Stimuli-responsive polymersomes of poly [2-(dimethylamino) ethyl methacrylate]-b-polystyrene


Amphiphilic diblock copolymers may assemble in aqueous solutions to form vesicles delimited by a polymeric double layer, also known as polymersomes, considered a more robust option to liposomes. Diblock copolymers may respond to pH, temperature, and other conditions. Because of such properties, polymersomes are currently being studied as drug delivery systems or as nanoreactors. pH-responsive polymersomes are potentially crucial because unusual pH gradients are present in cells under several physiological and pathological conditions. We synthesized two diblock copolymers of poly [2-(dimethylamino) ethyl methacrylate]-block-polystyrene (PDMAEMA-b-PS) via RAFT. We both developed new materials and better-understood polymersomes' properties with pH and temperature-responsive groups with these polymers. GPC, 1H-NMR, and FTIR characterized copolymers. The ionization equilibrium of the PDMAEMA amino groups on the polymersomes was analyzed by potentiometric titration and Zeta potential measurements. The hydrodynamic radius of the polymersomes in different pH and temperatures was analyzed by DLS. Entrapment of an electron paramagnetic resonance probe indicated the presence of a hydrophilic inner core. Negative staining transmission electron microscopy showed spherical aggregates and confirmed the diameter around 80 nm. These polymersomes with dual stimulus–response (i.e., pH and temperature) may be a platform for gene delivery and nanoreactors.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9


  1. 1.

    Che H, van Hest JCM (2016) Stimuli-responsive polymersomes and nanoreactors. J Mater Chem B 4:4632–4647.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Hu X, Zhang Y, Xie Z et al (2017) Stimuli-responsive polymersomes for biomedical applications. Biomacromol 18:649–673.

    CAS  Article  Google Scholar 

  3. 3.

    Agut W, Brûlet A, Schatz C et al (2010) pH and temperature responsive polymeric micelles and polymersomes by self-assembly of poly[2-(dimethylamino)ethyl methacrylate]-b-poly(glutamic acid) double hydrophilic block copolymers. Langmuir 26:10546–10554.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Pawar PV, Gohil SV, Jain JP, Kumar N (2013) Functionalized polymersomes for biomedical applications. Polym Chem 4:3160.

    CAS  Article  Google Scholar 

  5. 5.

    Yildirim T, Traeger A, Sungur P et al (2017) Polymersomes with endosomal pH-induced vesicle-to-micelle morphology transition and a potential application for controlled doxorubicin delivery. Biomacromol 18:3280–3290.

    CAS  Article  Google Scholar 

  6. 6.

    Discher DE, Ahmed F (2006) Polymersomes. Annu Rev Biomed Eng 8:323–341

    CAS  Article  Google Scholar 

  7. 7.

    Wen J, Yuan L, Yang Y et al (2013) Self-assembly of monotethered single-chain nanoparticle shape amphiphiles. ACS Macro Lett 2:100–106.

    CAS  Article  Google Scholar 

  8. 8.

    Kozlovskaya V, Kharlampieva E (2020) Self-assemblies of thermoresponsive poly( N -vinylcaprolactam) polymers for applications in biomedical field. ACS Appl Polym Mater 2:26–39.

    CAS  Article  Google Scholar 

  9. 9.

    Ren Y, Jiang X, Yin J (2008) Copolymer of poly(4-vinylpyridine)-g-poly(ethylene oxide) respond sharply to temperature, pH and ionic strength. Eur Polymer J 44:4108–4114.

    CAS  Article  Google Scholar 

  10. 10.

    Neve A, Cantatore FP, Maruotti N, et al (2014) Extracellular matrix modulates angiogenesis in physiological and pathological conditions. In: BioMed Research International. Accessed 21 Jul 2020

  11. 11.

    Glass L, Mackey MC (1979) Pathological conditions resulting from instabilities in physiological control systems*. Ann N Y Acad Sci 316:214–235.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Obara M, Szeliga M, Albrecht J (2008) Regulation of pH in the mammalian central nervous system under normal and pathological conditions: facts and hypotheses. Neurochem Int 52:905–919.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Gupta P, Vermani K, Garg S (2002) Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov Today 7:569–579.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Onaca O, Enea R, Hughes DW, Meier W (2009) Stimuli-responsive polymersomes as nanocarriers for drug and gene delivery. Macromol Biosci 9:129–139.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Ward MA, Georgiou TK (2011) Thermoresponsive polymers for biomedical applications. Polymers 3:1215–1242.

