Chemical-physical criticality and toxicological potential of lipid nanomaterials contained in a COVID-19 mRNA vaccine
Keywords:COVID-19 mRNA vaccine, LNP, lipid nanoparticles, nanomaterials, nanoforms, electrolytes, reactive oxygen species, aggregate, agglomerate, flocculate
The medicinal preparation called Comirnaty by Pfizer-BioNTech is an aqueous dispersion of lipid nanomaterials, intended to constitute, after thawing and dilution, the finished product for intramuscular injection. In the present study, we examine some evident chemical-physical criticalities of the preparation, regarding the manifest instability of its qualitative-quantitative composition, as well as its consequent toxicological potential, in this case related to the possible formation of ROS (reactive oxygen species), after intramuscular inoculation, in different biological sites, such as, potentially, kidneys, liver, heart, brain, etc., causing dysfunctions and alterations thereof.
Of particular concern is the presence in the formulation of the two functional excipients, ALC-0315 and ALC-0159, never used before in a medicinal product, nor registered in the European Pharmacopoeia, nor in the European C&L inventory. The current Safety Data Sheets of the manufacturer are omissive and non-compliant, especially with regard to the provisions of current European regulations on the registration, evaluation, authorization and restriction of nanomaterials.
The presence of electrolytes in the preparation and the subsequent dilution phase after thawing and before inoculation raise well-founded concerns about the precarious stability of the resulting suspension and the Polydispersity index of the nanomaterials contained in it, factors that can be hypothesized as the root causes of numerous post-vaccination adverse effects recorded at statistical-epidemiological level. Further immediate studies and verifications are recommended, taking into consideration, if necessary and for purely precautionary purposes, the immediate suspension of vaccinations with the Pfizer-BioNTech Comirnaty preparation.
Barone, F., De Angelis, I., Andreoli, C., Battistelli, C. L., Arcangeli, C., & Leter, G. (2017). Metodi in vitro e in silico per la valutazione del potenziale tossicologico dei nanomateriali. ENEA -Focus 3/2017 Energia, ambiente e innovazione, DOI 10.12910/EAI2017-045
Bruinink, A., Wang, J., & Wick, P. (2015). Effect of particle agglomeration in nanotoxicology. Arch Toxicol 89, 659–675. https://doi.org/10.1007/s00204-015-1460-6
Bushmanova, S.V., Ivanov, A.O., Buyevich, & Yu. A. (1994). The effect of an electrolyte on phase separation in colloids. Physica A: Statistical Mechanics and its Applications, Volume 202 (1–2), 175-195, ISSN 0378-4371, https://doi.org/10.1016/0378-4371(94)90173-2
Chompoosor A., Saha K., Ghosh P.S., Macarthy D.J., Miranda O.R., Zhu Z.J., Arcaro K.F., & Rotello V.M. (2010, October 18). The role of surface functionality on acute cytotoxicity, ROS generation and DNA damage by cationic gold nanoparticles. Small. 6(20):2246-9. https://doi.org/10.1002/smll.201000463
Demple, B., & Harrison, L. (1994). Repair of oxidative damage to DNA: enzymology and biology. Annu Rev Biochem. 63:915-48. doi: 10.1146/annurev.bi.63.070194.004411.
Di Bucchianico, S., Fabbrizi, M.R., Cirillo, S., Uboldi, C., Gilliland, D., Valsami-Jones, E., & Migliore, L. (2014, May 8). Aneuploidogenic effects and DNA oxidation induced in vitro by differently sized gold nanoparticles. Int J Nanomedicine. 9(1):2191-2204. https://doi.org/10.2147/IJN.S58397
Dufour, E.K., Kumaravel, T., Nohynek, G.J., Kirkland, D., & Toutain, H. (2006, September). Clastogenicity, photo-clastogenicity or pseudo-photo-clastogenicity: Genotoxic effects of zinc oxide in the dark, in pre-irradiated or simultaneously irradiated Chinese hamster ovary cells. Mutation Research. 607(2):215-224. https://doi.org/10.1016/j.mrgentox.2006.04.015
Fröhlich, E. (2012). The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int J Nanomedicine. 7:5577-5591 https://doi.org/10.2147/IJN.S36111
Imlay, J.A., Linn S. (1988, June 3). DNA damage and oxygen radical toxicity. Science. 240(4857):1302-9. https://www.science.org/doi/10.1126/science.3287616
