Cited by 349Nanoparticle-Based Drug DeliveryInhalation and Respiratory Drug DeliveryRNA Interference and Gene Delivery

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Oxygen Radical-Mediated Pulmonary Toxicity Induced by Some Cationic Liposomes

Dokka, Sujatha, Toledo, David, Shi, Xianglin, Castranova, Vincent, Rojanasakul, Yon·2000·Pharmaceutical Research

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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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Background
Lipid-based delivery of CpG oligodeoxynucleotides for cancer immunotherapy
Wilson, K. D., & Tam, Y. K. (2009) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2.2.181 · Cited by 7
Tuning the Surface Charge of Self-Assembled Polydiacetylene Vesicles to Control Aggregation and Cell Binding
Nelson, A. D., Shiveshwarkar, P., Lim, B., Rojas, G., Abure, I., Shrestha, A., & Jaworski, J. W. (2020) · Biosensors · doi:10.3390/bios10100132 · Cited by 7
Lipid membrane-based therapeutics and diagnostics
de Carvalho, P. M. B., Makowski, M., Domingues, M. M., Martins, I. C., & Santos, N. C. (2021) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2021.108858 · Cited by 7
Engineered liposomes as drug delivery and imaging agents
Behera, A., Padhi, S., & Nayak, A. K. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-89953-6.00010-6 · Cited by 7
Preparation and Preliminary Evaluation of Dual-functional Nanoparticles for MRI and siRNA Delivery.
Sun, J., Zhou, Y., Jin, G., Jin, Y. J., & Quan, J. (2021) · PubMed Central · doi:10.22037/ijpr.2021.115099.15219 · Cited by 7
In VivoEvaluation of Acute and Chronic Nanotoxicity
Nehoff, H. L., Parayath, N. N., Taurin, S., & Greish, K. F. (2014) · doi:10.1002/9781118856017.ch3 · Cited by 7
Positive Charge, Negative Effect: The Impact of Cationic Nanoparticles in The Brain
M�ller, P., & Lykkesfeldt, J. (2014) · Nanomedicine · doi:10.2217/nnm.14.91 · Cited by 7
Deciphering the Role of Chondroitin Sulfate in Increasing the Transfection Efficiency of Amphipathic Peptide-Based Nanocomplexes
Sundaram, D. N. M., Vij, M., Pandey, T., Natarajan, P., Sharma, R., Mishra, S., & Ganguli, M. (2018) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.8b00069 · Cited by 6
Nano-delivery of Food-Derived Biomolecules: An Overview
Jhala, D., Rather, H., & Vasita, R. (2018) · Springer eBooks · doi:10.1007/978-981-13-1123-9_20 · Cited by 5
Delivery Aspects for Implementing siRNA Therapeutics for Blood Diseases
Dezfouli, S. A., Michailides, M. E., & Uludağ, H. (2024) · Biochemistry · doi:10.1021/acs.biochem.4c00327 · Cited by 5
Increased production of soluble vascular endothelial growth factors receptor-1 in CHO-cell line by using new combination of chitosan-protein lipid nanoparticles.
Farnia, P., Ghanavi, J., Bahrami, A., Bandehpour, M., Kazemi, B., & Velayati, A. A. (2015) · Europe PMC (PubMed Central) · Cited by 5
Toxicity Evaluation of Nanomedicine
Panghal, A., & Flora, S. J. S. (2022) · Springer eBooks · doi:10.1007/978-3-031-12398-6_19 · Cited by 5
Liposomal encapsulation enhances the activity of immunostimulatory oligonucleotides
Tam, Y. K. (2006) · Future Lipidology · doi:10.2217/17460875.1.1.35 · Cited by 5
“Although the toxic nature of these responses is less clear in the context of immunostimulatory applications, such as those described here, they do contribute directly to secondary effects, such as dose-dependent hematologic changes typified by profound leukopenia, thrombocytopenia and neutropenia [40,41] and organ-rel…”
Background
Synthesis of Fullerene-Acid Conjugates
Zhang, J., Li, Y., & Zhang, Y. D. (2012) · Advanced materials research · doi:10.4028/www.scientific.net/amr.463-464.538 · Cited by 5
Ganoderma lucidum Polysaccharide Potentiates mRNA-LNP Efficacy: Synergizing Oxidative Stress Mitigation with Innate Immune Modulation
Tao, L.-L., Zhai, Z., Chen, N.-Y., Cheng, Y., & Liu, X.-H. (2026) · Pharmaceutics · doi:10.3390/pharmaceutics18020259 · Cited by 4
“However, the potential toxicity of LNPs has been demonstrated to induce abnormal levels of reactive oxygen species (ROS) in vivo, leading to oxidative stress [4,5].”
Smart Telomerase-Gated DNA cage for precise siRNA release in cancer cells
