Iranian Polymer Journal

, Volume 28, Issue 2, pp 99–112 | Cite as

Synthesis and optimization of poly (N,N-diethylacrylamide) hydrogel and evaluation of its anticancer drug doxorubicin’s release behavior

  • Sushma Havanur
  • Varisha Farheenand
  • P. E. JagadeeshBabuEmail author
Original Research


A macroporous temperature-responsive poly(N,N-diethylacrylamide) (PDEA) hydrogel was synthesized and optimized through free radical polymerization. The optimized hydrogel was achieved by evaluating the swelling characteristics, physical stability and mechanical strength through altering the components namely concentration of N,N-diethylacrylamide (monomer), ammonium peroxodisulfate (initiator), N,N′-methylbisacrylamide (cross-linker) and N,N,N′,N′-tetramethylethylenediamine (accelerator). The equilibrium swelling behavior was performed gravimetrically, and the PDEA hydrogel synthesized at 36 °C exhibited a maximum swelling of 18.332 g.g−1. Also, the LCST of the prepared PDEA hydrogel was found to be around 29 °C. However, the results of time-controlled swelling and deswelling kinetics indicated that hydrogels are temperature sensitive. Further, characterization of the hydrogel was performed using scanning electron microscopy, differential scanning calorimetry, thermal gravimetric analysis, and Fourier transform infrared spectroscopy. The hydrogel was assessed for its cytotoxicity in MDA-MB-231 cell line by MTT assay. The release behavior of anticancer drug doxorubicin (DOX), a hydroxyl derivative of anthracycline, was studied at above and below the LCST temperature. It was found that the DOX release from the DOX-loaded hydrogels was significantly improved when the surrounding temperature of the release media was increased near to physiological temperature. The cumulative release profile of hydrogel at different temperatures was fitted to different kinetic model equations and non-Fickian diffusion release mechanism was revealed. These results suggest that PDEA has a potential application as an intelligent drug carrier.


Temperature responsive Poly (N,N-diethylacrylamide) Free radical polymerization Cytotoxicity Doxorubicin Swelling Release mechanism 


