| 1. |
- Bölükbas, Deniz, et al.
(författare)
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Organ-Restricted Vascular Delivery of Nanoparticles for Lung Cancer Therapy
- 2020
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Ingår i: Advanced Therapeutics. - : Wiley. - 2366-3987. ; 3:7
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Tidskriftsartikel (refereegranskat)abstract
- Nanoparticle-based targeted drug delivery holds promise for treatment of cancers. However, most approaches fail to be translated into clinical success due to ineffective tumor targeting in vivo. Here, the delivery potential of mesoporous silica nanoparticles (MSN) functionalized with targeting ligands for epidermal growth factor receptor and C─C chemokine receptor type 2 is explored in lung tumors. The addition of active targeting ligands on MSNs enhances their uptake in vitro but fails to promote specific delivery to tumors in vivo, when administered systemically via the blood or locally to the lung into immunocompetent murine lung cancer models. Ineffective tumor targeting is due to efficient clearance of the MSNs by the phagocytic cells of the liver, spleen, and lung. These limitations, however, are successfully overcome using a novel organ-restricted vascular delivery (ORVD) approach. ORVD in isolated and perfused mouse lungs of Kras-mutant mice enables effective nanoparticle extravasation from the tumor vasculature into the core of solid lung tumors. In this study, ORVD promotes tumor cell-specific uptake of nanoparticles at cellular resolution independent of their functionalization with targeting ligands. Organ-restricted vascular delivery thus opens new avenues for optimized nanoparticles for lung cancer therapy and may have broad applications for other vascularized tumor types.
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| 2. |
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| 3. |
- Costa, Rita, et al.
(författare)
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A drug screen with approved compounds identifies amlexanox as a novel Wnt/β-catenin activator inducing lung epithelial organoid formation
- 2021
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 178:19, s. 4026-4041
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Emphysema is an incurable disease characterized by loss of lung tissue leading to impaired gas exchange. Wnt/β-catenin signalling is reduced in emphysema, and exogenous activation of the pathway in experimental models in vivo and in human ex vivo lung tissue improves lung function and structure. We sought to identify a pharmaceutical able to activate Wnt/β-catenin signalling and assess its potential to activate lung epithelial cells and repair. Experimental Approach: We screened 1216 human-approved compounds for Wnt/β-catenin signalling activation using luciferase reporter cells and selected candidates based on their computationally predicted protein targets. We further performed confirmatory luciferase reporter and metabolic activity assays. Finally, we studied the regenerative potential in murine adult epithelial cell-derived lung organoids and in vivo using a murine elastase-induced emphysema model. Key Results: The primary screen identified 16 compounds that significantly induced Wnt/β-catenin-dependent luciferase activity. Selected compounds activated Wnt/β-catenin signalling without inducing cell toxicity or proliferation. Two compounds were able to promote organoid formation, which was reversed by pharmacological Wnt/β-catenin inhibition, confirming the Wnt/β-catenin-dependent mechanism of action. Amlexanox was used for in vivo evaluation, and preventive treatment resulted in improved lung function and structure in emphysematous mouse lungs. Moreover, gene expression of Hgf, an important alveolar repair marker, was increased, whereas disease marker Eln was decreased, indicating that amlexanox induces pro-regenerative signalling in emphysema. Conclusion and Implications: Using a drug screen based on Wnt/β-catenin activity, organoid assays and a murine emphysema model, amlexanox was identified as a novel potential therapeutic agent for emphysema.
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| 4. |
- Doryab, Ali, et al.
(författare)
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A Biomimetic, Copolymeric Membrane for Cell-Stretch Experiments with Pulmonary Epithelial Cells at the Air-Liquid Interface
- 2021
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Ingår i: Advanced Functional Materials. - : Wiley. - 1616-301X .- 1616-3028. ; 31:10
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Tidskriftsartikel (refereegranskat)abstract
- Chronic respiratory diseases are among the leading causes of death worldwide, but only symptomatic therapies are available for terminal illness. This in part reflects a lack of biomimetic in vitro models that can imitate the complex environment and physiology of the lung. Here, a copolymeric membrane consisting of poly(ε-)caprolactone and gelatin with tunable properties, resembling the main characteristics of the alveolar basement membrane is introduced. The thin bioinspired membrane (0.5 μm) is stretchable (up to 25% linear strain) with appropriate surface wettability and porosity for culturing lung epithelial cells under air–liquid interface conditions. The unique biphasic concept of this membrane provides optimum characteristics for initial cell growth (phase I) and then switch to biomimetic properties for cyclic cell-stretch experiments (phase II). It is showed that physiologic cyclic mechanical stretch improves formation of F-actin cytoskeleton filaments and tight junctions while non-physiologic over-stretch induces cell apoptosis, activates inflammatory response (IL-8), and impairs epithelial barrier integrity. It is also demonstrated that cyclic physiologic stretch can enhance the cellular uptake of nanoparticles. Since this membrane offers considerable advantages over currently used membranes, it may lead the way to more biomimetic in vitro models of the lung for translation of in vitro response studies into clinical outcome.
