Assessment of pH Responsive Delivery of Methotrexate Based on PHEMA-st-PEG-DA Nanohydrogels

Javad Farzanfar; Fatemeh Farjadian; Amir Roointan; Soliman Mohammadi-Samani; Lobat Tayebi

Macromolecular Research, Vol.29, No.1, 54-61, January, 2021

DOI10.1007/s13233-021-9007-6 Export Citation

Assessment of pH Responsive Delivery of Methotrexate Based on PHEMA-st-PEG-DA Nanohydrogels

Javad Farzanfar^{1, 2}, Fatemeh Farjadian^{1, †}, Amir Roointan³, Soliman Mohammadi-Samani^{1, 2, †}, and Lobat Tayebi⁴

¹Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
²Department of Pharmaceutics, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
³Regenerative Medicine Research Center (RMRC), Isfahan University of Medical Sciences, Isfahan, Iran
⁴School of Dentistry, Marquette University, Milwaukee, USA

E-mail:,

Nanohydrogels (NHs) are novel and attractive carriers for various anticancer factors delivery. The objective of present study is development of a safe NH for pH responsive delivery of methotrexate (MTX). Herein, poly (hydroxyethyl methacrylate) is utilized as the main structure, which is cross-linked with poly(ethyleneglycol) diacrylate (PEG-DA) through reversible addition fragmentation chain transfer polymerization technique. After synthesis, the developed structure is characterized using different methods, including 1H NMR, FT-IR, size exclusion chromatography, transmission electron microscopy and dynamic light scattering. The results confirm successful synthesis of the NH with acceptable yield and nano scale mean size of 194 nm. Methotrexate is conjugated with the aforementioned structure through pH responsive esteric bond. The efficiency of the prepared NH in loading and release of the anticancer drug, methotrexate, is tested. The developed NH shows great potential in methotrexate loading, as well as a faster release rate of methotrexate in acidic pH. The results of in vitro toxicity assessment on MCF-7 as a breast cancer cell line reveal an improved cytotoxicity induction by the methotrexate loaded particles when compared with the free MTX molecules. The suitable size (<200 nm), great potential in loading and release of the methotrexate and cytotoxicity induction in cancer cells are the reliable features of NH as an ideal anti-cancer vehicle.

Keywords:RAFT synthesis;nanohydrogel;PHEMA;PEG-DA;methotrexate;drug delivery;cancer

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[1] Farjadian F, Ghasemi A, Gohari O, Roointan A, Karimi M, Hamblin MR, Nanomedicine, 14, 93 (2018)

[2] Farjadian F, Moghoofei M, Mirkiani S, Ghasemi A, Rabiee N, Hadifar S, Beyzavi A, Karimi M, Hamblin MR, Biotechnol. Adv., 36, 968 (2018)

[3] Farjadian F, Roointan A, Mohammadi-Samani S, Hosseini M, Chem. Eng. J., 359, 684 (2018)

[4] Hosseini M, Farjadian F, Makhlouf ASH, in Industrial Applications for Intelligent Polymers and Coatings, Springer, pp 1 2016.

[5] Roointan A, Kianpour S, Memari F, Gandomani M, Hayat SMG, Mohammadi-Samani S, J. Polym. Mater. Polym. Biomater., 67, 1028 (2018)

[6] Erol O, Pantula A, Liu W, Gracias DH, Adv. Mater. Technol., 4, 190004 (2019)

[7] Akram M, Hussain R, in Nanocellulose and Nanohydrogel Matrices: Biotechnological and Biomedical Applications, pp 297 2017.

