion dollars annually (Treggiari et al., 2004; Rubenfeld et al., 2005; Raghavendran et al., 2011). Pneumocytes, unique cells in the alveolar epithelium, are responsible for

• facilitating gas exchange,
• regulating fluid transport, and
• secreting surfactant to reduce alveolar surface tension.

When the alveolar barrier is disrupted, proteinaceous exudates and extracellular components of necrotic pneumocytes activate resident alveolar macrophages causing massive cytokine release (Ware and Matthay, 2000).  The inflammatory response, if left uncontrolled, can lead to further deterioration of the lung epithelium and the development of a fibroproliferative environment (Raghavendran et al., 2011).

In the July 2012 issue of Mucosal Immunity, Eickmeier et al., discuss the presence of

1. resolvins,
2. proresolving lipid mediators, and
3. present exciting findings on their role in the natural resolution of ALI (Eickmeier et al., 2012).

Resolution phase interaction products (resolvins) are omega-3 polyunsaturated fatty acid derivatives of potent anti-inflammatory precursors, eicosapentaenoic acid (EPA), and docasahexaenoic acid (DHA) (Serhan et al., 2002). “E-series” and “D-series” resolvins are derived from EPA and DHA, respectively. The airway mucosa has been shown to be rich in DHA (Freedman et al., 2004), however, the conversion of DHA to D-series resolvins has not been shown. Resolvin D1 (RvD1), a derivative of DHA, has been found in murine resolving inflammatory peritoneal exudates (Serhan et al., 2002). To investigate the potential role that RvD1 may play in the resolution of ALI, Eickmeier et al. used a murine aspiration pneumonitis acute lung injury (APALI) model induced by hydrochloric acid (HCl) administration into the left lung. Picogram quantities of RvD1 were found using metabolipidomics analysis following HCl instillation. Immunohistochemical analysis showed enhanced expression of RvD1 receptor (ALX/FPR2) as early as 2 h post-APALI. This suggested that there was a conversion of DHA to RvD1 following lung injury. Activation of ALX/FPR2 dampens the inflammatory responses through blockage of proinflammatory MAP kinase and NF-κB signaling (Chiang et al., 2006).  Eickmeier et al. demonstrated that the conversion of DHA in pulmonary mucosa alleviates the effects of inflammation in APALI. AT-RvD1 showed therapeutic effects, and bronchio-alveolar lavage fluid (BALF) collected from AT-RvD1 treated mice contained decreased leukocytes and proinflammatory cytokines in comparison to control. AT-RvD1 treated mice demonstrated decreased lung resistance and improved lung mechanics in comparison to controls. The authors showed that AT-RvD1 restored barrier integrity in APALI mice in comparison to control. The anti-inflammatory effects of ALX/FPR2 activation were shown to be a result of

• reduced activation and nuclear translocation of the transcription factor NF-κB.

Eickmeier et al., demonstrated that mice treated with AT-RvD1 demonstrated reduced

• NF-κB phosphorylation, which is necessary for the activation,
• translocation and DNA binding functions of this proinflammatory molecule.

The work of Eickmeier et al. revealed that RvD1 is a central mediator in the endogenous attenuation of inflammation seen in APALI. In most cases of ALI, the injury is indeed self-limiting and resolves on its own (Dos Santos and Slutsky, 2006). This work gives insight to the mechanism involved in the lung injury resolution process. A recent clinical study demonstrates that,
ALI progression is associated with

• increased ventilator time and
• longer intensive care unit (ICU) stays.

These patients show an enhanced proinflammatory cytokine profile which was also correlated with increased morbidity (Dolinay et al., 2012). Previous reports have also demonstrated that ALI/ARDS patients represent 34% of yearly costs for all ICU trauma patients (Treggiari et al., 2004). In the case that the ALI does not resolve, the patient is at risk for developing acute respiratory distress syndrome in as little as 3 days (Marshall et al., 1998). Finding endogenous mediators that may control the ungoverned inflammation seen in ALI is a pivotal step to finding a treatment for this disease that entails more than just supportive care (Marshall et al., 1998). The work of Eickmeier et al. has paved the way for the exploration of the beneficial effects of resolvins in the incidences of other sterile injuries, such as atherosclerosis, gout, Alzheimer’s disease, and diabetes.