    CAS  Article  Google Scholar 

  16. 16.

    Discher DE, Ortiz V, Srinivas G et al (2007) Emerging applications of polymersomes in delivery: From molecular dynamics to shrinkage of tumors. Prog Polym Sci 32:838–857.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Kita-Tokarczyk K, Grumelard J, Haefele T, Meier W (2005) Block copolymer vesicles—using concepts from polymer chemistry to mimic biomembranes. Polymer 46:3540–3563.

    CAS  Article  Google Scholar 

  18. 18.

    Leong J, Teo JY, Aakalu VK et al (2018) Engineering polymersomes for diagnostics and therapy. Adv Healthc Mater 7:1701276.

    CAS  Article  Google Scholar 

  19. 19.

    Barrella MC, Capua AD, Adami R et al (2017) Impact of intermolecular drug-copolymer interactions on size and drug release kinetics from pH-responsive polymersomes. Supramol Chem 29:796–807.

    CAS  Article  Google Scholar 

  20. 20.

    de Souza JCP, Naves AF, Florenzano FH (2012) Specific thermoresponsiveness of PMMA-block-PDMAEMA to selected ions and other factors in aqueous solution. Colloid Polym Sci 290:1285–1291.

    CAS  Article  Google Scholar 

  21. 21.

    Lee H, Son SH, Sharma R, Won Y-Y (2011) A Discussion of the pH-Dependent Protonation Behaviors of Poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) and Poly(ethylenimine-ran-2-ethyl-2-oxazoline) (P(EI-r-EOz)). J Phys Chem B 115:844–860.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Xiong Z, Peng B, Han X et al (2011) Dual-stimuli responsive behaviors of diblock polyampholyte PDMAEMA-b-PAA in aqueous solution. J Colloid Interface Sci 356:557–565.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Oh J-M, Lee H-J, Shim H-K, Choi S-K (1994) Synthesis and surface activity of novel ABA type triblock cationic amphiphiles. Polym Bull 32:149–154.

    CAS  Article  Google Scholar 

  24. 24.

    Xue Y, Wei D, Zheng A et al (2014) Study of stimuli-sensitivities of amphiphilic modified star poly[N,N-(dimethylamino)ethyl methacrylate] and its ability of DNA complexation. J Macromol Sci A 51:898–906.

    CAS  Article  Google Scholar 

  25. 25.

    Arslan H, Zırtıl O, Bütün V (2013) The synthesis and solution behaviors of novel amphiphilic block copolymers based on d-galactopyranose and 2-(dimethylamino)ethyl methacrylate. Eur Polymer J 49:4118–4129.

    CAS  Article  Google Scholar 

  26. 26.

    Xiong Q, Ni P, Zhang F, Yu Z (2004) Synthesis and characterization of 2-(Dimethylamino)ethyl Methacrylate Homopolymers via aqueous RAFT polymerization and their application in miniemulsion polymerization. Polym Bull 53:1–8.

    CAS  Article  Google Scholar 

  27. 27.

    Zhang C, Maric M (2011) Synthesis of stimuli-responsive, water-soluble Poly[2-(dimethylamino)ethyl methacrylate/styrene] statistical copolymers by nitroxide mediated polymerization. Polymers 3:1398–1422.

    CAS  Article  Google Scholar 

  28. 28.

    Zhu YJ, Tan YB, Du X (2008) Preparation and self-assembly behavior of polystyrene-block-poly (dimethylaminoethyl methacrylate) amphiphilic block copolymer using atom transfer radical polymerization. Express Polym Lett 2:214–225.

    CAS  Article  Google Scholar 

  29. 29.

    Song Y, Zhang T, Song X et al (2015) Polycations with excellent gene transfection ability based on PVP-g-PDMAEMA with random coil and micelle structures as non-viral gene vectors. J Mat Chem B 3:911–918.

    CAS  Article  Google Scholar 

  30. 30.