  1. 1.
    Chai Q, Jiao Y, Yu X (2017) Hydrogels for biomedical applications: their characteristics and the mechanisms behind them. Gels 3:6–21CrossRefGoogle Scholar
  2. 2.
    Bajpai AK, Sandeep KS, Smitha B, Sanjana K (2008) Responsive polymers in controlled drug delivery. Prog Polym Sci 33:1088–1118CrossRefGoogle Scholar
  3. 3.
    Pinar I, Ozgur O (2017) Novel stimuli-responsive hydrogels derived from morpholine:synthesis, characterization and absorption uptake of textile azo dye. Iran Polym J 26:391–404CrossRefGoogle Scholar
  4. 4.
    Kamath K, Park K (1993) Biodegradable hydrogels in drug delivery. Adv Drug Deliv Rev 11:59–84CrossRefGoogle Scholar
  5. 5.
    Park K, Shalaby WSW, Park H (1993) Biodegradable hydrogel for drug delivery. Technomic Publishing Co., Inc. Lancaster,Google Scholar
  6. 6.
    Liu F, Tao GL, Zhuo RX (1993) Synthesis of thermal phase-separating reactive polymers and their applications in immobilized enzymes. Polym J 25:561–567CrossRefGoogle Scholar
  7. 7.
    Kim JJ, Park K (1999) Smart hydrogels for bioseparation. Bioseparation 7:177–184CrossRefGoogle Scholar
  8. 8.
    Chen JK, Chang CJ (2014) Fabrications and applications of stimulus-responsive polymer films and patterns on surfaces: a review. Materials 7:805–875CrossRefGoogle Scholar
  9. 9.
    Hoffman AS (2012) Hydrogels for biomedical applications. Adv Drug Deliv Rev 64:18–23CrossRefGoogle Scholar
  10. 10.
    Sosnik A, Seremeta KP (2017) Polymeric hydrogels as technology platform for drug delivery applications. Gels 3:25–47CrossRefGoogle Scholar
  11. 11.
    Caló E, Khutoryanskiy VV (2015) Biomedical applications of hydrogels: a review of patents and commercial products. Eur Polym J 65:252–267CrossRefGoogle Scholar
  12. 12.
    Ullah F, Othman MB, Javed F, Ahmad Z, MdAkil H (2015) Classification, processing and application of hydrogels: a review. Mater Sci Eng C 57:414–433CrossRefGoogle Scholar
  13. 13.
    Kondiah PJ, Choonara YE, Kondiah PPD, Marimuthu T, Kumar P, du Toit LC, Pillay V (2016) A review of injectable polymeric hydrogel systems for application in bone tissue engineering. Molecules 21:1580–1611CrossRefGoogle Scholar
  14. 14.
    Bahram M, Mohseni N, Moghtader M (2016) In: Majee SB (ed) An introduction to hydrogels and some recent applications. IntechOpen LondonCrossRefGoogle Scholar
  15. 15.
    Strandman S, Zhu XX (2015) Thermo-responsive block copolymers with multiple phasetransition temperatures in aqueous solutions. Prog Polym Sci 42:154–176CrossRefGoogle Scholar
  16. 16.
    Xiao XC (2007) Effect of the initiator on thermosensitive rate of poly(N-isopropylacrylamide) hydrogels. Express Polym Lett 1:232–235CrossRefGoogle Scholar
  17. 17.
    Karimi M, Sahandi PZ, Ghasemi A, Amiri M, Bahrami M (2016) Temperature-responsive smart nanocarriers for delivery of therapeutic agents: applications and recent advances. ACS Appl Mater Interfaces 8:21107–21133CrossRefGoogle Scholar
  18. 18.
    Patil JS, Gurav PB, Mandave SV, Jadhav SM, Kulkarni RG (2014) Hydrogel system, a ‘smart’ and ‘intelligent’ drug delivery device: a systematic and concise review. Ind J Nov Drug Deliv 6:93–105Google Scholar
  19. 19.
    Rizwan M, Yahya R, Hassan A, Yar M, Azzahari AD, Selvanathan V, Sonsudin F, Abouloula CN (2017) pH sensitive hydrogels in drug delivery: brief history, properties, swelling, and release mechanism, material selection and applications. Polymers 9:137–174CrossRefGoogle Scholar
  20. 20.
    Simões S, Figueiras A, Veiga F (2012) Modular hydrogels for drug delivery. J Biomater Nanobiotechnol 3:185–199CrossRefGoogle Scholar