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| 5. |
- Doryab, Ali, et al.
(författare)
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Evolution of Bioengineered Lung Models : Recent Advances and Challenges in Tissue Mimicry for Studying the Role of Mechanical Forces in Cell Biology
- 2019
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Ingår i: Advanced Functional Materials. - : Wiley. - 1616-301X .- 1616-3028.
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Forskningsöversikt (refereegranskat)abstract
- Mechanical stretch under both physiological (breathing) and pathophysiological (ventilator-induced) conditions is known to significantly impact all cellular compartments in the lung, thereby playing a pivotal role in lung growth, regeneration and disease development. In order to evaluate the impact of mechanical forces on the cellular level, in vitro models using lung cells on stretchable membranes have been developed. Only recently have some of these cell-stretching devices become suitable for air–liquid interface cell cultures, which is required to adequately model physiological conditions for the alveolar epithelium. To reach this goal, a multi-functional membrane for cell growth balancing biophysical and mechanical properties is critical to mimic (patho)physiological conditions. In this review, i) the relevance of cyclic mechanical forces in lung biology is elucidated, ii) the physiological range for the key parameters of tissue stretch in the lung is described, and iii) the currently available in vitro cell-stretching devices are discussed. After assessing various polymers, it is concluded that natural-synthetic copolymers are promising candidates for suitable stretchable membranes used in cell-stretching models. This work provides guidance on future developments in biomimetic in vitro models of the lung with the potential to function as a template for other organ models (e.g., skin, vessels).
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| 6. |
- Esteve-Codina, Anna, et al.
(författare)
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Gender specific airway gene expression in COPD sub-phenotypes supports a role of mitochondria and of different types of leukocytes
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term "response to stress" was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females.
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| 7. |
- Kokot, Hana, et al.
(författare)
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Prediction of Chronic Inflammation for Inhaled Particles : the Impact of Material Cycling and Quarantining in the Lung Epithelium
- 2020
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Ingår i: Advanced Materials. - : Wiley. - 0935-9648 .- 1521-4095. ; 32:47
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Tidskriftsartikel (refereegranskat)abstract
- On a daily basis, people are exposed to a multitude of health-hazardous airborne particulate matter with notable deposition in the fragile alveolar region of the lungs. Hence, there is a great need for identification and prediction of material-associated diseases, currently hindered due to the lack of in-depth understanding of causal relationships, in particular between acute exposures and chronic symptoms. By applying advanced microscopies and omics to in vitro and in vivo systems, together with in silico molecular modeling, it is determined herein that the long-lasting response to a single exposure can originate from the interplay between the newly discovered nanomaterial quarantining and nanomaterial cycling between different lung cell types. This new insight finally allows prediction of the spectrum of lung inflammation associated with materials of interest using only in vitro measurements and in silico modeling, potentially relating outcomes to material properties for a large number of materials, and thus boosting safe-by-design-based material development. Because of its profound implications for animal-free predictive toxicology, this work paves the way to a more efficient and hazard-free introduction of numerous new advanced materials into our lives.
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| 8. |
- Kreyling, Wolfgang G., et al.
