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 been reported to stimulate the secretion of pro-inflammatory cytokines and reactive oxygen species.
“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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“The reduction in viability may be due to non-specific interaction with the cell membrane causing transient pore formation and lysis as a result of excess positive charge and amphiphilic nature of these cationic vectors [52].”
BackgroundYang, X., Iyer, A. K., Singh, A., Milane, L. S., Choy, E., Hornicek, F. J., Amiji, M. M., & Duan, Z. (2014) · Pharmaceutical Research · doi:10.1007/s11095-014-1602-1 · Cited by 89 · see citing works
“and enhance the immune response to siRNA in vitro (40).”
Targeting Anticancer Drugs to Tumor Vasculature Using Cationic Liposomes
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Advantages and risks of nanotechnologies in cancer patients and occupationally exposed workers
Lamberti, M., Zappavigna, S., Sannolo, N., Porto, S., & Caraglia, M. (2014) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2014.913568 · Cited by 88 · see citing works
“For example cationic liposomes can interact with serum proteins, lipoproteins and the extracellular matrix, leading to aggregation or release of agents that are loaded before reaching the target cells leading to systemic toxicity [73].”
BackgroundIntracellular Protein Delivery: Approaches, Challenges, and Clinical Applications
Chan, A., & Tsourkas, A. (2023) · BME Frontiers · doi:10.34133/bmef.0035 · Cited by 90 · see citing works
“In addition, cationic lipids commonly used in protein LNP formulations such as DOTAP, DOTMA, or DOSPA have documented cytotoxic effects in vivo via generation of reactive oxygen species [239].”
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“Furthermore, Dokka et al. ( 27 ) reported that cationic liposomes composed of LipofectAMINE, frequently used as a Fig. 5. Effects of cholesterol content (A) or PEG coating (B) on intracellular peroxide levels in RAW264.7 cells treated with cationic liposomes.”
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“These include inflammation, hepatotoxicity, and hematologic toxicity [62, 63].”
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Liposomal antibiotics for the treatment of infectious diseases
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“Another study investigated cationic liposome toxicity in the lungs and showed that positively charged liposomes can induce toxic reactive oxygen intermediates [113].”
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“The surface charge-mediated toxicity is crucial to the point that liposomes with positive surface charge (cationic liposomes) are useless clinically (Dokka et al. 2000; Spagnou et al. 2004; Lv et al. 2006).”
BackgroundInfluentialFactors affecting the pharmacokinetics and pharmacodynamics of liposomal drugs
Song, G. K., Wu, H., Yoshino, K., & Zamboni, W. C. (2012) · Journal of Liposome Research · doi:10.3109/08982104.2012.655285 · Cited by 78 · see citing works
“It was found that multivalent cationic liposome LipofectAMINE was much more toxic than the monovalent cationic liposome, DOTAP, and that neutral and negative liposomes were not toxic at similar concentrations (Dokka et al., 2000).”
BackgroundSargazi, S., Arshad, R., Ghamari, R., Rahdar, A., Bakhshi, A., Fathi‐karkan, S., Ajalli, N., Bilal, M., & Diez-Pascual, A. M. (2022) · Cell Biology International · doi:10.1002/cbin.11841 · Cited by 77 · see citing works
“because they are commercially available without chemical synthesis; however, the most prominent problem with lipid systems is their clinical toxicity and nonspecific activation of inflammatory cytokines (Dokka et al., 2000).”
BackgroundLipid Nanoparticles for Organ-Specific mRNA Therapeutic Delivery
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- 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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