In this study, magnetite nanoparticles were prepared and coated with poly(ethylene glycol) terminated by alendronate to ensure firm binding to the iron oxide surface. Magnetic nanoparticles, designated as magnetite coated with poly(ethylene glycol)-alendronate (Fe3O4@PEG-Ale), were characterized in terms of number-average (Dn) and hydrodynamic (Dh) size, ζ-potential, saturation magnetization, and composition. The effect of particles on blood pressure, vascular functions, nitric oxide (NO), and superoxide production in the tissues of spontaneously hypertensive rats, as well as the effect on red blood cell (RBC) parameters, was investigated after intravenous administration (1 mg Fe3O4/kg of body weight). Results showed that Fe3O4@PEG-Ale particles did negatively affect blood pressure, heart rate and RBC deformability, osmotic resistance and NO production. In addition, Fe3O4@PEG-Ale did not alter functions of the femoral arteries. Fe3O4@PEG-Ale induced increase in superoxide production in the kidney and spleen, but not in the left heart ventricle, aorta and liver. NO production was reduced only in the kidney. In conclusion, the results suggest that acute intravenous administration of Fe3O4@PEG-Ale did not produce negative effects on blood pressure regulation, vascular function, and RBCs in hypertensive rats.

Department of Molecular Biology Faculty of Natural Sciences Comenius University Mlynská Dolina Ilkovičova 6 842 15 Bratislava Slovakia

Institute for Heart Research Centre of Experimental Medicine Slovak Academy of Sciences Dúbravská Cesta 9 841 04 Bratislava Slovakia

Institute of Macromolecular Chemistry Czech Academy of Sciences Heyrovského Nám 2 162 06 Prague Czech Republic

Institute of Normal and Pathological Physiology Centre of Experimental Medicine Slovak Academy of Sciences Sienkiewiczova 1 813 71 Bratislava Slovakia

Institute of Pharmacology and Clinical Pharmacology Faculty of Medicine Comenius University Sasinkova 4 811 08 Bratislava Slovakia

Institute of Physiology Faculty of Medicine Comenius University Sasinkova 2 813 72 Bratislava Slovakia

Zobrazit více v PubMed

Wu Y., Lu Z., Li Y., Yang J., Zhang X. Surface modification of iron oxide-based magnetic nanoparticles for cerebral theranostics: Application and prospection. Nanomaterials. 2020;10:1441. doi: 10.3390/nano10081441. PubMed DOI PMC

González-Gómez M.A., Belderbos S., Yañez-Vilar S., Piñeiro Y., Cleeren F., Bormans G., Deroose C.M., Gsell W., Himmelreich U., Rivas J. Development of superparamagnetic nanoparticles coated with polyacrylic acid and aluminum hydroxide as an efficient contrast agent for multimodal imaging. Nanomaterials. 2019;9:1626. doi: 10.3390/nano9111626. PubMed DOI PMC

Stephen Z.R., Kievit F.M., Zhang M. Magnetite nanoparticles for medical MR imaging. Mater. Today. 2011;14:330–338. doi: 10.1016/S1369-7021(11)70163-8. PubMed DOI PMC

Fütterer S., Andrusenko I., Kolb U., Hofmeister W., Langguth P. Structural characterization of iron oxide/hydroxide nanoparticles in nine different parenteral drugs for the treatment of iron deficiency anaemia by electron diffraction (ED) and X-ray powder diffraction (XRPD) J. Pharm. Biomed. 2013;86:151–160. doi: 10.1016/j.jpba.2013.08.005. PubMed DOI

Wáng Y.X.J., Idée J.M. A comprehensive literatures update of clinical researches of superparamagnetic resonance iron oxide nanoparticles for magnetic resonance imaging. Quant. Imaging Med. Surg. 2017;7:88–122. doi: 10.21037/qims.2017.02.09. PubMed DOI PMC

Zhang Y.N., Poon W., Tavares A.J., McGilvray I.D., Chan W.C.W. Nanoparticle-liver interactions: Cellular uptake and hepatobiliary elimination. J. Control. Release. 2016;240:332–348. doi: 10.1016/j.jconrel.2016.01.020. PubMed DOI

