Dual thermo- and pH-responsive poly(N-isopropylacrylamide-co-(2-dimethylamino) ethyl methacrylate)-g-PEG nanoparticle system and its potential in controlled drug release

  • Aylar Najafipour
  • Ali Reza Mahdavian
  • Hojjat Sadeghi Aliabadi
  • Afshin FassihiEmail author
Original Paper


Stimulus-responsive nanoparticles have been widely used for many applications in biotechnology and medicine. In this study, dual thermo- and pH-responsive P(NIPAM-co-DMAEMA)-g-PEG nanoparticles has been synthesized by emulsion polymerization. The obtained nanoparticles were characterized by TEM, DLS, UV–Vis, 1HNMR and GPC analytical methods. The P(NIPAM-co-DMAEMA)-g-PEG nanoparticles showed higher LCST than poly(N-isopropylacrylamide) nanoparticles at 45 °C. Swelling and drug release measurements were taken under different conditions. The released amount of methotrexate (MTX) at normal physiological pH and temperature was limited (24%), while an accumulation drug release of about 70% was obtained after 48 h at pH = 5.5 under hyperthermia conditions (45 °C). MTX release data from the prepared nanoparticles were applied to the various conventional kinetic equations. The model with the highest R2 was considered as the best one. MCF-7 cell line was used to evaluate the cytotoxicity of the unloaded and MTX-loaded nanoparticles alone or in combination with hyperthermia. The results showed that the MTX-loaded nanoparticles in combination with hyperthermia suppressed tumor growth efficiently. According to the results, it can be concluded that the prepared nanoparticles might be regarded as promising agents in controlled drug delivery and multimodal cancer therapy to achieve a more effective treatment.


Dual responsive NIPAM DMAEMA PEGylation Controlled drug release 



The authors would like to thank the School of Pharmacy, Isfahan University of Medical Science, Isfahan, Iran, for financing this project.

Author contributions

This article was extracted from the Ph.D. research project of Aylar Najafipour. She performed all the lab experiments by herself. Ali Reza Mahdavian, Hojjat Sadeghi Aliabadia and Afshin Fassihi were the supervisors of the chemistry part of this project.

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest in this report.


  1. 1.
    Zugazagoitia J, Guedes C, Ponce S, Ferrer I, Molina-Pinelo S, Paz-Ares L (2016) Current challenges in cancer treatment. Clin Ther 38(7):1551–1566. CrossRefGoogle Scholar
  2. 2.
    Zhao C-Y, Cheng R, Yang Z, Tian Z-M (2018) Nanotechnology for cancer therapy based on chemotherapy. Molecules 23(4):826–855. CrossRefGoogle Scholar
  3. 3.
    Oliva N, Conde J, Wang K, Artzi N (2017) Designing hydrogels for on-demand therapy. Acc Chem Res 50(4):669–679. CrossRefGoogle Scholar
  4. 4.
    Brigger I, Dubernet C, Couvreur P (2002) Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev 54(5):631–651. CrossRefGoogle Scholar
  5. 5.
    Deshpande PP, Biswas S, Torchilin VP (2013) Current trends in the use of liposomes for tumor targeting. Nanomedicine 8(9):1509–1528. CrossRefGoogle Scholar
  6. 6.
    Chai Q, Jiao Y, Yu X (2017) Hydrogels for biomedical applications: their characteristics and the mechanisms behind them. Gels 3(1):6–21. CrossRefGoogle Scholar
  7. 7.
    Ferreira NN, Ferreira LMB, Cardoso VMO, Boni FI, Souza ALR, Gremião MPD (2018) Recent advances in smart hydrogels for biomedical applications: from self-assembly to functional approaches. Eur Polym J 99:117–133. CrossRefGoogle Scholar
  8. 8.
    Harrison IP, Spada F (2018) Hydrogels for atopic dermatitis and wound management: a superior drug delivery vehicle. Pharmaceutics 10(2):71–84. CrossRefGoogle Scholar
  9. 9.
    Zhao C, Zhuang X, He P, Xiao C, He C, Sun J, Chen X, Jing X (2009) Synthesis of biodegradable thermo- and pH-responsive hydrogels for controlled drug release. Polymer 50(18):4308–4316. CrossRefGoogle Scholar
  10. 10.
    Lin C-L, Chiu W-Y, Lee C-F (2005) Thermal/pH-sensitive core-shell copolymer latex and its potential for targeting drug carrier application. Polymer 46(23):10092–10101. CrossRefGoogle Scholar
  11. 11.
    Peng C-L, Tsai H-M, Yang S-J, Luo T-Y, Lin C-F, Lin W-J, Shieh M-J (2011) Development of thermosensitive poly(n-isopropylacrylamide-co-((2-dimethylamino) ethyl methacrylate))-based nanoparticles for controlled drug release. Nanotechnology 22(26):265608–265619. CrossRefGoogle Scholar
  12. 12.
    Huang Y, Yong P, Chen Y, Gao Y, Xu W, Lv Y, Yang L, Reis RL, Pirraco RP, Chen J (2017) Micellization and gelatinization in aqueous media of pH- and thermo-responsive amphiphilic ABC (PMMA82-b-PDMAEMA150-b-PNIPAM65) triblock copolymer synthesized by consecutive RAFT polymerization. RSC Adv 7(46):28711–28722. CrossRefGoogle Scholar
  13. 13.
    Jokerst JV, Lobovkina T, Zare RN, Gambhir SS (2011) Nanoparticle PEGylation for imaging and therapy. Nanomedicine 6(4):715–728. CrossRefGoogle Scholar
  14. 14.
    Guerrini L, Alvarez-Puebla R, Pazos-Perez N (2018) Surface modifications of nanoparticles for stability in biological fluids. Materials 11(7):1154–1182. CrossRefGoogle Scholar
  15. 15.
    Suk JS, Xu Q, Kim N, Hanes J, Ensign LM (2016) PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev 99:28–51. CrossRefGoogle Scholar
  16. 16.
    Zheng Y, Wang L, Lu L, Wang Q, Benicewicz BC (2017) pH and thermal dual-responsive nanoparticles for controlled drug delivery with high loading content. ACS Omega 2(7):3399–3405. CrossRefGoogle Scholar
  17. 17.
    Yadavalli T, Ramasamy S, Chandrasekaran G, Michael I, Therese HA, Chennakesavulu R (2015) Dual responsive PNIPAM–chitosan targeted magnetic nanopolymers for targeted drug delivery. J Magn Magn Mater 380:315–320. CrossRefGoogle Scholar
  18. 18.
    Wang J, Su S, Qiu J (2017) Biocompatible swelling graphene oxide reinforced double network hydrogels with high toughness and stiffness. New J Chem 41(10):3781–3789. CrossRefGoogle Scholar
  19. 19.
    Reis S, Gomes MJ, Martins S, Ferreira D, Segundo MA (2014) Lipid nanoparticles for topical and transdermal application for alopecia treatment: development, physicochemical characterization, and in vitro release and penetration studies. Int J Nanomed 9:1231–1242. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical SciencesIsfahan University of Medical SciencesIsfahanIran
  2. 2.Polymer Science DepartmentIran Polymer and Petrochemical InstituteTehranIran

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