Jena, N.R. (2012, July). DNA damage by reactive species: Mechanisms, mutation and repair. J Biosci. 37(3): 503-17. https://doi.org/10.1007/s12038-012-9218-2
Kang, S.J., Kim B.M., Lee Y.J., & Chung H.W. (2008, June). Titanium dioxide nanoparticles trigger p53-mediated damage response in peripheral blood lymphocytes. Environ Mol Mutagen. 49(5):399-405. https://doi.org/10.1002/em.20399
Kirsch-Volders, M., Vanhauwaert, A., De Boeck, M., & Decordier, I. (2002, July 25). Importance of detecting numerical versus structural chromosome aberrations. Mutat Res. 504(1-2):137-48. https://doi.org/10.1016/S0027-5107(02)00087-8
Levine, A.S., Sun, L., Tan, R., Gao, Y., Yang, L., Chen, H., Teng, Y., & Lan, L. (2017). The oxidative DNA damage response: A review of research undertaken with Tsinghua and Xiangya students at the University of Pittsburgh. Sci. China Life Sci. 60, 1077–1080 https://doi.org/10.1007/s11427-017-9184-6
Liou, G.Y., & Storz, P. (2010, May). Reactive oxygen species in cancer. Free Radic Res. 44(5):479-96. https://doi.org/10.3109/10715761003667554
Maki, H., & Sekiguchi, M. (1992). MutT protein specifically hydrolyses a potent mutagenic substrate for DNA synthesis. Nature 355, 273–275. https://doi.org/10.1038/355273a0
Mateuca R., Lombaert N., Aka P.V., Decordier I., & Kirsch-Volders M. (2006, November). Chromosomal changes: induction, detection methods and applicability in human biomonitoring. Biochimie. 88(11):1515-31. https://doi.org/10.1016/j.biochi.2006.07.004
Moghimi, S. M. (2021, March). Allergic Reactions and Anaphylaxis to LNP-Based COVID-19 Vaccines. Perspective. Volume 29, issue 3, pp. 898-900. https://doi.org/10.1016/j.ymthe.2021.01.030
Nel, A., Xia, T., Mädler, L., & Li, N. (2006, February 3). Toxic potential of materials at the nanolevel. Science. 311(5761):622-7. https://www.science.org/doi/10.1126/science.1114397
Proquin, H., Rodríguez-Ibarra, C., Moonen, C.G., Urrutia Ortega, I.M., Briedé, J.J., de Kok,T.M., van Loveren, H., & Chirino, Y.I. (2017, January). Titanium dioxide food additive (E171) induces ROS formation and genotoxicity: contribution of micro and nano-sized fractions. Mutagenesis. 32(1):139-149. https://doi.org/10.1093/mutage/gew051
Rusyn, I., Asakura, S., Pachkowski, B., Bradford ,B.U., Denissenko, M.F., Peters. J.M., Holland, S.M., Reddy, J.K., Cunningham, M.L., & Swenberg, J.A. (2004). Expression of base excision DNA repair genes is a sensitive biomarker for in vivo detection of chemical-induced chronic oxidative stress: identification of the molecular source of radicals responsible for DNA damage by peroxisome proliferators. Cancer Res 64(3):1050–1057 https://doi.org/10.1158/0008-5472.CAN-03-3027
Singh, N., Manshian, B., Jenkins, G.J., Griffiths, S.M., Williams, P.M., Maffeis, T.G., Wright, C.J., & Doak, S.H. (2009, August). NanoGenotoxicology: the DNA damaging potential of engineered nanomaterials. Biomaterials. 30(23-24):3891-914. https://doi.org/10.1016/j.biomaterials.2009.04.009
Tadros, T.F. (2018). 7. Flocculation of colloidal dispersions. Volume 1 Basic Principles of Interface Science and Colloid Stability - Berlin, Boston: De Gruyter, pp. 117-128. https://doi.org/10.1515/9783110540895-008
Tenchov, R., Bird, R., Curtze, A. E., & Zhou, Q. (2021). Lipid Nanoparticles - From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement, ACS Nano 2021 15 (11), 16982-17015, https://pubs.acs.org/doi/pdf/10.1021/acsnano.1c04996
Tretyakova, N.Y., Groehler, A. 4th, & Ji, S. (2015). DNA-Protein Cross-Links: Formation, Structural Identities, and Biological Outcomes. Acc. Chem. Res. 48, 6, 1631–1644. https://doi.org/10.1021/acs.accounts.5b00056
Yu, Z., Li, Q., Wang, J., Yu, Y., Wang, Y., & Zhou, Q. (2020). Reactive Oxygen Species-Related Nanoparticle Toxicity in the Biomedical Field - Nanoscale Res Lett 15, 115 https://doi.org/10.1186/s11671-020-03344-7
Yun, C.H., Bae, C.S., & Ahn, T. (2016). Cargo-Free Nanoparticles Containing Cationic Lipids Induce Reactive Oxygen Species and Cell Death in HepG2 Cells - Biol Pharm Bull. 39(8):1338-46 https://doi.org/10.1248/bpb.b16-00264
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