The aim of our study was to monitor the antiproliferative/ cytotoxic and genotoxic effects of both, poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) and titanium dioxide (TiO2) nanoparticles on the tumor (HT-29, MCF-7, U118MG) and healthy (HEK-293T) cell lines during 2D cultivation and during cultivation in the spheroid form (3D cultivation). Cells or spheroids were cultivated with nanoparticles (0.01, 0.1, 1, 10, 50, and 100 ?g/ml) for 72 hours. The cytotoxic effect was determined by the MTT test and the genotoxic effect by the comet assay. We found that 2D cultivation of tumor cell lines with PEG-b-PLA and TiO2 nanoparticles had an anti-proliferative effect on human colon cancer cell line HT-29, human breast cancer cell line MCF-7, human glioma cell line U-118MG during 72h cultivation, but not on control/healthy HEK-293T cells. At the concentrations used, the tested nanoparticles caused no cytotoxic effect on tumor cell lines. Nanoparticles PEG-b-PLA induced significant damage to DNA in HT-29 and MCF-7 cells, while TiO2 nanoparticles in MCF-7 and U-118MG cells. Only PEG-b-PLA nanoparticles caused cytotoxic (IC50 = 7 mikrog/ml) and genotoxic effects on the healthy cell line HEK-293T after 72h cultivation. The cells which were cultivated in spheroid forms were more sensitive to both types of nanoparticles. After 72h cultivation, we observed the cytotoxic effect on both, the tumor and healthy cell lines.

Institute of Medical Chemistry Biochemistry and Clinical Biochemistry Faculty of Medicine Comenius University Bratislava Slovak Republic

Zobrazit více v PubMed

Kavoosi F, Modaresi F, Sanaei M, Rezaei Z. Medical and dental applications of nanomedicines. J Pathol Microbiol Immunol. 2018;126:795–803. doi: 10.1111/apm.12890. PubMed DOI

Hofmann-Amtenbrink M, Grainger DW, Hofmann H. Nanoparticles in medicine: Current challenges facing inorganic nanoparticle toxicity assessments and standardizations. Nanomedicine: Nanotechnology, Biology and Medicine. 2015;11:1689–1694. doi: 10.1016/j.nano.2015.05.005. PubMed DOI

Rizvi SAA, Saleh AM. Applications of nanoparticle systems in drug delivery technology. Saudi Pharm J, 2018;26:64–70. doi: 10.1016/j.jsps.2017.10.012. PubMed DOI PMC

Liu J, Jiang X, Ashley C, Brinker CJ. Electrostatically mediated liposome fusion and lipid exchange with a nanoparticle-supported bilayer for control of surface charge, drug containment, and delivery. J Am Chem Soc. 2009;131:7567–7569. doi: 10.1021/ja902039y. PubMed DOI PMC

Friedman AD, Claypool SE, Liu R. The Smart Targeting of Nanoparticles. Curr Pharm Des. 2013;19:6315–6329. doi: 10.2174/13816128113199990375. PubMed DOI PMC

Czajka M, Sawicki K, Sikorska K, Popek S, Kruszewski M, Kapka-Skrzypczak L. Toxicity of titanium dioxide nanoparticles in central nervous system. Toxicol In Vitro, 2015;29:1042–1052. doi: 10.1016/j.tiv.2015.04.004. PubMed DOI

Bahadar H, Maqbool F, Niaz K, Abdollahi Toxicity of Nanoparticles and an Overview of Current Experimental Models. Iran Biomed J. 2016;20:1–11. PubMed PMC

Lakkireddy HR, Bazile D. Toxicity of nanoparticles and an overview of current experimental models. Iran Biomed J. 2016;20:1–11. PubMed PMC

Mohamad NH, Morsi MM, Ahmed AE, Sherif K. Microwave-assisted preparation of Nano-hydroxyapatite for bone substitutes. Ceramics International, 2016;42:3725–3744. doi: 10.1016/j.ceramint.2015.11.044. DOI

Tam YT, To KK, Chow AH. Fabrication of doxorubicin nanoparticles by controlled antisolvent precipitation for enhanced intracellular delivery. Colloids Surf B Biointerfaces. 2016;139:249–58. doi: 10.1016/j.colsurfb.2015.12.026. PubMed DOI

Saucier-Sawyer JK, Deng Y, Seo YE, Cheng CJ, Zhang J, Quijano E, Saltzman WM. Systemic delivery of blood-brain barrier targeted polymeric nanoparticles enhances delivery to brain tissue. J Drug Target. 2015;23:736–749. doi: 10.3109/1061186X.2015.1065833. PubMed DOI PMC