Br J Pharmacol. 2008 March; 153(S1): S200–S215.

Published online 2007 October 29. doi:  10.1038/sj.bjp.0707489

PMCID: PMC2268040

Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus

C N Serhan^1,2,* and N Chiang¹

Author information ► Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

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Abstract

Complete resolution of an acute inflammatory response and its return to homeostasis are essential for healthy tissues. We here consider work to characterize cellular and molecular mechanisms that govern the resolution of self-limited inflammation. Systematic temporal analyses of evolving inflammatory exudates using

1. mediator lipidomics-informatics,
2. proteomics, and
3. cellular trafficking with murine resolving exudates demonstrate

• novel endogenous pathways of local-acting mediators that share both anti-inflammatory and pro-resolving properties.

In murine systems, resolving-exudate leukocytes switch their phenotype to actively generate new families of mediators from major omega-3 fatty acids EPA and DHA termed resolvins and protectins. Recent advances on their biosynthesis and actions are reviewed with a focus on the E-series resolvins (RvE1, RvE2), D series resolvins (RvD1, RvD2) and the protectins including neuroprotectin D1/protectin D1 (NPD1/PD1) as well as their aspirin-triggered epimeric forms.  These endogenous agonists of resolution pathways constitute a novel genus of chemical mediators that possess

• pro-resolving,
• anti-inflammatory, and
• antifibrotic as well as
• host-directed antimicrobial actions.
  These may be useful in the design of new therapeutics and treatments for diseases with the underlying trait of uncontrolled inflammation and redox organ stress.

Keywords: leukocytes, eicosanoids, resolvins, acute inflammation, ω-3 fatty acids, protectins

Introduction

Acute inflammation has several outcomes that include

• progression to chronic inflammation,
• scarring and fibrosis or
• complete resolution (Cotran et al., 1999).

With the isolation of endogenous anti-inflammatory and pro-resolving mediators and their characterization, it became clear that resolution is an active process involving biochemical circuits that

• actively biosynthesize local mediators within the resolution phase, such as the resolvins (Serhan, 1997; Serhan et al., 2000,2002).

The resolution phase has emerged as a new terrain for drug design and resolution-directed therapeutics (Gilroy et al., 2004; Lawrence et al., 2005). A pro-resolving small molecule can, in addition to serving as

• an agonist of anti-inflammation, also
• promote the uptake and clearance of apoptotic neutrophils (polymorphonuclear leukocyte, PMN)
  • from the site of inflammation by macrophages (Maderna and Godson, 2005;Serhan, 2005).

A recent consensus report from investigators at the forefront of this emerging area has addressed these definitions to help delineate this new terrain (Serhan et al., 2007). Some agents such as the widely used COX-2 inhibitors proved to be resolution toxic (Gilroy et al., 1999; Bannenberg et al., 2005; Serhan et al., 2007), whereas others can possess pro-resolving actions, such as

• glucocorticoids (Rossi and Sawatzky, 2007),
• cyclin-dependent kinase inhibitors (Rossi et al., 2006) and
• aspirin (Serhan et al., 1995; Serhan, 2007).

Interest in natural resolving mechanisms has been heightened in recent years (Henson, 2005; Luster et al., 2005; Serhan and Savill, 2005) because inflammation (characterized by the cardinal symptoms dolor, calor, rubor and loss of function) is now recognized as a central feature in the pathogenesis of many prevalent diseases in modern Western civilization, such as

• atherosclerosis (Libby, 2002),
• cancer (Coussens and Werb, 2002),
• asthma (Barnes, 1999),
• autoimmune disease, and
• various neuropathological disorders including

1. stroke,
2. Alzheimer’s and
3. Parkinson’s diseases (Majno and Joris, 1996;Nathan, 2002; Erlinger et al., 2004; Hansson et al., 2006).