Arami H., Khandhar A., Liggitt D., Krishnan K.M. In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide nanoparticles. Chem. Soc. Rev. 2015;44:8576–8607. doi: 10.1039/C5CS00541H. PubMed DOI PMC

Líšková S., Bališ P., Mičurová A., Kluknavský M., Okuliarová M., Puzserová A., Škrátek M., Sekaj I., Maňka J., Valovič P., et al. Effect of iron oxide nanoparticles on vascular function and nitric oxide production in acute stress-exposed rats. Physiol. Res. 2020;69:1067–1083. doi: 10.33549/physiolres.934567. PubMed DOI PMC

Kolenko Y.V., Bañobre-López M., Rodríguez-Abreu C., Carbó-Argibay E., Sailsman A., Piñeiro-Redondo Y., Cerqueira M.F., Petrovykh D.Y., Kovni K., Lebedev O.I., et al. Large-scale synthesis of colloidal Fe3O4 nanoparticles exhibiting high heating efficiency in magnetic hyperthermia. J. Phys. Chem. C. 2014;118:8691–8701. doi: 10.1021/jp500816u. DOI

Roca A.G., Marco J.F., Morales M.P., Serna C.J. Effect of nature and particle size on properties of uniform magnetite and maghemite nanoparticles. J. Phys. Chem. C. 2007;111:18577–18584. doi: 10.1021/jp075133m. DOI

Barrow M., Taylor A., Fuentes-Caparrós A.M., Sharkey J., Daniels L.M., Mandal P., Park B.K., Murray P., Rosseinsky M.J., Adams D.J. SPIONs for cell labelling and tracking using MRI: Magnetite or maghemite? Biomater. Sci. 2018;6:101–106. doi: 10.1039/C7BM00515F. PubMed DOI PMC

Luong D., Sau S., Kesharwani P., Iyer A.K. Polyvalent folate-dendrimer-coated iron oxide theranostic nanoparticles for simultaneous magnetic resonance imaging and precise cancer cell targeting. Biomacromolecules. 2017;18:1197–1209. doi: 10.1021/acs.biomac.6b01885. PubMed DOI PMC

NDong C., Tate J.A., Kett W.C., Batra J., Demidenko E., Lewis L.D., Hoopes P.J., Gerngross T.U., Griswold K.E. Tumor cell targeting by iron oxide nanoparticles is dominated by different factors in vitro versus in vivo. PLoS ONE. 2015;10:e0115636. doi: 10.1371/journal.pone.0115636. PubMed DOI PMC

Andrade R.G.D., Veloso S.R.S., Castanheira E.M.S. Shape anisotropic iron oxide-based magnetic nanoparticles: Synthesis and biomedical applications. Int. J. Mol. Sci. 2020;21:2455. doi: 10.3390/ijms21072455. PubMed DOI PMC

Dalzon B., Torres A., Reymond S., Gallet B., Saint-Antonin F., Collin-Faure V., Moriscot C., Fenel D., Schoehn G., Aude-Garcia C., et al. Influences of nanoparticles characteristics on the cellular responses: The example of iron oxide and macrophages. Nanomaterials. 2020;10:266. doi: 10.3390/nano10020266. PubMed DOI PMC

Gonzalez I., Mestach D., Leiza J.R., Asua J.M. Adhesion enhancement in waterborne acrylic latex binders synthesized with phosphate methacrylate monomers. Prog. Org. Coat. 2008;61:38–44. doi: 10.1016/j.porgcoat.2007.09.012. DOI

Guénin E., Hardouin J., Lalatonne Y., Motte L. Bivalent alkyne-bisphosphonate as clickable and solid anchor to elaborate multifunctional iron oxide nanoparticles with microwave enhancement. J. Nanopart. Res. 2012;14:965. doi: 10.1007/s11051-012-0965-7. DOI

Chen B.W., He Y.C., Sung S.Y., Le T.T.H., Hsieh C.L., Chen J.Y., Wei Z.H., Yao D.J. Synthesis and characterization of magnetic nanoparticles coated with polystyrene sulfonic acid for biomedical applications. Sci. Technol. Adv. Mater. 2020;21:471–481. doi: 10.1080/14686996.2020.1790032. PubMed DOI PMC