Shi H, Magaye R, Castranova V, Zhao J. Titanium dioxide nanoparticles: a review of current toxicological data. Part Fibre Toxicol. 2013;10:15. doi: 10.1186/1743-8977-10-15. PubMed DOI PMC

Lin Z, Monteiro-Riviere NA, Riviere JE. Pharmacokinetics of metallic nanoparticles. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015;7:189–217. doi: 10.1002/wnan.1304. PubMed DOI

Grande F, Tucci P. Titanium dioxide nanoparticles: a risk for human health? Mini Rev Med Chem. 2016;16:762–769. doi: 10.2174/1389557516666160321114341. PubMed DOI

Rollerova E, Jurcovicova J, Mlynarcikova A, Sadlonova I, Bilanicova D, Wsolova L, Kiss A, Kovriznych J, Kronek J, Ciampor F, Vavra I, Scsukova S. Delayed adverse effects of neonatal exposure to polymeric nanoparticle poly(ethylene glycol)-block-polylactide methyl ether on hypothalamic-pituitary-ovarian axis development and function in Wistar rats. Reprod Toxicol. 2015;57:165–175. doi: 10.1016/j.reprotox.2015.07.072. PubMed DOI

Volkovova K, Handy RD, Staruchova M, Tulinska J, Kebis A, Pribojova J, Ulicna O, Kucharská J, Dusinska M. Health effects of selected nanoparticles in vivo: liver function and hepatotoxicity following intravenous injection of titanium dioxide and Na-oleate-coated iron oxide nanoparticles in rodents. Nanotoxicology. 2015;1:95–105. doi: 10.3109/17435390.2013.815285. PubMed DOI

Bizik J, Kankuri E, Ristimäki A, Taïeb A, Vapaatalo H, Lubitz W, Vaheri A. Cell-cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression. Cell Death Differ. 2004;11:183–195. doi: 10.1038/sj.cdd.4401317. PubMed DOI

Collins A, Dusinská M, Franklin M, Somorovská M, Petrovská H, Duthie S, Fillion L, Panayiotidis M, Raslová K, Vaughan N. Comet assay in human biomonitoring studies: Reliability, validation and applications. Environ Mol Mutagen. 1997;30:139–146. doi: 10.1002/(SICI)1098-2280(1997)30:2<139::AID-EM6>3.0.CO;2-I. PubMed DOI

Wolfram J, Zhu M, Yang Y, Shen J, Gentile E, Paolino D, Fresta M, Nie G, Chen C, Shen H, Ferrari M, Zhao Y. Safety of nanoparticles in medicine. Curr Drug Targets. 2015;16:1671–1681. doi: 10.2174/1389450115666140804124808. PubMed DOI PMC

Rezazadeh M, Davatsaz Z, Emami J, Hasanzadeh F, Jahanian-Najafabadi A. Preparation and characterization of spray-dried inhalable powders containing polymeric micelles for pulmonary delivery of paclitaxel in lung cancer. J Pharm Pharm Sci. 2018;21(1s):200–214. doi: 10.18433/jpps30048. PubMed DOI

Kumar P, Yuvakkumar R, Vijayakumar S, Vaseeharan B. Cytotoxicity of phloroglucinol engineered silver (Ag) nanoparticles against MCF-7 breast cancer cell lines. Materials Chemistry and Physics. 2018;220:402–408. doi: 10.1016/j.matchemphys.2018.08.074. DOI

Kukia NR, Rasmi Y, Abbasi A, Koshoridze N, Shirpoor A, Burjanadze G, Saboory E. Bio-Effects of TiO2 nanoparticles on human colorectal cancer and umbilical vein endothelial cell lines. Asian Pac J Cancer Prev. 2018;19:2821–2829. doi: 10.22034/APJCP.2018.19.10.2821. PubMed DOI PMC

van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T, de Vries HE. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist Updat. 2015;19:1–12. doi: 10.1016/j.drup.2015.02.002. PubMed DOI

Zhang F, Xu CL, Liu CM. Drug delivery strategies to enhance the permeability of the blood-brain barrier for treatment of glioma. Drug Des Devel Ther. 2015;9:2089–2100. doi: 10.2147/DDDT.S79592. PubMed DOI PMC

Glaser T, Han I, Wu L, Zeng X. Targeted Nanotechnology in Glioblastoma Multiforme. Front Pharmacol. 2017;8:166. doi: 10.3389/fphar.2017.00166. PubMed DOI PMC

