LLDPE/TiO₂-ZnO Nanocomposite Films induces Transitory Oxidative Stress Response on Human Fibroblast and Blood Cell Lines Models

Abstract:

Healthcare-associated infections (HAIs) are a major safety concern globally that contribute to mortality rates amongst patients especially associated with indwelling or implanted medical devices. The advanced metal-oxide nanocomposites (MNPs) embedded in polymer matrix present an outstanding antibacterial profile, especially for MDR strains owing to reactive oxygen species (ROS) and free radicals’ mode of action. To date, there is still a lack of knowledge on the implication of external reactive species from MNPs-based polymers to humans. This study investigates the bio-interaction of TiO2-ZnO nanocomposite films embedded in linear low-density polyethylene (LLDPE/ TiO2-ZnO) on human fibroblast and blood cell lines model at molecular genes and protein level. The initial analysis of the in vitro bio-interaction responses on fibroblast and blood cell line models showed signs of cell membrane integrity disturbance, which might be due to free radicals’ activities, such as the release of intracellular ROS and Zn ions (Zn²⁺) during the initial cellular adaptation process on the TiO2–ZnO polymer nanocomposite film. Further findings found that cell–polymer nanocomposite film interaction could possibly trigger transitory oxidative stress response and cellular redox regulation via NF-kβ interactions. However, further comprehensive studies are needed to support this study, especially involving animal models.

• Periodical: Journal of Biomimetics, Biomaterials and Biomedical Engineering (Volume 61)
• Pages: 77-91
• DOI: https://doi.org/10.4028/p-2aa27K
• Online since: July 2023
• Authors: Nor Hazliana Harun, Rabiatul Basria S.M.N. Mydin*, Srimala Sreekantan, Khairul Arifah Saharuddin, Azman Seeni
• Keywords: Antibacterial Polymer, Antimicrobial, Biomedical Polymer, LLDPE, Metal-Oxide Nanocomposites, TiO₂ Nanocomposite, ZnO Nanocomposite

References

[1] Ananda, T., Modi, A., Chakraborty, I., Managuli, V., Mukhopadhyay, C. and Mazumder, N. Nosocomial Infections and Role of Nanotechnology. Bioengineering. 2002; 9(2): 51.

DOI: 10.3390/bioengineering9020051

[2] M. Azizi-Lalabadi, A. Ehsani, B. Divband, and M. Alizadeh-Sani. Antimicrobial activity of Titanium dioxide and Zinc oxide nanoparticles supported in 4A zeolite and evaluation the morphological characteristic. Scientific reports. 2019; 9(1): 1-10.

DOI: 10.1038/s41598-019-54025-0

[3] Canaparo, R., Foglietta, F., Limongi, T. and Serpe, L., 2020. Biomedical applications of reactive oxygen species generation by metal nanoparticles. Materials. 2020: 14(1): 53.

DOI: 10.3390/ma14010053

[4] Z. Yu, Q. Li, J. Wang, Y Yu, Y. Wang, Q. Zhou and P. Li. Reactive oxygen species- related nanoparticle toxicity in the biomedical field. Nanoscale research letters. 2020; 15: 1-14.

DOI: 10.1186/s11671-020-03344-7

[5] H.J. Johnston, G. Hutchison, F.M. Christensen, S. Peters, S. Hankin, and V. Stone. A review of the in vivo and in vitro toxicity of silver and gold particulates: particle attributes and biological mechanisms responsible for the observed toxicity. Critical reviews in toxicology. 2010; 40(4): 328-346.

DOI: 10.3109/10408440903453074

[6] Saharudin, K. A., Sreekantan, S., Basiron, N., Khor, Y. L., Harun, N. H., SMN Mydin, R. B., . Md Akil, H., Seeni, A & Vignesh, K. 2018. Bacteriostatic activity of LLDPE nanocomposite embedded with sol–gel synthesized TiO2/ZnO coupled oxides at various ratios. Polymers, 10(8), 878.

DOI: 10.3390/polym10080878

[7] Harun, N. H., Mydin, R. B. S. N., Sreekantan, S., Saharudin, K. A., Basiron, N., & Seeni, A. 2020a. The bactericidal potential of LLDPE with TiO2/ZnO nanocomposites against multidrug resistant pathogens associated with hospital acquired infections. Journal of Biomaterials Science, Polymer Edition, 31(14), 1757-1769.

