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Oxygen Radical-Mediated Pulmonary Toxicity Induced by Some Cationic Liposomes
Abstract
Purpose The objectives of this study are to investigate the toxicity associated with polycationic liposomes and to elucidate the underlying mechanism. We tested the hypothesis that the positive charge of liposomes is a key determinant of toxicity by testing differently charged liposomes in mice.Methods Differently charged liposomal systems including cationic liposomes, LipofectAMINE and DOTAP, and neutral and negative liposomes were evaluated for their toxicity after pulmonary administration in mice. LDH assay and differential cell counts were performed to measure toxicity and pulmonary inflammation, respectively. Reactive oxygen intermediates (ROI) were assessed by chemiluminescence.Results Instillation of cationic liposomes elicited dose-dependent toxicity and pulmonary inflammation. This effect was more pronounced with the multivalent cationic liposome LipofectAMINE as compared to the monovalent cationic DOTAP. Neutral and negative liposomes did not exhibit lung toxicity. Toxicity associated with cationic liposomes correlated with the oxidative burst induced by the liposomes. LipofectAMINE induced a dose-dependent increase in ROI generation. This effect was less pronounced with DOTAP and absent with neutral and negative liposomes.Conclusions ROI play a key role in cationic lipid-mediated toxicity. Polyvalent cationic liposomes cause a release of ROI which are responsible for the pulmonary toxicity.
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“Cationic and ionizable lipids have also been reported to stimulate the secretion of pro-inflammatory cytokines and reactive oxygen species170–173.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [171]
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Monoolein-based nanocarriers for enhanced folate receptor-mediated RNA delivery to cancer cells
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“Additionally, lipoplexes are also susceptible of activating the immunological complement system, leading to rapid clearance by macrophages of the reticuloendothelial system, and induce strong toxicity (Dokka et al., 2000; Lv et al., 2006).”
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Gene Delivery into Mammalian Cells: An Overview on Existing Approaches Employed In Vitro and In Vivo
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“There are several in vivo studies reporting cytotoxicity of cationic lipids upon administration [31, 32].”
BackgroundCationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells
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“Previous studies by our group indicated that DOTAP, in the absence of LPS, did not induce lung inflammation when used at the same concentration reported in this study (10, 11).”
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Inhibition of endotoxin-induced lung inflammation by interleukin-10 gene transfer in mice
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“78 DOTAP (1,2-dioleoyl-3-trimethylammonium propane)-based particles, a subclass of cationic lipids, accumulate in the liver and spleen, thereby limiting their systemic and antitumor efficacy.”
Remodeling the tumor immune microenvironment via siRNA therapy for precision cancer treatment
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“…liposomes can be prepared using a wide range of materials as well as the complexes which are formed by liposomes and siRNA are easily endocytosed by cells, their in vivo application is constrained by cytotoxicity like cell membrane rupture and the generation of reactive oxygen species (ROS) [99] .”
BackgroundComplexes of nucleolipid liposomes with single-stranded and double-stranded nucleic acids
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Extracellular matrix-based materials for neural interfacing
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Toxicological evaluation of lactose and chitosan delivered by inhalation
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“The development of delivery systems for protein drugs with short biological half lives using biodegradable polymers is of current interest [7].”
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BackgroundLipoxygenase May Be Involved in Cationic Liposome-Induced Macrophage Apoptosis
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Biocompatible cationic lipids for the formulation of liposomal DNA vectors
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Enhancing Targeted Therapy in Breast Cancer by Ultrasound-Responsive Nanocarriers
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Metadata
- Authors
- Dokka, S., Toledo, D., Shi, X., Castranova, V., & Rojanasakul, Y.
- Affiliations
- West Virginia University (US)
- National Institute for Occupational Safety and Health (US)
- Corresponding author
- Rojanasakul, Yon
- Venue
- Pharmaceutical Research
- Published
- 2000-05
- Volume
- 17
- Issue
- 5
- Pages
- 521-525
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- OpenAlex
- W1580639099
- Cited by
- 349
- References
- 14
- Citations by year
- 2026: 12 · 2025: 8 · 2024: 19 · 2023: 25 · 2022: 17 · 2021: 18 · 2020: 6 · 2019: 16 · 2018: 19 · 2017: 17 · 2016: 17 · 2015: 26 · 2014: 21 · 2013: 19 · 2012: 18
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Pharmaceutical Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- West Virginia University
- National Institutes of Health (1r15hl062959-01)
- National Heart, Lung, and Blood Institute (HL-62959)
- National Institute for Occupational Safety and Health
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- cationic liposomes, pulmonary toxicity, reactive oxygen species, lipofectamine, DOTAP, liposome charge, respiratory burst, lung inflammation, liposomal gene delivery, chemiluminescence
- MeSH terms
- Animals, Bronchoalveolar Lavage Fluid, Cations, Cyclic N-Oxides, L-Lactate Dehydrogenase, Liposomes, Luminescent Measurements, Lung Diseases, Male, Mice, Inbred BALB C, Nitrogen Oxides, Free Radical Scavengers, Reactive Oxygen Species, Mice
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