Markowska-Szczupak A, Ulfig A, Morawski W. The application of titanium dioxide for deactivation of bioparticulates: An overview. Catalysis Today. 2011;169:249–257. doi: 10.1016/j.cattod.2010.11.055. DOI

Rozhkova EA, Ulasov I, Lai B, Dimitrijevic NM, Lesniak MS, Rajh T. A high-performance nanobio photocatalyst for targeted brain cancer therapy. Nano Lett. 2009;9:3337–3342. doi: 10.1021/nl901610f. PubMed DOI PMC

Shi Z, Niu Y, Wang Q, Shi L, Guo H, Liu Y, Zhu Y, Liu S, Liu C, Chen X, Zhang R. Reduction of DNA damage induced by titanium dioxide nanoparticles through Nrf2 in vitro and in vivo. J Hazard Mater. 2015;298:310–319. doi: 10.1016/j.jhazmat.2015.05.043. PubMed DOI

Zhang R, Niu Y, Li Y, Zhao C, Song B, Li Y, Zhou Y. Acute toxicity study of the interaction between titanium dioxide nanoparticles and lead acetate in mice. Environ Toxicol Pharmacol. 2010;30:52–60. doi: 10.1016/j.etap.2010.03.015. PubMed DOI

Sugibayashi K, Todo H, Kimura E. Safety evaluation of titanium dioxide nanoparticles by their absorption and elimination profiles. J Toxicol Sci. 2008;33:293–298. doi: 10.2131/jts.33.293. PubMed DOI

Zhang Z, Xiong X, Wan J, Xiao L, Gan L, Feng Y, Xu H, Yang X. Cellular uptake and intracellular trafficking of PEG-b-PLA polymeric micelles. Biomaterials. 2012;33:7233–7240. doi: 10.1016/j.biomaterials.2012.06.045. PubMed DOI

Ong CS, Zhou X, Han J, Huang CY, Nashed A, Khatri S, Mattson G, Fukunishi T, Zhang H, Hibino N. In vivo therapeutic applications of cell spheroids. Biotechnol Adv. 2018;36:494–505. doi: 10.1016/j.biotechadv.2018.02.003. PubMed DOI

Zanoni M, Piccinini F, Arienti C, Zamagni A, Santi S, Polico R, Bevilacqua A, Tesei A. 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained. Sci Rep. 2016;6:19103. doi: 10.1038/srep19103. PubMed DOI PMC

Lao Z, Kelly CJ, Yang XY, Jenkins WT, Toorens E, Ganguly T, Evans SM, Koch CJ. Improved methods to generate spheroid cultures from tumor cells, tumor cells & fibroblasts or tumor-fragments: microenvironment, microvesicles and MiRNA. PLoS One. 2015;10:e0133895. doi: 10.1371/journal.pone.0133895. PubMed DOI PMC

Tng DJH, Song P, Lin G, Soehartono AM, Yang G, Yang CH, Yin F, 1, Tan CH, Yong KT. Synthesis and characterization of multifunctional hybrid-polymeric nanoparticles for drug delivery and multimodal imaging of cancer. Int J Nanomedicine. 2015;10:5771–5786. doi: 10.2147/IJN.S86468. PubMed DOI PMC

Radhakrishnan VS, Dwivedi SP, Siddiqui MH, Prasad T. In vitro studies on oxidative stress-independent, Ag nanoparticles-induced cell toxicity of Candida albicans, an opportunistic pathogen Int J Nanomedicine 2018. 13 T-NANO 2014 Abstracts 91 96 10.2147/IJN.S125010 PubMed DOI PMC

Xiao RZ, Zeng ZW, Zhou GL, Wang JJ, Li FZ, Wang AM. Recent advances in PEG-PLA block copolymer nanoparticles. Int J Nanomedicine. 2010;5:1057–1065. doi: 10.2147/IJN.S14912. PubMed DOI PMC

Shin HC, Cho, Lai C, Kozak KR, Kolesar JM, Kwon GS. Pharmacokinetic study of 3-in-1 poly(ethylene glycol)-block-poly(D, L-lactic acid) micelles carrying paclitaxel, 17-allylamino-17-demethoxygeldanamycin, and rapamycin. J Control Release. 2012;163:93–99. doi: 10.1016/j.jconrel.2012.04.024. PubMed DOI PMC

Jong WHD, Borm PJA. Drug delivery and nanoparticles: Applications and hazards. Int J Nanomedicine. 2008;3:133–149. doi: 10.2147/IJN.S596. PubMed DOI PMC