DOI: 10.1080/09205063.2020.1775759

[8] Harun, N. H., Mydin, R. B. S., Sreekantan, S., Saharudin, K. A., Basiron, N., Aris, F., Wan Mohd Zain, W.N. & Seeni, A. 2020b. Bactericidal capacity of a heterogeneous TiO2/ZnO nanocomposite against multidrug-resistant and non-multidrug-resistant bacterial strains associated with nosocomial infections. ACS omega, 5(21), 12027-12034.

DOI: 10.1021/acsomega.0c00213

[9] Harun, N. H., Mydin, R. B. S., Sreekantan, S., Saharuddin, K. A., & Seeni, A. 2020c. In vitro biodegradation evaluation of linear low density polyethylene embedded with TiO2/ZnO couple oxides. In IOP Conference Series: Materials Science and Engineering (Vol. 932, No. 1, p.012032). IOP Publishing.

DOI: 10.1088/1757-899x/932/1/012032

[10] Harun, N.H., Mydin, R.B.S., Sreekantan, S., Saharuddin, K.A. and Seeni, A. In vitro bio- interaction responses and hemocompatibility of nano-based linear low-density polyethylene polymer embedded with heterogeneous TiO2/ZnO nanocomposites for biomedical applications. Journal of Biomaterials Science, Polymer Edition. 2021; 32(10):1301-1311.

DOI: 10.1080/09205063.2021.1916866

[11] Yu, Z., Li, Q., Wang, J., Yu, Y., Wang, Y., Zhou, Q. and Li, P. Reactive oxygen species- related nanoparticle toxicity in the biomedical field. Nanoscale research letters. 2020; 15(1): 1-14.

DOI: 10.1186/s11671-020-03344-7

[12] Sun, Y., Lu, Y., Saredy, J., Wang, X., Drummer IV, C., Shao, Y., Saaoud, F., Xu, K., Liu, M., Yang, W.Y. and Jiang, X. ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes. Redox biology. 2020; 37: 101696.

DOI: 10.1016/j.redox.2020.101696

[13] Baird, L. and Yamamoto, M. The molecular mechanisms regulating the KEAP1-NRF2 pathway. Molecular and cellular biology. 2020; 40(13): .e00099-20.

DOI: 10.1128/mcb.00099-20

[14] He, F., Ru, X. and Wen, T. NRF2, a transcription factor for stress response and beyond. International Journal of Molecular Sciences. 2020; 21(13): 4777.

DOI: 10.3390/ijms21134777

[15] Pei, X., Jiang, H., Xu, G., Li, C., Li, D. and Tang, S. Lethality of zinc oxide nanoparticles surpasses conventional zinc oxide via oxidative stress, mitochondrial damage and calcium overload: A comparative hepatotoxicity study. International Journal of Molecular Sciences. 2022; 23(12): 6724.

DOI: 10.3390/ijms23126724

[16] R.Y. Pelgrift and A.J. Friedman. Nanotechnology as a therapeutic tool to combat microbial resistance. Advanced drug delivery reviews. 2013; 65(13-14):1803-1815.

DOI: 10.1016/j.addr.2013.07.011

[17] M. Dizdaroglu, and P. Jaruga. Mechanisms of free radical-induced damage to DNA. Free radical research. 2012; 46(4): 382-419.

DOI: 10.3109/10715762.2011.653969

[18] Han, B., Pei, Z., Shi, L., Wang, Q., Li, C., Zhang, B., Su, X., Zhang, N., Zhou, L., Zhao, B. and Niu, Y., 2020. TiO2 nanoparticles caused DNA damage in lung and extra- pulmonary organs through ROS-activated FOXO3a signaling pathway after intratracheal administration in rats. International Journal of Nanomedicine, 15, p.6279.

DOI: 10.2147/ijn.s254969

[19] S.R. Saptarshi, B.N. Feltis, P.F. Wright and A.L. Lopata. Investigating the immunomodulatory nature of zinc oxide nanoparticles at sub-cytotoxic levels in vitro and after intranasal instillation in vivo. Journal of nanobiotechnology. 2015; 13(1): 1-11.