Guibert C., Dupuis V., Peyre V., Fresnais J. Hyperthermia of magnetic nanoparticles: Experimental study of the role of aggregation. J. Phys. Chem. C. 2015;119:28148–28154. doi: 10.1021/acs.jpcc.5b07796. DOI

Turcheniuk K., Tarasevych A.V., Kukhar V.P., Boukherroub R., Szunerits S. Recent advances in surface chemistry strategies for the fabrication of functional iron oxide based magnetic nanoparticles. Nanoscale. 2013;5:10729–10752. doi: 10.1039/c3nr04131j. PubMed DOI

Wang Y.X.J. Superparamagnetic iron oxide based MRI contrast agents: Current status of clinical application. Quant. Imaging Med. Surg. 2011;1:35–40. doi: 10.3978/j.issn.2223-4292.2011.08.03. PubMed DOI PMC

Larsen E.K.U., Nielsen T., Wittenborn T., Rydtoft L.M., Lokanathan A.R., Hansen L., Østergaard L., Kingshott P., Howard K.A., Besenbacher F., et al. Accumulation of magnetic iron oxide nanoparticles coated with variably sized polyethylene glycol in murine tumors. Nanoscale. 2012;4:2352–2361. doi: 10.1039/c2nr11554a. PubMed DOI

Ronnander P.L., Simon H., Spilgies A., Koch A., Scherr S. Dissolving polyvinylpyrrolidone-based microneedle systems for in-vitro delivery of sumatriptan succinate. Eur. J. Pharm. Sci. 2018;114:84–92. doi: 10.1016/j.ejps.2017.11.031. PubMed DOI

Boda S.K., Wang H., John J.V., Reinhardt R.A., Xie J. Dual delivery of alendronate and E7-BMP-2 peptide via calcium chelation to mineralized nanofiber fragments for alveolar bone regeneration. ACS Biomater. Sci. Eng. 2020;6:2368–2375. doi: 10.1021/acsbiomaterials.0c00145. PubMed DOI PMC

Bernatova I. Endothelial dysfunction in experimental models of arterial hypertension: Cause or consequence? Biomed. Res. Int. 2014;2014:598271. doi: 10.1155/2014/598271. PubMed DOI PMC

Gumienna-Kontecka E., Silvagni R., Lipinski R., Lecouvey M., Marincola F.C., Crisponi G., Nurchib V.M., Leroux Y., Kozlowski H. Bisphosphonate chelating agents: Complexation of Fe(III) and Al(III) by 1-phenyl-1-hydroxymethylene bisphosphonate and its analogues. Inorg. Chim. Acta. 2002;339:111–118. doi: 10.1016/S0020-1693(02)00918-0. DOI

Waterborg J.H. The Lowry method for protein quantitation. In: Walker J.M., editor. The Protein Protocols Handbook. 3rd ed. Humana Press; Totowa, NJ, USA: 2009. pp. 7–10.

Kluknavsky M., Balis P., Skratek M., Manka J., Bernatova I. (–)-Epicatechin reduces the blood pressure of young borderline hypertensive rats during the post-treatment period. Antioxidants. 2020;9:96. doi: 10.3390/antiox9020096. PubMed DOI PMC

Radosinska J., Jasenovec T., Radosinska D., Balis P., Puzserova A., Skratek M., Manka J., Bernatova I. Ultra-small superparamagnetic iron-oxide nanoparticles exert different effects on erythrocytes in normotensive and hypertensive rats. Biomedicines. 2021;9:377. doi: 10.3390/biomedicines9040377. PubMed DOI PMC

Cornell R.M., Schwertmann U. The Iron Oxides: Structure, Properties, Reactions, Occurrences and Uses. John Wiley; Weinheim, Germany: 2003. DOI

Labouta H.I., Gomez-Garcia M., Sarsons C.D., Nguyen T., Kennard J., Ngo W., Terefe K., Iragorri N., Lai P., Rinker K.D., et al. Surface-grafted polyethylene glycol conformation impacts the transport of PEG-functionalized liposomes through a tumour extracellular matrix model. RSC Adv. 2018;8:7697–7708. doi: 10.1039/C7RA13438J. PubMed DOI PMC

