Cell and Organ Transplantology. 2021; 9(1):44-52.
DOI: 10.22494/cot.v9i1.121
The assessment of the toxicity of nanocomplexes containing gadolinium orthovanadate nanoparticles and cholesterol
Goltsev A.¹
, Bondarovych M.¹, Babenko N.¹, Gaevska Yu.¹, Ostankova L.¹, Ostankov M.¹, Volkova N.¹, Klochkov V.²
- ¹Institute for Problems of Cryobiology and Сryomedicine, National Academy of Sciences of Ukraine, Kharkiv, Ukraine
- ²Institute for Scintillation Materials, National Academy of Sciences of Ukraine, Kharkiv, Ukraine
Abstract
Nanocomplexes (NCs) synthesized at the Institute for Scintillation Materials of the National Academy of Sciences of Ukraine, consisting of nanoparticles (NPs) of gadolinium orthovanadate and cholesterol, are promising compounds that can be used as probes and fluorescent labels for tumor cells or experimental oncopathology treatment. However, the biosafety of such substances remains unclear.
The purpose of the study was to evaluate the acute toxic effect of nanocomplexes on the healthy mice.
Materials and methods. Nanocomplexes containing nanoparticles of GdYVO4:Eu3+ and cholesterol in 5 % glucose solution were administered to BALB/c mice once intraperitoneally in volumes of 0.1 mL, 0.5 mL, 1 mL, 2 mL, which corresponds to 5.9-6, 5 mg, 29.5-32.5 mg, 59.1-65.0 mg, 118.2-130.0 mg/kg body weight. Control animals were injected with the same volumes of 5 % glucose solution. On the 14th day, the morphological characteristics of organs, the number of CD34+CD38– cells among bone marrow total nucleated cells, the activity of gamma-glutamyl transferase (GGT) and glucose-6-phosphate dehydrogenase (G6PD) in liver homogenates were determined.
Results. With the administration of NPs at a dose of less than 118.2 mg/kg body weight, no fatalities and symptoms of intoxication were showed, but there was a dose-dependent increase in the content of GGT in the liver of experimental animals. The use of NPs at a dose of 118.2-130.0 mg/kg body weight resulted in the death of 50 % of the animals on the 3rd day. In this group, on the 14th day, there were neoplasms in the spleen of one of the surviving animals, a decrease in the number of bone marrow total nucleated cell on the background of increased hematopoietic stem cells with CD34+CD38– phenotype, necrotic and dystrophic changes in the liver, and decreased activity of the G6PD enzyme.
Conclusions. The potential median lethal dose of gadolinium orthovanadate nanoparticles and cholesterol in nanocomplexes was determined, which was 118.2-130.0 mg/kg animal body weight, which allows to classify them as low-toxic substances.
Key words: nanoparticles; nanocomplexes; gadolinium orthovanadate; median lethal dose
Full Text PDF| 1. Chekman I. S. Fiziologichni ta farmakologichni vlastyvosti nanorozmirnyh struktur. [Physiological and pharmacological properties of nanosized structures]. Fiziologichnyj zhurnal – Physiological journal. 2015; 61(6):129138. [In Ukrainian]
https://doi.org/10.15407/fz61.06.129 PMid:27025054 |
||||