DOI: 10.1186/s12951-015-0067-7

[20] J.J.E. Li, S. Muralikrishnan, C.T. Ng, L.Y.L. Yung, Land B.H. Bay. Nanoparticle- induced pulmonary toxicity. Experimental biology and medicine. 2010; 235(9): 1025- 1033.

DOI: 10.1258/ebm.2010.010021

[21] Khan, Mahmood Ahmad, and Mohd Jahir Khan. Nano-gold displayed anti- inflammatory property via NF-kB pathways by suppressing COX-2 activity. Artificial Cells, Nanomedicine, and Biotechnology. 2018; 46: 1149-1158.

DOI: 10.1080/21691401.2018.1446968

[22] Dukhinova, M.S., Prilepskii, A.Y., Shtil, A.A. and Vinogradov, V.V., 2019. Metal oxide nanoparticles in therapeutic regulation of macrophage functions. Nanomaterials, 9(11), p.1631.

DOI: 10.3390/nano9111631

[23] Wang, S., Alenius, H., El-Nezami, H. and Karisola, P., 2022. A New Look at the Effects of Engineered ZnO and TiO2 Nanoparticles: Evidence from Transcriptomics Studies. Nanomaterials, 12(8), p.1247.

DOI: 10.3390/nano12081247

[24] L.K. Braydich-Stolle, J.L. Speshock, A. Castle, M. Smith, R.C. Murdock, and S.M. Hussain. Nanosized aluminum altered immune function. ACS nano. 2010; 4(7): 3661- 3670.

DOI: 10.1021/nn9016789

[25] S. Singh, T. Shi, R. Duffin, C. Albrecht, D. van Berlo, D. Höhr, and R.P. Schins. Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: role of the specific surface area and of surface methylation of the particles. Toxicology and applied pharmacology. 2017; 222(2): 141- 151.

DOI: 10.1016/j.taap.2007.05.001

[26] W. Wu, J.M. Samet, D.B. Peden and P.A. Bromberg. Phosphorylation of p.65 is required for zinc oxide nanoparticle–induced interleukin 8 expression in human bronchial epithelial cells. Environmental health perspectives. 2010; 118(7): 982-987.

DOI: 10.1289/ehp.0901635

[27] Sivandzade, F., Prasad, S., Bhalerao, A. and Cucullo, L. NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: molecular mechanisms and possible therapeutic approaches. Redox biology. 2019; 21: 101059.

DOI: 10.1016/j.redox.2018.11.017

[28] Ramadan, M.A., Shawkey, A.E., Rabeh, M.A. and Abdellatif, A.O. Expression of P53, BAX, and BCL-2 in human malignant melanoma and squamous cell carcinoma cells after tea tree oil treatment in vitro. Cytotechnology. 2019; 71(1): 461-473.

DOI: 10.1007/s10616-018-0287-4

[29] Y. Fan, H. Lu, L. An, C. Wang, Z. Zhou, F. Feng, and Q. Zhao. Effect of active fraction of Eriocaulon sieboldianum on human leukemia K562 cells via proliferation inhibition, cell cycle arrest and apoptosis induction. Environmental toxicology and pharmacology. 2016; 43: 13-20.

DOI: 10.1016/j.etap.2015.11.001

[30] Khanzadeh, T., Hagh, M.F., Talebi, M., Yousefi, B., Azimi, A. and Baradaran, B. Investigation of BAX and BCL2 expression and apoptosis in a resveratrol-and prednisolone-treated human T-ALL cell line, CCRF-CEM. Blood research. 2018; 53(1): 53.

DOI: 10.5045/br.2018.53.1.53

[31] S. Mohan, S. I. Abdelwahab, B. Kamalidehghan, S. Syam, K.S. May, N.S.M. Harmal, and A. Zajmi. Involvement of NF-κB and Bcl2/Bax signaling pathways in the apoptosis of MCF7 cells induced by a xanthone compound Pyranocycloartobiloxanthone A. Phytomedicine. 2012; 19(11): 1007-1015.

DOI: 10.1016/j.phymed.2012.05.012

[32] W.K. Ng, L.S. Yazan and M. Ismail. Thymoquinone from Nigella sativa was more potent than cisplatin in eliminating of SiHa cells via apoptosis with downregulation of Bcl-2 protein. Toxicology in vitro. 2011; 25(7): 1392-1398.

DOI: 10.1016/j.tiv.2011.04.030