Resolution of inflammation is required for the return from inflammatory disease to health, that is, catabasis (Bannenberg et al., 2005). New evidence from this laboratory and others indicates that the catabasis from inflammation to the ‘normal’ noninflamed state is not merely passive termination of inflammation but rather an actively regulated program of resolution (Serhan et al., 2007). This event is accompanied by lipid mediator class switching from pro-inflammatory prostaglandins (PGs) and leukotrienes (LT) to the biosynthesis of anti-inflammatory mediators, such as lipoxins (LXs) (Levy et al., 2001), as well as the appearance of new families of pro-resolving mediators biosynthesized in exudates from ω-3 polyunsaturated fatty acid (PUFA) precursors (Serhan et al., 2000, 2002; Hong et al., 2003) (Figure 1a).   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268040/bin/0707489f1.gif

The essential roles of omega-3 PUFAs in preventing disease in rodents were established in 1929 (Burr and Burr, 1929). In humans, the beneficial actions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major omega-3 PUFA, remains a topic of interest because structure–activity relationships remained to be established.  One theory suggests that the omega-3 PUFA compete with the storage of arachidonic acid (AA),

• replacing it and blocking the production of pro-inflammatory eicosanoids (Lands, 1987).

Along with the pro-inflammatory PGs and LT, the n−6 essential fatty acid AA is precursor to LX and aspirin-triggered LX, which possess potent anti-inflammatory and pro-resolving actions. Therefore, the popular view of essential n−6 and n−3 PUFA actions in inflammation and homeostasis was incomplete.   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268040/table/tbl1/?report=thumb

The evidence available to date  indicates that

• ω-3 PUFAs are precursors to potent novel mediators that 
• are enzymatically generated and identified in the resolving inflammatory exudates
  (Serhan et al., 2000, 2002; Hong et al., 2003).

The term resolvins (resolution-phase interaction products) was first introduced to signify that the new structures were endogenous mediators possessing potent anti-inflammatory and immunomodulatory actions demonstrated in the nanogram dose range in vivo(Serhan et al., 2002). These include

• reducing neutrophil traffic and pro-inflammatory cytokines, as well as
• lowering the magnitude of the inflammatory response in vivo (Serhan et al., 2000, 2002).

The terms protectin and neuroprotectin (when generated in neural tissues) (Serhan et al., 2006a) were introduced given the anti-inflammatory (Hong et al., 2003) as well as the protective actions of the
DHA-derived mediator NPD1/PD1 in neural systems (Mukherjee et al., 2004),

• stroke (Marcheselli et al., 2003) and
• Alzheimer’s disease (Lukiw et al., 2005).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268040/bin/0707489f2.gif

RvE1 possesses an interesting and novel distinct structure consisting of

• a conjugated diene plus
• conjugated diene chromophore present within the same molecule.

Both biogenic (Serhan et al., 2000) and total organic syntheses were achieved and its complete stereochemical assignment was established along with that of several related natural isomers (Arita et al., 2005a). RvE1 proved to be 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoicacid.

Human recombinant 5-LOX generates resolvin E2 (RvE2) from a common precursor of E-series resolvins, namely 18-HEPE. RvE2, which is 5S,18-dihydroxyeicosapentaenoic acid, stopped zymosan-induced PMN infiltration, displaying potent anti-inflammatory properties in murine peritonitis (Tjonahen et al., 2006). In addition, RvE1 and RvE2, when given together, displayed additive action in controlling PMN infiltration. These results demonstrate that RvE2, together with RvE1, may contribute to the beneficial actions of ω-3 fatty acids in human diseases. Moreover, they indicate that the 5-LOX, in human leukocytes, is a pivotal enzyme that is temporally and spatially regulated in vivo to produce either pro- or anti-inflammatory local chemical mediators.