| 2. Leonenko NS, Demetskaya OV, Leonenko OB. Osoblyvosti fizyko-himichnyh vlastyvostej ta toksychnoi’ dii’ nanomaterialiv – do problemy ocinky i’hn’ogo nebezpechnogo vplyvu na zhyvi organizmy (ogljad literatury) [Features of physicochemical properties and toxic effects of nanomaterials – to the problem of assessing their dangerous effects on living organisms (review)]. Suchasni problemy toksykologii’, harchovoi’ ta himichnoi’ bezpeky – Modern problems of toxicology, food and chemical safety. 2016; 1:64-76. [In Ukrainian] | ||||
| 3. Poole Ch, Owens F. Nanotehnologyy. 2-e, dopolnennoe yzdanye. Moskva: Tehnosfera [Nanotechnology. 2nd, revised edition. Moscow: Technosphere]. 2006. 424 p. [In Russian] | ||||
| 4. Checkman IS. Nanochastynky: vlastyvosti ta perspektyvy zastosuvannja [Nanoparticles: properties and application prospects]. Ukrai’ns’kyj biohimichnyj zhurnal – Ukrainian Biochemical Journal. 2009; 81(1):122-129. [In Ukrainian] | ||||
| 5. Klochkov VK, Kavok NS, Malyukin YuV, Seminozhenko VP. Эffekt specyfycheskogo vzaymodejstvyja nanokrystallov GdYVO4:Eu^3+ s jadramy kletok [Effect of specific interaction of GdYVO4: Eu ^ 3 + nanocrystals with cell nuclei]. Dopovidi NAN Ukrai’ny – Reports of the National Academy of Sciences of Ukraine. 2010; 10:81-86. [In Russian] | ||||
| 6. Donaldson K, Stone V. Current hypotheses on the mechanisms of toxicity of ultrafine particles. Ann Ist Super Sanita. 2003; 39(3):405-410. | ||||
| 7. Kavok NS, Averchenko KA, Klochkov VK, et al. Mitochondrial potential changes in single rat hepatocytes: The effect of orthovanadate nanoparticles doped with rare-earth elements. Eur Phys J Plus. 2014; 371(12):127-130. https://doi.org/10.1140/epje/i2014-14127-9 PMid:25533054 |
||||
| 8. Escudero A, Becerro AI, Carrillo-Carrion C, et al. Rare earth based nanostructured materials: Synthesis, functionalization, properties and bioimaging and biosensing applications. Nanophotonics. 2017; 6(5):881-921. https://doi.org/10.1515/nanoph-2017-0007 |
||||
| 9. Goltsev AM, Malyukin YV, Babenko NM, et al. Antitumor activity of spherical nanoparticles GdYVO4:Eu3+ depends on pre-incubation time. Appl. Nanosci. 2020; 10(8):2749-2758. https://doi.org/10.1007/s13204-020-01284-3 |
||||
| 10. Rehder D. The potentiality of vanadium in medicinal applications. Future Med Chem. 2012; 4(14):1823-1837. https://doi.org/10.4155/fmc.12.103 PMid:23043479 |
||||
| 11. Sakurai H, Yoshikawa Y, Yasui H. Current state for the development of metallopharmaceutics and anti-diabetic metal complexes. Chem Soc Rev. 2008. 37, № 11. P. 2383-2392. https://doi.org/10.1039/b710347f PMid:18949111 |
||||
| 12. Mehdi MZ, Pandey SK, Théberge JF, Srivastava AK. Insulin signal mimicry as a mechanism for the insulin-like eff ects of vanadium. Cell Biochem Biophys. 2006; 44(1):73-81. https://doi.org/10.1385/CBB:44:1:073 |
||||
| 13. Treviño S, Díaz A, Sánchez-Lara E, et al. Vanadium in Biological Action: Chemical, Pharmacological Aspects, and Metabolic Implications in Diabetes Mellitus. Biol Trace Elem Res. 2019; 188:68-98. https://doi.org/10.1007/s12011-018-1540-6 PMid:30350272 PMCid:PMC6373340 |
||||
| 14. Fu PP, Xia Q, Hwang HM, et al. Mechanisms of nanotoxicity: Generation of reactive oxygen species. J Food Drug Anal. 2014; 22(1):64-75. https://doi.org/10.1016/j.jfda.2014.01.005 PMid:24673904 |
||||
| 15. Köpf-Maier P, Köpf H. Metallocene complexes: organometallic antitumor agents. Drugs Future. 1986; 11:297-319. https://doi.org/10.1358/dof.1986.011.04.237197 |