[8] Bolla PK, Rodriguez VA, Kalhapure RS, Renukuntla J, J. Drug Deliv. Sci. Technol., 46, 416 (2018)

[9] Massoumi B, Mozaffari Z, Jaymand M,, Int. J. Biol. Macromol., 117, 418 (2018)

[10] Rizwan M, Yahya R, Hassan A, Yar M, Azzahari A, Selvanathan V, Sonsudin F, Abouloula C, Polymers, 9, 137 (2017)

[11] Li J, Mooney DJ, Nature Reviews Materials, 1, 1 (2016)

[12] Mishra SS, Sharma AK, Pharma Innovation J., 7, 182 (2018)

[13] Gangadharappa H, Prasad SMC, Singh RP, J. Drug Deliv. Sci. Technol., 41, 488 (2017)

[14] Lai WF, He ZD, J. Control. Release, 243, 269 (2016)

[15] Moad G, Polym. Chem., 8, 177 (2017)

[16] Farjadian F, Schwark S, Ulbricht M, Polym. Chem., 6, 1584 (2015)

[17] Kotanen CN, Janagam DR, Idziak R, Rhym L, Sullivan R, Wilson AM, Lowe TL, Guiseppi-Elie A, Europ. Polym. J., 72, 438 (2015)

[18] Bhat A, Smith B, Dinu CZ, Guiseppi-Elie A, Mater. Sci. Eng. C-Biomimetic Supramol. Syst., 98, 89 (2019)

[19] Gatti S, Agostini A, Ferrari R, Moscatelli D, Polymers, 6, 389 (2017)

[20] Choi G, Kim TH, Oh JM, Choy JH, Coord. Chem. Rev., 359, 32 (2018)

[21] Davaran S, Fazeli H, Ghamkhari A, Rahimi F, Molavi O, Anzabi M, Salehi R, J. Biomater. Sci., Polym. Ed., 29, 1265 (2018)

[22] Farjadian F, Ghasemi S, Mohammadi-Samani S, Int. J. Pharm., 504, 110 (2016)

[23] de Oliveira C, Buttenbender S, Prado W, Beckenkamp A, Asbahr A, Buffon A, Guterres S, Pohlmann A, Nanomaterials, 8, 24 (2018)

[24] Silva N, Riveros A, Yutronic N, Lang E, Chornik B, Guerrero S, Samitier J, Jara P, Kogan M, Nanomaterials, 8, 985 (2018)

[25] Zhao J, Zhao M, Yu C, Zhang X, Liu J, Cheng X, Lee RJ, Sun F, Teng L, Li Y, Int. J. Nanomedicine, 12, 6735 (2017)

[26] Xie J, Fan Z, Li Y, Zhang Y, Yu F, Su G, Xie L, Hou Z, Int. J. Nanomedicine, 13, 1381 (2018)

[27] Roointan A, Farzanfar J, Mohammadi-Samani S, Behzad-Behbahani A, Farjadian F, Int. J. Pharm., 552, 301 (2018)

[28] Farjadian F, Ghasemi S, Andami Z, Tamami B, Iranian Polym. J., 29, 197 (2020)

[29] Farjadian F, Rezaeifard S, Naeimi M, Ghasemi S, Mohammadi-Samani S, Welland ME, Tayebi L, Int. J. Nanomedicine, 14, 6901 (2019)

[30] Ghasemi S, Harandi ZA, RSC Adv., 8, 14570 (2018)

[31] Perrier S, Macromolecules, 50(19), 7433 (2017)

[32] Farzanfar J, Rezvani AR, Res. Chem. Intermed., 41, 8975 (2015)

[33] Xu Q, Sigen A, Gao Y, Guo L, Creagh-Flynn J, Zhou D, Greiser U, Dong Y, Wang F, Tai H, Acta Biomater., 75, 63 (2018)

[34] Rosenblum D, Joshi N, Tao W, Karp JM, Peer D, Nat. Commun., 9, 1410 (2018)

[35] Kydd J, Jadia R, Velpurisiva P, Gad A, Paliwal S, Rai P, Pharmaceutics, 9, 46 (2017)

[36] Golombek SK, May JN, Theek B, Appold L, Drude N, Kiessling F, Lammers T, Adv. Drug Deliv. Rev., 130, 17 (2018)

[37] Mohammadi-Samani S, Zojaji S, Entezar-Almahdi E, J. Drug Deliv. Sci. Technol., 47, 427 (2018)

[38] Chen J, Yang X, Huang L, Lai H, Gan C, Luo X, Drug Deliv., 25, 1932 (2018)

[39] Schwall C, Banerjee I, Materials, 2, 577 (2009)

[40] Kohler N, Sun C, Wang J, Zhang MQ, Langmuir, 21(19), 8858 (2005)