Resolvins of the E-series comprise several molecules. Among them, RvE1 was the first isolated and studied in depth. RvE1 displayed potent stereoselective actions in vivo and with isolated cells.
At nanomolar levels in vitro, RvE1 dramatically reduced

1. human PMN transendothelial migration,
2. dendritic cell (DC) migration and
3. interleukin (IL)-12 production
   (Serhan et al., 2002; Arita et al., 2005a).

• In several animal models RvE1 displays potent counterregulatory actions that protect against leukocyte-mediated tissue injury and excessive pro-inflammatory gene expression (Arita et al., 2005a,2005c; Hasturk et al., 2006).
•  RvE1 was shown to reduce neovascularization in oxygen-induced retinopathy (Connor et al., 2007) and
• enhance CD55-dependent clearance of PMN from epithelial surfaces (Campbell et al., 2007).

These new findings provide evidence for

• endogenous mechanism(s) that may account for some of the widely touted beneficial actions noted with dietary supplementation with ω-3 PUFA (EPA and DHA),
• thereby providing new approaches for the treatment of gastrointestinal mucosal and oral inflammation.

The new families of EPA- and DHA-derived chemical mediators, namely the resolvins and protectins, qualify as ‘resolution agonists’ along with the n−6 derived agonists of resolution, the LX, in this new arena of immunomodulation and tissue protection. These are conserved structures in evolution, because rainbow trout biosynthesize resolvins and protectins, which are present in their neural and hematopoietic tissues (Hong et al., 2005). Their functional roles in fish and lower phyla remain to be established, but are likely to involve

1. cell trafficking,
2. motility and
3. protection.

Additionally, they now open new avenues to design ‘resolution-targeted’-based therapies where aberrant uncontrolled inflammation and/or impaired resolution are components of the disease pathophysiology.

Lipoxin A4 Regulates Natural Killer Cell and Type 2 Innate Lymphoid Cell Activation in Asthma
C Barnig, M Cernadas, S Dutile,…BR Levy.
Sci Transl Med 27 Feb 2013: 5(174) 174ra26   http://dx.doi.org/10.1126/scitranslmed.3004812   http://www.scitranslmed.com//LipoxinA4_Regulates_Natural_Killer_Cell_and_Type2_Innate_Lymphoid_Cell_Activation_in_Asthma/

Asthma is a prevalent disease of chronic inflammation in which endogenous counterregulatory signaling pathways are dysregulated. Recent evidence suggests that innate lymphoid cells (ILCs), including natural killer (NK) cells and type 2 ILCs (ILC2s), can participate in the regulation of allergic airway responses, in particular airway mucosal inflammation.
Both NK cells and ILC2s expressed

• the pro-resolving ALX/FPR2 receptors. 

Lipoxin A4, a natural pro-resolving ligand for ALX/FPR2 receptors, significantly

• increased NK cell–mediated eosinophil apoptosis and 
• decreased IL-13 release by ILC2s. 

Together, these findings indicate that ILCs are targets for lipoxin A4 to decrease airway inflammation and mediate the catabasis of eosinophilic inflammation

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Neutrophil granulocyte migrates from the blood vessel to the matrix, sensing proteolytic enzymes, in order to determine intercellular connections (to the improvement of its mobility) and envelop bacteria through Phagocytosis. (Photo credit: Wikipedia)

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State of the art in oncologic imaging of lungs.

Posted in Biomarkers & Medical Diagnostics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, HealthCare IT, Imaging-based Cancer Patient Management, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Uncategorized, tagged American Cancer Society, Cancer - General, cancer deaths, cancer imaging, cancer mortality, Clinical trial, CT, FDA, health, lung, lung adenocarcinoma, Lung cancer, medicine, National Institutes of Health, NCI, Non-small cell lung cancer, PET, PET/CT, relative survival rate, research, science on January 23, 2013| 5 Comments »

State of the art in oncologic imaging of lungs.