  21. 21.
    Wang L, Li B, Xu F, Xu Z, Wei D, Feng Y, Wang Y, Jia D, Zhou Y (2017) UV-crosslinkable and thermo-responsive chitosan hybrid hydrogel for NIR-triggered localized on-demand drug delivery. Carbohydr Polym 174:904–914CrossRefGoogle Scholar
  22. 22.
    Wei W, Qi X, Li J, Zuo G, Sheng W, Zhang J, Dong W (2016) Smart macroporous salecan/poly (N,N-diethylacrylamide) semi-IPN hydrogel for anti-inflammatory drug delivery. ACS Biomater Sci Eng 2:1386–1394CrossRefGoogle Scholar
  23. 23.
    Işıklan N, Kazan H (2018) Thermoresponsive and biocompatible poly(vinyl alcohol)-graft poly(N,N-diethylacrylamide) copolymer: microwave-assisted synthesis, characterization, and swelling behavior. J Appl Polym Sci 135:45969CrossRefGoogle Scholar
  24. 24.
    Işıklan N, Ş Tokmak (2018) Microwave based synthesis and spectral characterization of thermo-sensitive poly(N,N-diethylacrylamide) grafted pectin copolymer. Int J Biol Macromol 113:669–680CrossRefGoogle Scholar
  25. 25.
    Ngadaonye JI, Geever LM, Killion J, Higginbotham CL (2013) Development of novel chitosan-poly(N,N-diethylacrylamide) IPN films for potential wound dressing and biomedical applications. J Polym Res 20:161–174CrossRefGoogle Scholar
  26. 26.
    Ngadaonye JI, Geever LM, McEvoy KE, Killion J, Brady DB, Higginbotham CL (2014) Evaluation of novel antibiotic-eluting thermoresponsive chitosan-PDEAAm based wound dressings. Int J Polym Mater Po 63:873–883CrossRefGoogle Scholar
  27. 27.
    Li H, Wu R, Zhu J, Guo P, Ren W, Xu S, Wang J (2015) pH/temperature double responsive behaviors and mechanical strength of laponite-crosslinked poly(DEA-co-DMAEMA) nanocomposite hydrogels. J Polym Sci B 53:876–884CrossRefGoogle Scholar
  28. 28.
    Kohsaka Y, Tanimoto Y (2016) Synthesis of thermo-responsive polymer via radical (co)polymerization of N,N-dimethyl-α-(hydroxymethyl)acrylamide with N,N-diethyl acrylamide. Polymers 8:374–381CrossRefGoogle Scholar
  29. 29.
    Hanyková L, Spěváček J, Radecki M, Zhigunov A, Kouřilová H, Sedláková Z (2016) Phase transition in hydrogels of thermoresponsive semi-interpenetrating and interpenetrating networks of poly(N,N-diethylacrylamide) and polyacrylamide. Eur Polym J 85:1–13CrossRefGoogle Scholar
  30. 30.
    Maheswari B, Babu PEJ, Agarwal M (2014) Role of N-vinyl-2-pyrrolidinone on the thermoresponsive behavior of PNIPAm hydrogel and its release kinetics using dye and vitamin-B12 as a model drug. J Biomater Sci Polym Ed 25:269–286CrossRefGoogle Scholar
  31. 31.
    Qi X, Wei W, Li J, Liu Y, Hu X, Zhang J, Bi L, Dong W (2015) Fabrication and characterization of a novel anticancer drug delivery system: salecan/poly(methacrylic acid) semi-interpenetrating polymer network hydrogel. ACS Biomater Sci Eng 1:1287–1299CrossRefGoogle Scholar
  32. 32.
    Dash S, Murthy PN, Nath L, Chowdhury P (2010) Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm 67:217–223Google Scholar
  33. 33.
    Siegel RA, Rathbone MJ (2012) In: Siepmann J, Siegel RA, Rathbone MJ (eds) Fundamentals and applications of controlled release drug delivery. Springer, New YorkGoogle Scholar
  34. 34.
    Šponarov ÁD, Horák D (2008) Poly (N,N-diethyl acrylamide) microspheres by dispersion polymerization. J Poly Sci Part A Pol Chem 46:6263–6271CrossRefGoogle Scholar
  35. 35.
    Flory PJ (1953) Principles of polymer chemistry. Cornell University Press, New YorkGoogle Scholar
  36. 36.
    Barron V, Killion JA, Pilkington L, Burke G, Geever LM, Lyons JG, McCullagh E, Higginbotham CL (2016) Development of chemically cross-linked hydrophilic–hydrophobic hydrogels for drug delivery applications. Eur Polym J 75:25–35CrossRefGoogle Scholar
