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Non-Viral Delivery of Genome-Editing Nucleases for Gene Therapy
Published in Yashwant Pathak, Gene Delivery, 2022
PEGylation of glycosaminoglycan-binding peptides coupled with DNA through electrostatic charge interactions, which formed NPs that targeted bronchial epithelial cell lines with precision cut lung slices in vitro, showing that PEGylation rates of >40% were the optimal formulation [106]. Additionally, other supra-magnetic iron oxide NPs or gold nanoparticles have shown to internalization into tumor or stem cells upon modification of CPP [107–110]. Cytotoxicity of liposomal CPP can be reduced by coating the LP surface with neutral PEG, which also stabilized the NPS, and these specialized CPP nanoparticles also enhanced the gene silencing capacity invitro [111]. Another studies showed that modification of TAT peptide labeled with LPS containing doxorubicin enhanced the efficacy of targeted delivery of therapeutic molecules, resulting in an increase in anti-tumor activity and decrease in systemic side effects [111–113].
3D In Vitro/Ex Vivo Systems
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Bethany M. Young, Alexandria Ritchie, Laleh Golshahi, Rebecca L. Heise
Precision cut lung slices are a beneficial alternative to in vivo animal models for pharmacotoxicology experimentation. While liver and kidney slices are more frequently used in the field of pharmacology, the use of lung slices for aerosols is also useful for assessing cytotoxicity and metabolism. The main advantage of these systems is that the cell-cell and cell-Extracellular Matrix (ECM) interactions are maintained with the controllability of a culture system. These slices can maximize the output of ex vivo lungs by giving multiple replicates and less expensive culturing conditions. Lung slices, if maintained correctly, preserve physiological function such as vascular and airway smooth muscle contraction, mucociliary function, and cytokine production (Morin et al. 2013).
Identifying a reference list of respiratory sensitizers for the evaluation of novel approaches to study respiratory sensitization
Published in Critical Reviews in Toxicology, 2021
Nikaeta Sadekar, Fanny Boisleve, Wolfgang Dekant, Allison D. Fryer, G. Frank Gerberick, Peter Griem, Christina Hickey, Nora L. Krutz, Olga Lemke, Cecile Mignatelli, Reynold Panettieri, Kent E. Pinkerton, Kevin J. Renskers, Paul Sterchele, Simone Switalla, Matthew Wolter, Anne Marie Api
Despite the challenges of identifying respiratory sensitizers and understanding their underlying mechanisms, the test methods are required to reflect human relevance. As such, any assay developed for testing adverse effects in the respiratory system needs a model that represents the characteristics of, or some features of, a healthy adult human. Thus, many approaches rely upon human tissues or cells, such as human precision-cut lung slices and human bronchial epithelial cells. An extensive body of research is available on in vitro models used to answer specific research questions with regards to the respiratory tract, for example, the A549 cell line (Nova et al. 2020; Tran et al. 2020), which is an immortalized alveolar epithelial type 2 cell line isolated from human pulmonary adenocarcinoma. However, such models do not represent the complex tissue structure. They may underestimate biological and functional aspects of healthy tissues in humans (Swain et al. 2010) and thus limit their value for predicting in vivo effects (Suter 2006; McKim 2010).
Current models of pulmonary fibrosis for future drug discovery efforts
Published in Expert Opinion on Drug Discovery, 2020
Toyoshi Yanagihara, Sy Giin Chong, Megan Vierhout, Jeremy A. Hirota, Kjetil Ask, Martin Kolb
Precision-cut lung slices (PCLS) have gained increasing attention as novel human lung fibrosis models [72–74]. Animal models are necessary tools to analyze and validate therapeutic targets in vivo, often complemented by human cell cultures. Nevertheless, the validation in the primary human lung is mostly limited to the analysis of single-cell types in two-dimensional (2D) cultures. PCLS retain native lung tissue architecture, ECM protein composition, and stiffness with viable lung resident cells, which allows testing of the effects of compounds at the diseased tissue level with high-throughput. Human lung tissue from lung resections or explants or animal tissues are filled with low melting point agarose and subsequently precision cut into 250–1000 µm thick slices and cultured in vitro. The most important advantage of using PCLS is that they can be used to assess the effects of drugs directly on lung structural cells. Tissues are used from human and rodent lungs, and a single mouse lung can generate approximately 30 slices for experiments, which is another potential advantage to reduce animal numbers used for research.
Senolytic drugs in respiratory medicine: is it an appropriate therapeutic approach?
Published in Expert Opinion on Investigational Drugs, 2018
Mario Cazzola, Maria Gakriella Matera, Paola Rogliani, Luigino Calzetta
When given in combination, dasatinib and quercetin improve lung function and indicators of fibrotic disease following bleomycin injury [29]. Also Lehmann and colleagues [43] showed that the dasatinib plus quercetin combination depleted senescent cells by inducing apoptosis and reduced SASP factors in mouse primary alveolar epithelial type II cells (AECIIs) derived from bleomycin-treated fibrotic lungs, while stabilizing epithelial cell marker expression and function. AECIIs are considered alveolar epithelial stem cells [61], and loss of AECIIs is sufficient to cause pulmonary fibrosis [62]. These findings were confirmed in the ex vivo model of precision-cut lung slices obtained from bleomycin-treated fibrotic mouse lungs. However, although early dasatinib plus quercetin treatment positively impacts exercise capacity and lung compliance, it does not alter fibrosis, the key pathological feature of human IPF [29].