Rahme K., Chen L., Hobbs R.G., Morris M.A., O’Driscoll C., Holmes J.D. PEGylated gold nanoparticles: Polymer quantification as a function of PEG lengths and nanoparticle dimensions. RSC Adv. 2013;3:6085–6094. doi: 10.1039/C3RA22739A. DOI

Iyengar S.J., Joy M., Ghosh C.K., Dey S., Kotnala R.K., Ghosh S. Magnetic, X-ray and Mössbauer studies on magnetite/maghemite core-shell nanostructures fabricated through an aqueous route. RSC Adv. 2014;4:64919–64929. doi: 10.1039/C4RA11283K. DOI

Khanna R.K., Moore M.H. Carbamic acid: Molecular structure and IR spectra. Spectrochim. Acta A Mol. Biomol. Spectrosc. 1999;55:961–967. doi: 10.1016/S1386-1425(98)00228-5. PubMed DOI

Patsula V., Horák D., Kučka J., Macková H., Lobaz V., Francová P., Herynek V., Heizer T., Páral P., Šefc L. Synthesis and modification of uniform PEG-neridronate-modified magnetic nanoparticles determines prolonged blood circulation and biodistribution in a mouse preclinical model. Sci. Rep. 2019;9:1–12. doi: 10.1038/s41598-019-47262-w. PubMed DOI PMC

Cummings S.R., Santora A.C., Black D.M., Russell R.G.G. History of alendronate. Bone. 2020;137:115411. doi: 10.1016/j.bone.2020.115411. PubMed DOI

Thomas J.C. The determination of log normal particle size distributions by dynamic light scattering. J. Colloid Interface Sci. 1987;117:187–192. doi: 10.1016/0021-9797(87)90182-2. DOI

Fischer K., Schmidt M. Pitfalls and novel applications of particle sizing by dynamic light scattering. Biomaterials. 2016;98:79–91. doi: 10.1016/j.biomaterials.2016.05.003. PubMed DOI

Iversen N.K., Frische S., Thomsen K., Laustsen C., Pedersen M., Hansen P.B., Bie P., Fresnais J., Berret J.F., Baatrup E., et al. Superparamagnetic iron oxide polyacrylic acid coated γ-Fe2O3 nanoparticles do not affect kidney function but cause acute effect on the cardiovascular function in healthy mice. Toxicol. Appl. Pharmacol. 2013;266:276–288. doi: 10.1016/j.taap.2012.10.014. PubMed DOI

Zhu M.T., Wang Y., Feng W.Y., Wang B., Wang M., Ouyang H., Chai Z.F. Oxidative stress and apoptosis induced by iron oxide nanoparticles in cultured human umbilical endothelial cells. J. Nanosci. Nanotechnol. 2010;10:8584–8590. doi: 10.1166/jnn.2010.2488. PubMed DOI

Astanina K., Simon Y., Cavelius C., Petry S., Kraegeloh A., Kiemer A.K. Superparamagnetic iron oxide nanoparticles impair endothelial integrity and inhibit nitric oxide production. Acta. Biomater. 2014;10:4896–4911. doi: 10.1016/j.actbio.2014.07.027. PubMed DOI

Yarjanli Z., Ghaedi K., Esmaeili A., Rahgozar S., Zarrabi A. Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation. BMC Neurosci. 2017;18:51. doi: 10.1186/s12868-017-0369-9. PubMed DOI PMC

Benyettou F., Hardouin J., Lecouvey M., Jouni H., Motte L. PEGylated versus non-PEGylated γ-Fe2O3@alendronate nanoparticles. J. Bioanal. Biomed. 2012;4:39–45. doi: 10.4172/1948-593X.1000062. DOI

Škrátek M., Dvurečenskij A., Kluknavský M., Barta A., Bališ P., Mičurová A., Cigáň A., Eckstein-Andicsová A., Maňka J., Bernátová I. Sensitive SQUID bio-magnetometry for determination and differentiation of biogenic iron and iron oxide nanoparticles in the biological samples. Nanomaterials. 2020;10:1993. doi: 10.3390/nano10101993. PubMed DOI PMC

Intraperitoneal versus intravenous administration of Flamma®-conjugated PEG-alendronate-coated upconversion nanoparticles in a mouse pancreatic cancer model

Effects of Iron Nanoparticles Administration on Ischemia/Reperfusion Injury in Isolated Hearts of Male Wistar Rats