  37. 37.
    Wang WB, Wang AQ (2010) Preparation, swelling and water-retention properties of cross-linked superabsorbent hydrogels based on guar gum. Adv Mater Res 96:177–182CrossRefGoogle Scholar
  38. 38.
    Zhang N, Liu M, Shen Y, Chen J, Dai L, Gao C (2011) Preparation, properties, and drug release of thermo- and pH-sensitive poly(2-dimethylamino)ethyl methacrylate)/poly(N,N-diethylacrylamide) semi-IPN hydrogels. J Mater Sci 46:1523–1534CrossRefGoogle Scholar
  39. 39.
    Yin L, Fei L, Cui F, Tang C, Yin C (2007) Superporous hydrogels containing poly(acrylic acid-co-acrylamide)/O-carboxymethyl chitosan interpenetrating polymer networks. Biomaterials 28:1258–1266CrossRefGoogle Scholar
  40. 40.
    Wang ZC, Xu XD, Chen CS, Wang GR, Wang B, Zhang XZ, Zhuo RX (2008) Study of novel hydrogels based on thermosensitive PNIPAAm with pH-sensitive PDMAEMA grafts. Colloids Surf B 67:245–252CrossRefGoogle Scholar
  41. 41.
    Babu PEJ, Kumar RS, Maheswari B (2011) Synthesis and characterization of temperature sensitive P-NIPAM macro/micro hydrogels. Colloids Surf A 384:466–472CrossRefGoogle Scholar
  42. 42.
    Chen J, Liu M, Chen W, Zhang N, Zhu S, Zhang S, Xiong Y (2011) Synthesis, swelling and drug-release behavior of a poly(N,N-diethyl acrylamide-co-(2-dimethylamino) ethyl methacrylate) hydrogel. J Biomater Sci Polym Ed 22:1049–1068CrossRefGoogle Scholar
  43. 43.
    Chen J, Liu M, Liu H, Ma L, Gao C, Zhu S, Zhang S (2010) Synthesis and properties of thermo- and pH-sensitive poly(diallyldimethylammonium chloride)/poly(N,N-diethylacrylamide) semi-IPN hydrogel. Chem Eng J 159:247–256CrossRefGoogle Scholar
  44. 44.
    Ngadaonye JI, Geever LM, Cloonan MO, Higginbotham CL (2012) Photopolymerised thermo-responsive poly(N,N-diethyl acrylamide)-based copolymer hydrogels for potential drug delivery applications. J Polym Res 19:9822–9837CrossRefGoogle Scholar
  45. 45.
    Qi X, Wei W, Li J, Zuo G, Hu X, Zhang J, Dong W (2016) Development of novel hydrogels based on Salecan and poly(N-isopropylacrylamide-co-methacrylic acid) for controlled doxorubicin release. RSC Adv 6:69869–69881CrossRefGoogle Scholar
  46. 46.
    Chen J, Liu M, Liu H, Ma L (2009) Synthesis, swelling and drug release behavior of poly(N,N-diethylacrylamide-co-N-hydroxymethyl acrylamide) hydrogel. Mater Sci Eng C 29:2116–2123CrossRefGoogle Scholar
  47. 47.
    Akın A, Işıklan N (2016) Microwave-assisted synthesis and characterization of sodium alginate-graft-poly (N,N′-dimethylacrylamide). Int J Biol Macromol 82:530–540CrossRefGoogle Scholar
  48. 48.
    Brazel CS, Peppas NA (1999) Mechanisms of solute and drug transport in relaxing, swellablehydrophilic glassy polymers. Polymer 40:3383–3398CrossRefGoogle Scholar
  49. 49.
    Hoffman AS (2002) Hydrogels for biomedical applications. Adv Drug Deliv Rev 54:3–12CrossRefGoogle Scholar
  50. 50.
    Zhao L, Zhang X, Liu X, Li J, Luan Y (2017) pH-responsive poly(ethylene glycol)-poly(ɛ-caprolactone)-poly(glutamic acid) polymersome as an efficient doxorubicin carrier for cancer therapy. Polym Int 66:1579–1586CrossRefGoogle Scholar
  51. 51.
    Fariba G, Ebrahim VF (2009) Hydrogels in controlled drug delivery systems. Iran Polym J 18:63–88Google Scholar

Copyright information

© Iran Polymer and Petrochemical Institute 2018

Authors and Affiliations

  • Sushma Havanur
    • 1
  • Varisha Farheenand
    • 1
  • P. E. JagadeeshBabu
    • 1
    Email author
  1. 1.Department of Chemical EngineeringNational Institute of Technology KarnatakaMangaloreIndia

Personalised recommendations