Author and Curator: Dror Nir, PhD

• 

This is the second post in a series in which I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging^†‡ that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications.

In this post I summaries the chapter on lung cancer imaging.

Lung Cancer Imaging

“Lung cancer remains the most common cause of death from cancer worldwide, having resulted in 1.38 million deaths (18.2% of all cancer deaths) in 2008.48 It also represents the leading cause of death in smokers and the leading cause of cancer mortality in men and women in the United States. In 2012, it was estimated that 226,160 new cases of lung cancer would be diagnosed (accounting for about 14% of cancer diagnoses) and that lung cancer would cause 160,340 deaths (about 29% of cancer deaths in men and 26% of cancer deaths in women) in the United States.1 The 1-year relative survival rate for the disease increased from 35% to 43% from 1975 through 1979 to 2003 through 2006.49 The 5-year survival rate is 53% for disease that is localized when first detected, but only 15% of lung cancers are diagnosed at this early stage.”

For cancer with such poor survival rates removal of the primary lesion by surgery at an early-stage disease is the best option. The current perception in regards to lung cancr is that patients may have subclinical disease for years before presentation. It is also known that early lung cancer lesions; adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are slow-growing, doubling time which can exceed 2 years.52 But, since at present, no lung cancer early-detection biomarker is clinically available, the diagnosis of this disease is primarily based on symptoms, and detection often occurs after curative intervention and when it’s already too late – see: Update on biomarkers for the detection of lung cancer and also Diagnosing lung cancer in exhaled breath using gold nanoparticles. Until biomarker is found, the burden of screening for this disease is on imaging.

“AIS and MIA generally appear as a single peripheral ground-glass nodule on CT. A small solid component may be present if areas of alveolar collapse or fibroblastic proliferation are present,50, 51 but any solid component should raise concern for a more invasive lesion (Fig. 8). Growth over time on imaging can often be difficult to assess due to the long doubling time of these AIS and MIA, which can exceed 2 years.52 However, indicators other than growth, such as air bronchograms, increasing density, and pleural retraction within a ground-glass nodule are suggestive of AIS or MIA.

CT image shows a ground glass nodule, which is the typical appearance of AIS, in the right upper lobe.

 

CT (A) demonstrated extensive consolidation with air bronchograms in the left upper lobe, which at surgical resection were found to represent adenocarcinoma of mixed subtype with predominate (70%) mucinous bronchioloalveolar subtype. PET imaging in the same patient (B) demonstrated uptake in the lingula higher than expected for bronchioloalveolar carcinoma and probably due to secondary inflammation/infection. CT (C) obtained 3 years after images (A) and (B) demonstrated biopsy-proven recurrent soft-tissue mass near surgical site. Fused FDG/PET images (D) demonstrate no uptake in the area. This finding is consistent with the decreased uptake usually seen in tumors of bronchioloalveolar histology (new terminology of MIA).

In August 2011 the results of the “National Lung Screening Trial “ which was funded by the National Cancer Institute (NCI) were published in NEJM; Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. This randomized study results showed that with low-dose CT screening of high-risk persons, there was a significant reduction of 20% in the mortality rate from lung cancer as compared to chest radiographs screening.

Based on these results one can find the following information regarding Lung Cancer Screening on the NCI web-site:

“Three screening tests have been studied to see if they decrease the risk of dying from lung cancer.

The following screening tests have been studied to see if they decrease the risk of dying from lung cancer:

• Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
• Sputum cytology: Sputum cytology is a procedure in which a sample of sputum (mucus that is coughed up from the lungs) is viewed under a microscope to check for cancer cells.
• Low-dose spiral CT scan (LDCT scan): A procedure that uses low-dose radiation to make a series of very detailed pictures of areas inside the body. It uses an x-ray machine that scans the body in a spiral path. The pictures are made by a computer linked to the x-ray machine. This procedure is also called a low-dose helical CT scan.