||||
| 16. Köpf-Maier P, Krahl D. Tumor inhibition by metallocenes: ultrastructural localization of titanium and vanadium in treated tumor cells by electron energy loss spectroscopy. Chem-Biol Interact. 1983; 44(3):317-328. https://doi.org/10.1016/0009-2797(83)90059-5 |
||||
| 17. Köpf-Maier P, Wagner W, Liss E. Cytokinetic behavior of Ehrlich ascites tumor after in vivo treatment with cis -diamminedichloroplatinum(II) and metallocene dichlorides . J Cancer Res Clin Oncol. 1981; 102(1):21-30. https://doi.org/10.1007/BF00410531 PMid:7199526 |
||||
| 18. Köpf-Maier P. Development of necroses virus, activation and giant cell formation after treatment of Ehrlich ascites tumor with metallocene dichlorides. J Cancer Res Clin Oncol. 1982; 103:145-164. https://doi.org/10.1007/BF00409645 PMid:7096436 |
||||
| 19. Rodriguez-Mercado JJ, Mateos-Nava RA, Altamirano-Lozano MA. DNA damage induction in human cells exposed to vanadium oxides in vitro. Toxicol In Vitro. 2011; 25(8):1996-2002. https://doi.org/10.1016/j.tiv.2011.07.009 PMid:21803147 |
||||
| 20. Molinuevo MS, Barrio DA, Cortizo AM, Etcheverry SB. Antitumoral properties of two new vanadyl (IV) complexes in osteoblasts in culture: role of apoptosis and oxidative stress. Cancer Chemother Pharmacol. 2004; 53(2):163-172. https://doi.org/10.1007/s00280-003-0708-7 PMid:14551736 |
||||
| 21. Korbecki J, Baranowska-Bosiacka I, Gutowska I, Chlubek D. Biochemical and medical importance of vanadium compounds. Acta Biochimica Polonica. 2012; 59(2):195-200. https://doi.org/10.18388/abp.2012_2138 PMid:22693688 |
||||
| 22. Klochkov VK. Instytut scyntyljacijnyh materialiv NAN Ukrai’ny, vlasnyk. Sposib otrymannja vodnoi’ dyspersii’ holesterynu [Institute of Scintillation Materials of the National Academy of Sciences of Ukraine, owner. The method of obtaining an aqueous dispersion of cholesterol]. Patent Ukrai’ny – Patent of Ukraine 10801. 10.03.2015. [In Ukrainian] | ||||
| 23. Al – Jarallah A, Trigatti BL. A role for the scavenger receptor, class B type I in high density lipoprotein dependent activation of cellular signaling pathways. Biochim Biophys Acta. 2010; 1801(1):1239-1248. https://doi.org/10.1016/j.bbalip.2010.08.006 PMid:20732452 |
||||
| 24. Goltsev AN, Babenko NN, Gaevskaya YA, et al. Nanotechniques inactivate cancer stem cells. Nanoscale Res Let. 2017; 12(1):415. https://doi.org/10.1186/s11671-017-2175-9 PMid:28622715 PMCid:PMC5472644 |
||||
| 25. Rukovodstvo po eksperimental’nomu (doklinicheskomu) izucheniyu novykh farmakologicheskikh veshchestv / pod obshchey red. Khabrieva RU. [Guidelines for experimental (preclinical) study of new pharmacological substances / ed. Khabrieva RU.]. Moskva: OAO Izdatel’stvo «Meditsina» – Moscow: JSC Publishing House «Medicine». 2005. 832 p. [In Russian] | ||||
| 26. Doklinichni doslidzhennja likars’kyh zasobiv (metodychni rekomendacii’) / za red. OV Stefanova [Preclinical studies of drugs (guidelines) / ed. Stefanova ОВ.]. Kyi’v: Avicena – Kyiv: Avicenna. 2001. 528 p. [In Ukrainian] | ||||