Han, X., Lu, Y., Wu, H., Guan, X., Ma, X., Chu, Y., Zou, B., & Zhou, G. (2023) · Chemical Engineering Journal · doi:10.1016/j.cej.2023.143782 · Cited by 4
Targeted siRNA delivery to lung epithelia reduces airway inflammation in a mouse model of allergic asthma
Ullah, I., Choi, H. S., Choi, C., Chung, K., Jung, J. W., Yun, G., Heo, S., Yi, Y., Kang, E., Kim, S., et al. (2024) · Biotechnology and Bioprocess Engineering · doi:10.1007/s12257-024-00027-3 · Cited by 4
“Additionally, RVG9R prevents inflammatory responses associated with cationic liposomes, demonstrating its safety [57].”
Nanotoxicology
Simón‐Vázquez, R., Peleteiro, M., Lozano‐Fernández, T., González‐Fernández, Á., & Casal, A. (2012) · Frontiers of nanoscience · doi:10.1016/b978-0-12-415769-9.00015-7 · Cited by 5
Modified Concatemeric Oligonucleotide Complexes: New System for Efficient Oligonucleotide Transfer into Mammalian Cells
Gusachenko, O. N., Pyshnyi, D. V., Vlassov, V. V., & Аркадьевна, З. М. (2008) · Human Gene Therapy · doi:10.1089/hum.2007.049 · Cited by 4
“These include cytotoxicity of lipid-based carriers, immune response to virus-based particles, and so on (Lappalainen et al ., 1994; Filion and Phillips, 1997; Worgall et al ., 1997; Timme et al ., 1998; Nyberg-Hoffman and Aguilar-Cordova, 1999; Dokka et al ., 2000; Raper et al ., 2003).”
Liposome-mediated gene delivery: A comprehensive review of biophysical parameters, lipid composition and targeting strategies
Sale, E. J., Satari, M., & Hajipour-Verdom, B. (2025) · ADMET & DMPK · doi:10.5599/admet.3065 · Cited by 3
“Despite this deficiency, anionic liposomes have become of interest as promising gene delivery vehicles due to the disadvantages of cationic liposomes, like inactivation by serum, instability in storage, and in vitro and in vivo cytotoxicity [76, 77].”
Cationic lipid-based nanoparticles for therapeutic delivery in cancer treatment: physicochemical characteristics, therapeutic cargos, and clinical potential
Bae, C.-S., & Ahn, T. (2026) · Han-guk hyeonmigyeong hakoeji/Applied microscopy · doi:10.1186/s42649-026-00130-0 · Cited by 4
“Unlike their neutral and negatively charged counterparts, they may induce lung inflammation and toxicity by stimulating the production of ROS (Dokka et al. 2000).”
RNA drugs and nonviral nanocarriers in oncology – present status and emerging concepts
Aigner, A. M. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152512 · Cited by 3
Nanotechnology Enabled Inhalation of Bio-therapeutics for Pulmonary Diseases: Design Considerations and Challenges
Joshi, N. (2018) · Current Pathobiology Reports · doi:10.1007/s40139-018-0183-9 · Cited by 3
General justification in terms of effectiveness and toxicities for the use of nanocarriers
Handali, S., & Rezaei, M. (2023) · Journal of Nanoparticle Research · doi:10.1007/s11051-023-05826-y · Cited by 3
“2,2,6,6-Tetramethylpi-peridine-1-oxyl (TEMPO) as a stable nitroxide free radical exhibited antioxidant activity by ROS scavenging.”
BackgroundInfluential
Apoptosis induced by cationic liposome based on the mitochondrial signaling pathway in vitro
Du, S., Wang, Y., Li, M., Zhao, Y., Zhi, D., Cui, S., & Zhang, S. (2024) · Journal of Materials Science · doi:10.1007/s10853-024-10192-8 · Cited by 3
“The primary factor contribute to this cytotoxicity is the cationic headgroup [12, 13].”
Cholesterol depletion induced by RNA interference targetingDHCR24protects cells from liposome-induced cytotoxicity
Yang, B., Mao, J. Y., Jiang, S., Wei, J., Li, Y., Gao, B., & Lu, X. (2019) · Preparative Biochemistry & Biotechnology · doi:10.1080/10826068.2019.1591979 · Cited by 3
“It has also been reported that the positive charge of the liposomes is a key factor of toxicity, with some studies using mice to test differently charged liposomes including Lipofectamine, DOTAP, neutral and negatively charged liposomes.([13]) It has been demonstrated in the previous study that the cationic liposomes…”
Background
Development, characterization, and in vitro evaluation of phosphatidylcholine–sodium cholate-based nanoparticles for siRNA delivery to MCF-7 human breast cancer cells
Pérez, S. E., Gándola, Y. B., Carlucci, A. M., & González, L. (2015) · Journal of Nanoparticle Research · doi:10.1007/s11051-015-2937-1 · Cited by 3