    Zhu C, Jung S, Luo S et al (2010) Co-delivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers. Biomaterials 31:2408–2416.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Moad G, Rizzardo E, Thang SH (2009) Living radical polymerization by the RAFT process: sa second update. Aust J Chem 62:1402.

    CAS  Article  Google Scholar 

  32. 32.

    Florenzano FH (2008) Perspectivas Atuais para a Obtenç\ ao Controlada de Polímeros e sua Caracterizaç\ ao. Polímeros: Ciência e Tecnologia 18:100–105

  33. 33.

    Mertoglu M (2005) The synthesis of well-defined functional homo-and block copolymers in aqueous media via Reversible Addition-Fragmentation Chain Transfer (RAFT) Polymerization. Universidade de Postdam

  34. 34.

    Stenzel MH (2008) RAFT polymerization: an avenue to functional polymeric micelles for drug delivery. Chem Commun.

    Article  Google Scholar 

  35. 35.

    Moad G, Thang SH (2009) RAFT polymerization: materials of the future, science of today: radical polymerization: the next stage. Aust J Chem 62:1379.

    CAS  Article  Google Scholar 

  36. 36.

    Rizzardo E, Chen M, Chong B, et al (2007) RAFT polymerization: adding to the picture. In: Macromolecular symposia. pp 104–116

  37. 37.

    Souza VV, Noronha MLdeC, Almeida FLA et al (2011) Cmc of PMMA-block-PDMAEMA measured by NPN fluorescence. Polym Bull 67:875–884.

    CAS  Article  Google Scholar 

  38. 38.

    Kim MR, Cheong IW (2016) Stimuli-triggered formation of polymersomes from W/O/W multiple double emulsion droplets containing poly(styrene)-block-poly(N-isopropylacrylamide-co-spironaphthoxazine methacryloyl). Langmuir 32:9223–9228.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Kawahara N, Kojoh S, Matsuo S et al (2006) Synthetic method of polyethylene-poly(methylmethacrylate) (PE-PMMA) polymer hybrid via reversible addition-fragmentation chain transfer (RAFT) polymerization with functionalized polyethylene. Polym Bull 57:805–812.

    CAS  Article  Google Scholar 

  40. 40.

    Moore JC (1964) Gel permeation chromatography. I. A new method for molecular weight distribution of high polymers. J Polym Sci A: Gener Paper 2:835–843.

    Article  Google Scholar 

  41. 41.

    Shen, (2012) Preparation and characterization of PMMA and its derivative via RAFT technique in the presence of disulfide as a source of chain transfer agent. J Memb Separ Tech.

    Article  Google Scholar 

  42. 42.

    Ma S, Xiao M, Wang R (2013) Formation and structural characteristics of thermosensitive multiblock copolymer vesicles. Langmuir 29:16010–16017.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Saraiva GKV, de Souza VV, Coutinho de Oliveira L et al (2019) Characterization of PMMA-b-PDMAEMA aggregates in aqueous solutions. Colloid Polym Sci 297:557–569.

    CAS  Article  Google Scholar 

  44. 44.

    Lim Soo P, Eisenberg A (2004) Preparation of block copolymer vesicles in solution. J Polym Sci B Polym Phys 42:923–938.

    CAS  Article  Google Scholar 

  45. 45.

    Rauckman EJ, Rosen GM, Abou-Donia MB (1976) Synthesis of a useful spin labeled probe, 1-oxyl-4-carboxyl-2,2,6,6-tetramethylpiperidine. J Org Chem 41:564–565.

    CAS  Article  Google Scholar 

  46. 46.

    Farkuh L, Hennies PT, Nunes C et al (2019) Characterization of phospholipid vesicles containing lauric acid: physicochemical basis for process and product development. Heliyon.

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Schacher F, Rudolph T, Wieberger F et al (2009) Double stimuli-responsive ultrafiltration membranes from polystyrene-block-poly(N,N-dimethylaminoethyl symers. ACS Appl Mater Interfaces 1:1492–1503.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Liu Q, Yu Z, Ni P (2004) Micellization and applications of narrow-distribution poly[2-(dimethylamino)ethyl methacrylate]. Colloid Polym Sci 282:387–393.