Screening with low-dose spiral CT scans has been shown to decrease the risk of dying from lung cancer in heavy smokers.

A lung cancer screening trial studied people aged 55 years to 74 years who had smoked at least 1 pack of cigarettes per day for 30 years or more. Heavy smokers who had quit smoking within the past 15 years were also studied. The trial used chest x-rays or low-dose spiral CT scans (LDCT) scans to check for signs of lung cancer.

LDCT scans were better than chest x-rays at finding early-stage lung cancer. Screening with LDCT also decreased the risk of dying from lung cancer in current and former heavy smokers.

A Guide is available for patients and doctors to learn more about the benefits and harms of low-dose helical CT screening for lung cancer.

Screening with chest x-rays or sputum cytology does not decrease the risk of dying from lung cancer.

Chest x-ray and sputum cytology are two screening tests that have been used to check for signs of lung cancer. Screening with chest x-ray, sputum cytology, or both of these tests does not decrease the risk of dying from lung cancer.”

The authors of Advances in oncologic imaging^†‡ found out that for pre-treatment staging and post treatment follow-up of lung cancer patients mainly involves CT (preferably contrast enhanced, FDG PET and PET/CT. “Integrated PET/CT has been found to be more accurate than PET alone, CT alone, or visual correlation of PET and CT for staging NSCLC (Non-small-cell lung carcinoma).59 “

The standard treatment of choice for localized disease remains surgical resection with or without chemo-radiation therapy (stage dependant). “The current recommendations for routine follow-up after complete resection of NSCLC are as follows: for 2 years following surgery a contrast-enhanced chest CT scan every 4 to 6 months and then yearly non-contrast chest CT scans.62 Detection of recurrence on CT is the primary goal in the initial years, and therefore, optimally, a contrast-enhanced scan should be obtained to evaluate the mediastinum. In subsequent years, when identifying an early second primary lung cancer becomes of more clinical importance, a non-contrast CT chest scan suffices to evaluate the lung parenchyma.

CT (A) of 78-year-old male who was status post–left lobe lobectomy and left upper lobe wedge resection shows recurrent nodule at the surgical resection site. Fused PET/CT (B) demonstrates increased [18F]FDG uptake in the corresponding nodule at the surgical resection site consistent with recurrent tumor.

In patients undergoing chemotherapies: “ [¹⁸F]FDG PET response correlates with histologic response.63 [¹⁸F]FDG PET scan data can provide an early readout of response to chemotherapy in patients with advanced-stage lung cancer.64

In patients treated by recently developed “Targeted Therapies” such as Radiofrequency ablation (RFA) the authors found out that PET/CT is the preferred imaging modality for post treatment follow-up.

“ Most patients treated with pulmonary ablation will have had a pre-procedure CT or a fusion PET/CT scan, which allows more precise anatomic localization of abnormalities seen on PET. Generally, either CT or PET/CT is performed within a few weeks of the procedure to provide a new baseline to which future images can be compared to assess for changes in size, degree of enhancement or [¹⁸F]FDG avidity.67”

CT (A) demonstrates new left upper lobe mass representing new primary NSCLC in a patient who had a status post–right pneumonectomy for a prior NSCLC. CT (B) obtained in the same patient 2 weeks after radiofrequency ablation (RFA) demonstrates the postablation density in the left upper lobe. Fused PET/CT (C) obtained 4 months after RFA demonstrates mild [18F]FDG uptake at RFA site in the left upper lobe consistent with posttreatment inflammation. Fused PET/CT (D) obtained 7 months after RFA demonstrates new focal [18F]FDG uptake at post-RFA-opacity consistent with recurrent tumor.

Prostate Cancer Imaging

To be followed…

Other research papers related to the management of Lung cancer were published on this Scientific Web site:

Diagnosing lung cancer in exhaled breath using gold nanoparticles

Lung Cancer (NSCLC), drug administration and nanotechnology

Non-small Cell Lung Cancer drugs – where does the Future lie?

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

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