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Nanotoxicologic Effects of PLGA Nanoparticles Formulated with a Cell-Penetrating Peptide: Searching for a Safe pDNA Delivery System for the Lungs

1
Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2037, Australia
2
Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur-Royal College of Medicine Perak, (UniKL-RCMP), 30450 Ipoh, Perak, Malaysia
3
Evonik Industries AG, Kirschenallee, 64293 Darmstadt, Germany
*
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(1), 12; https://doi.org/10.3390/pharmaceutics11010012
Received: 24 October 2018 / Revised: 17 December 2018 / Accepted: 27 December 2018 / Published: 3 January 2019
(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)
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Abstract

The use of cell-penetrating peptides (CPPs) in combination with nanoparticles (NPs) shows great potential for intracellular delivery of DNA. Currently, its application is limited due to the potential toxicity and unknown long-term side effects. In this study NPs prepared using a biodegradable polymer, poly(lactic–co–glycolic acid (PLGA) in association with a CPP, was assessed on two lung epithelial cell lines (adenocarcinomic human alveolar basal epithelial cells (A549) and normal bronchial epithelial cells (Beas-2B cells)). Addition of CPP was essential for intracellular internalization. No effects were observed on the mitochondrial activity and membrane integrity. Cells exposed to the NPs–DNA–CPP showed low inflammatory response, low levels of apoptosis and no activation of caspase-3. Increase in necrotic cells (between 10%–15%) after 24 h of incubation and increase in autophagy, induced by NPs–DNA–CPP, are likely to be related to the lysosomal escape mechanism. Although oxidative stress is one of the main toxic mechanisms of NPs, NPs–DNA–CPP showed decreased reactive oxygen species (ROS) production on Beas-2B cells, with potential antioxidant effect of CPP and no effect on A549 cells. This NP system appears to be safe for intracellular delivery of plasmid DNA to the lung epithelial cells. Further investigations should be conducted in other lung-related systems to better understand its potential effects on the lungs. View Full-Text
Keywords: alveolar; bronchial; apoptosis; autophagy; gene delivery alveolar; bronchial; apoptosis; autophagy; gene delivery
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Gomes dos Reis, L.; Lee, W.-H.; Svolos, M.; Moir, L.M.; Jaber, R.; Windhab, N.; Young, P.M.; Traini, D. Nanotoxicologic Effects of PLGA Nanoparticles Formulated with a Cell-Penetrating Peptide: Searching for a Safe pDNA Delivery System for the Lungs. Pharmaceutics 2019, 11, 12.

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