“…strong interaction with blood components, uptake by the reticuloendothelial system (RES), targeting-related issues, and potential toxicity for lung and other organs were associated with the use of these delivery systems (Dokka et al. 2000; Spagnou et al. 2004; Lv et al. 2006; Guo and Huang 2012).”
Background
Intratracheal Instillation of Lipopolymeric Vectors and the Effect on Mice Lung Physiology
Xisto, D. G., Temprana, C. F., Martini, S. V., da Silva, A. L., Abreu, S. C., Silva, J. D., Crosseti, J., Rocco, P. R. M., Alonso, S. D. V., & Morales, M. M. (2012) · Cellular Physiology and Biochemistry · doi:10.1159/000336917 · Cited by 3
Can Nanotechnology Hit the Spot in aerosol-based Drug Delivery for Lung disorders?
Joshi, N. (2018) · Therapeutic Delivery · doi:10.4155/tde-2017-0112 · Cited by 3
Saving zone of stasis in burn wounds by nanoliposomal Mg‐ATP
Hayati, F., Ghamsari, S. M., Dehghan, M. M., & Hamid, T. (2022) · Wound Repair and Regeneration · doi:10.1111/wrr.13048 · Cited by 2
“encapsulation of Mg-ATP, a negatively charged molecule, DOTAP might be used in the nanoliposome structure, but there have been claims that cationic liposomes are cytotoxic due to interactions between positively charged lipids and cell organelle membranes.(31,32) It is also accepted that anionic liposomes are less toxi…”
Background
Innovative siRNA Strategies: Scaling New Horizons in Diabetic Foot Ulcer Therapeutics
Kolipaka, T., Pandey, G., Amulya, E., Singh, A. K., Srinivasarao, D. A., & Srivastava, S. K. (2026) · BioNanoScience · doi:10.1007/s12668-025-02389-1 · Cited by 2
“[96, 97] Polymeric System Particle size and Shape Structural Chemistry • Immunogenic response • The branched chains are more toxic compared to the lin - ear ones.”
From mechanisms to applications: Research advances and translational prospects of endogenous targeting LNPs
Feng, Y., Zhao, Y., Han, J., Li, F., Li, G., Wang, B., Chen, Q., & Song, J. (2026) · Nano Research · doi:10.26599/nr.2026.94908571 · Cited by 3
Functionalized lipoplexes and polyplexes for cancer therapy
Chhikara, N., Singh, J., Sharma, A., Sood, A., & Kumar, A. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-15518-5.00006-9 · Cited by 2
Unveiling the Interaction Mechanism of siRNA with Lipid Bilayers of Different Types for siRNA-Based Therapy
Zheng, D., Lu, Z. G., Li, J., Dong, J., Zhang, X., Zhang, X., & Cao, D. (2025) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.4c07520 · Cited by 2
Pharmacogenomics-based RNA interference nanodelivery: focus on solid malignant tumors
Rosen, Y., Upadhyay, U. M., & Elman, N. M. (2012) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2012.685932 · Cited by 2
“Cationic liposomes can activate complement, induce production of factors such as tumor necrosis factor-a, and interleukin-6 and -12 [1,62,63].”
Background
Advances on nucleic acid delivery with nonviral vectors
Lopes, R. M., Fonseca, N. A., Cruz, A. F., Gregório, A. C., Valério-Fernandes, Â., Moura, V., Simões, S., & Moreira, J. N. (2016) · Elsevier eBooks · doi:10.1016/b978-0-08-100741-9.00014-0 · Cited by 2
Cationic Nanoparticles Containing Cationic Peptide Cargo Synergistically Induce Cellular Reactive Oxygen Species and Cell Death in HepG2 Cells
Yun, C., Bae, C., & Ahn, T. (2018) · International Journal of Peptide Research and Therapeutics · doi:10.1007/s10989-018-9674-0 · Cited by 2
Lipid-Based Nanosystems for the Delivery of siRNA: Challenges and Trends
Fonseca, N. A., Lopes, R. M., Cruz, A. F., Gregório, A. C., Valério-Fernandes, Â., Moura, V., Simões, S., & Moreira, J. N. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813339-2.00016-5 · Cited by 3

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
ORCID: Shi, Xianglin
Rojanasakul, Yon
Venue: Pharmaceutical Research
Publisher: Springer Science and Business Media LLC
Published: 2000-05
Volume: 17
Issue: 5
Pages: 521-525
ISSN: 0724-8741 (ISSN-L)
1573-904X
DOI: 10.1023/a:1007504613351
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: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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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Oxygen Radical-Mediated Pulmonary Toxicity Induced by Some Cationic Liposomes

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