(författare)
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Generation and characterization of stable, highly concentrated titanium dioxide nanoparticle aerosols for rodent inhalation studies
- 2011
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Ingår i: Journal of Nanoparticle Research. - : Springer Science and Business Media LLC. - 1572-896X .- 1388-0764. ; 13:2, s. 511-524
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Tidskriftsartikel (refereegranskat)abstract
- The intensive use of nano-sized titanium dioxide (TiO2) particles in many different applications necessitates studies on their risk assessment as there are still open questions on their safe handling and utilization. For reliable risk assessment, the interaction of TiO2 nanoparticles (NP) with biological systems ideally needs to be investigated using physico-chemically uniform and well-characterized NP. In this article, we describe the reproducible production of TiO2 NP aerosols using spark ignition technology. Because currently no data are available on inhaled NP in the 10-50 nm diameter range, the emphasis was to generate NP as small as 20 nm for inhalation studies in rodents. For anticipated in vivo dosimetry analyses, TiO2 NP were radiolabeled with V-48 by proton irradiation of the titanium electrodes of the spark generator. The dissolution rate of the V-48 label was about 1% within the first day. The highly concentrated, polydisperse TiO2 NP aerosol (3-6 x 10(6) cm(-3)) proved to be constant over several hours in terms of its count median mobility diameter, its geometric standard deviation, and number concentration. Extensive characterization of NP chemical composition, physical structure, morphology, and specific surface area was performed. The originally generated amorphous TiO2 NP were converted into crystalline anatase TiO2 NP by thermal annealing at 950 A degrees C. Both crystalline and amorphous 20-nm TiO2 NP were chain agglomerated/aggregated, consisting of primary particles in the range of 5 nm. Disintegration of the deposited TiO2 NP in lung tissue was not detectable within 24 h.
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| 9. |
- Löndahl, Jakob, et al.
(författare)
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Measurement Techniques for Respiratory Tract Deposition of Airborne Nanoparticles: A Critical Review.
- 2014
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Ingår i: Journal of Aerosol Medicine and Pulmonary Drug Delivery. - : Mary Ann Liebert Inc. - 1941-2703 .- 1941-2711. ; 27:4, s. 229-254
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Forskningsöversikt (refereegranskat)abstract
- Abstract Determination of the respiratory tract deposition of airborne particles is critical for risk assessment of air pollution, inhaled drug delivery, and understanding of respiratory disease. With the advent of nanotechnology, there has been an increasing interest in the measurement of pulmonary deposition of nanoparticles because of their unique properties in inhalation toxicology and medicine. Over the last century, around 50 studies have presented experimental data on lung deposition of nanoparticles (typical diameter≤100 nm, but here≤300 nm). These data show a considerable variability, partly due to differences in the applied methodologies. In this study, we review the experimental techniques for measuring respiratory tract deposition of nano-sized particles, analyze critical experimental design aspects causing measurement uncertainties, and suggest methodologies for future studies. It is shown that, although particle detection techniques have developed with time, the overall methodology in respiratory tract deposition experiments has not seen similar progress. Available experience from previous research has often not been incorporated, and some methodological design aspects that were overlooked in 30-70% of all studies may have biased the experimental data. This has contributed to a significant uncertainty on the absolute value of the lung deposition fraction of nanoparticles. We estimate the impact of the design aspects on obtained data, discuss solutions to minimize errors, and highlight gaps in the available experimental set of data.
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| 10. |
- Schmid, Otmar, et al.
(författare)
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Derivation of the Density and Refractive Index of Organic Matter and Elemental Carbon from Closure between Physical and Chemical Aerosol Properties
- 2009
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Ingår i: Environmental Science & Technology. - : American Chemical Society (ACS). - 1520-5851 .- 0013-936X. ; 43:4, s. 1166-1172
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Tidskriftsartikel (refereegranskat)abstract
- Information on the density (p) and refractive index m(=n-ik) of elemental carbon (ECa) and organic matter (OMa), the main carbon components of atmospheric aerosols, has frequently been obtained from closure calculations between physical and chemical aerosol properties. However, this approach has suffered from large uncertainties since there were more unknown (or poorly known) parameters than defining equations. In this study, we propose a method that avoids this ambiguity mainly by considering both optical and mass closure and by expressing the three ECa parameters (p(Eca), n(Eca), k(ECa)) by a single (unknown) parameter. This allows mathematically rigorous determination of p(Eca), m(Eca), p(OMa) and m(OMa) from standard physico-chemical aerosol data and rigorous error analysis. The results are unambiguous and self-consistent, i.e., there is no difference between the chemically and physically derived p and m values of the atmospheric aerosol. Application of this method to our previously published data on biomass burning particles from Amazonia yields p(Eca) = 1.8(+/- 0.2) g/cm(3), m(ECa) = 1.9(+/- 0.1)-i0.20(-0.04/+0.02), p(OMa) = 1.39(+/- 0.13) g/cm(3) and m(OMa)=1.46(+/- 0.02), where the 1 sigma uncertainty limits given in parenthesis are based on the principles of error propagation. The relatively low imaginary part of mEca indicates the presence of only partially graphitized elemental carbon, which is consistent with biomass burning aerosol dominated bysmoldering combustion conditions.
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