| 27. Laboratorni metody doslidzhen’ u biologii’, tvarynnyctvi ta veterynarnij medycyni: Dovidnyk / za red. Vlizla VV. [Laboratory research methods in biology, animal husbandry and veterinary medicine: Handbook / ed. Vlizla VV]. L’viv: Spolom -Lviv: Spolom. 2012. 764 p. [In Ukrainian] | ||||
| 28. Belkina IO, Karpenko NA, Koreneva EM, et al. Korrektsiya rasstroystv reproduktivnoy funktsii samtsov krys s pomoshch’yu nanochastits ortovanadata gadoliniya [Correction of reproductive disorders in male rats using nanoparticles of gadolinium orthovanadate]. Vesci Nacyjanal”naj akadjemii navuk Belaruci. Seryja medycynskih navuk – Bulletin of the National Academy of Sciences of Belarus. Medical Sciences Series.2018; 15(3):293-305. [In Russian] https://doi.org/10.29235/1814-6023-2018-15-3-293-305 | ||||
| 29. Kulinskiy VI, Kolesnichenko LS. Sistema glutationa. II. Drugie fermenty, tiol-disul’fidnyy obmen, vospalenie i immunitet, funktsii [Glutathione system. II. Other enzymes, thiol-disulfide metabolism, inflammation and immunity, functions]. Biomedical Chemistry – Biomeditsinskaya khimiya. 2009; 55(4):365-379. [In Russian] | ||||
| 30. Stanton RC. Glucose-6-Phosphate Dehydrogenase, NADPH, and Cell Survival. IUBMB. 2012; 64(5):362-369. https://doi.org/10.1002/iub.1017 PMid:22431005 PMCid:PMC3325335 |
||||
| 31. Belkina IO. Gonadotoksychnist’ nanochastynok gadoliniju ortovanadatu za umov hronichnogo nadhodzhennja [Gonadotoxicity of gadolinium orthovanadate nanoparticles under conditions of chronic intake]. Problemy endokrynnoi’ patologii’ – Problems of endocrine pathology. 2017; 3:78-85. [In Ukrainian] | ||||
| 32. Koreneva EM, Karpenko NO, Smolenko NP. Vplyv nanochastynok ortovanadatu g’adoliniju ta dioksydu ceriju na spermogramu doroslyh samciv shhuriv iz neonatal’no indukovanymy rozladamy reproduktyvnoi’ funkcii’ [Influence of gadolinium orthovanadate nanoparticles and cerium dioxide on the spermogram of adult male rats with neonatally induced disorders of reproductive function]. Problemy endokrynnoi’ patologii’ – Problems of endocrine pathology. 2016; 1:48-55. [In Ukrainian] | ||||
| 33. Nikitchenko YuV, Klochkov VK, Kavok NS, et al. Nanochastitsy ortovanadata gadoliniya uvelichivayut vyzhivaemost’ starykh krys [Nanoparticles of gadolinium orthovanadate increase the survival rate of old rats]. Dopovidi NAN Ukrai’ny – Reports of the National Academy of Sciences of Ukraine. 2020; 2:29-36. [In Russian] https://doi.org/10.15407/dopovidi2020.02.029 | ||||
| 34. Karpenko NO, Korenieva YeM, Chystiakova Eye, et al. The influence of the rare-earth metals nanoparticles on the rat’s males reproductive function in the descending stage of ontogenesis. Ukr biopharm j. 2016; 45(4):75-80. https://doi.org/10.24959/ubphj.16.59 |
||||
| 35. Goltsev AN, Babenko NN, Gaevskaya YuA, et al. Application of nanoparticles based on rare earth orthovanadates to inactivate Ehrlich carcinoma growth. Biotechnol Acta. 2015; 8(4):113-121. https://doi.org/10.15407/biotech8.04.113 |
||||
Goltsev A, Bondarovych M, Babenko N, Ostankova L, Ostankov M, Volkova N, Klochkov V. The assessment of the toxicity of nanocomplexes containing gadolinium orthovanadate nanoparticles and cholesterol. Cell Organ Transpl. 2021; 9(1):44-52. Available from: https://doi.org/10.22494/cot.v9i1.121
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.