    CAS  Article  Google Scholar 

  49. 49.

    Chen J, Liu M, Gong H et al (2013) Synthesis of linear amphiphilic tetrablock quaterpolymers with dual stimulus response through the combination of ATRP and RAFT by a click chemistry site transformation approach. Polym Chem 4:1815–1825.

    CAS  Article  Google Scholar 

  50. 50.

    Tang J, Lee MFX, Zhang W et al (2014) Dual responsive pickering emulsion stabilized by poly[2-(dimethylamino)ethyl methacrylate] grafted cellulose nanocrystals. Biomacromol 15:3052–3060.

    CAS  Article  Google Scholar 

  51. 51.

    Yanez-Macias R, Alvarez-Moises I, Perevyazko I et al (2017) Effect of the degree of quaternization and molar mass on the cloud point of poly[2-(dimethylamino)ethyl methacrylate] aqueous solutions: a systematic investigation. Macromol Chem Phys 218:1700065.

    CAS  Article  Google Scholar 

  52. 52.

    Manganiello MJ, Cheng C, Convertine AJ et al (2012) Diblock copolymers with tunable pH transitions for gene delivery. Biomaterials 33:2301–2309.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    van de Wetering P, Cherng J-Y, Talsma H et al (1998) 2-(dimethylamino)ethyl methacrylate based (co)polymers as gene transfer agents. J Control Release 53:145–153.

    Article  PubMed  Google Scholar 

  54. 54.

    Emileh A, Vasheghani-Farahani E, Imani M (2007) Swelling behavior, mechanical properties and network parameters of pH- and temperature-sensitive hydrogels of poly((2-dimethyl amino) ethyl methacrylate-co-butyl methacrylate). Eur Polymer J 43:1986–1995.

    CAS  Article  Google Scholar 

  55. 55.

    Yıldız B, Işık B, Kış M, Birgül Ö (2003) pH-sensitive dimethylaminoethyl methacrylate (DMAEMA)/acrylamide (AAm) hydrogels: synthesis and adsorption from uranyl acetate solutions. J Appl Polym Sci 88:2028–2031.

    CAS  Article  Google Scholar 

  56. 56.

    Cotanda P, Wright DB, Tyler M, O’Reilly RK (2013) A comparative study of the stimuli-responsive properties of DMAEA and DMAEMA containing polymers. J Polym Sci, Part A: Polym Chem 51:3333–3338.

    CAS  Article  Google Scholar 

  57. 57.

    Han X, Zhang X, Zhu H et al (2013) Effect of composition of PDMAEMA-b-PAA block copolymers on their ph- and temperature-responsive behaviors. Langmuir 29:1024–1034.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    van de Wetering P, Moret EE, Schuurmans-Nieuwenbroek NME et al (1999) Structure−activity relationships of water-soluble cationic methacrylate/methacrylamide polymers for nonviral gene delivery. Bioconjugate Chem 10:589–597.

    Article  Google Scholar 

  59. 59.

    Luo T, Abdu S, Wessling M (2018) Selectivity of ion exchange membranes: a review. J Membr Sci 555:429–454.

    CAS  Article  Google Scholar 

  60. 60.

    Andreozzi P, Ricci C, Porcel JEM et al (2019) Mechanistic study of the nucleation and conformational changes of polyamines in presence of phosphate ions. J Colloid Interface Sci 543:335–342.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Aracava Y, Schreier S, Phadke R et al (1981) Spin label reduction kinetics, a procedure to study the effect of drugs on membrane-permeability—the effects of monosodium urate, dimethylsulfoxide and amphotericin-B. J Biochem Biophys Methods 5:83–94.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Stokes AM, Wilson JW, Warren WS (2012) Characterization of restricted diffusion in uni- and multi-lamellar vesicles using short distance iMQCs. J Magn Reson 223:31–40.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Zhu Y, Yang B, Chen S, Du J (2017) Polymer vesicles: Mechanism, preparation, application, and responsive behavior. Prog Polym Sci 64:1–22.

    CAS  Article  Google Scholar 

Download references


IMC, HC and FHF thanks to FAPESP (Proc. 2013/08166-5). IMC thanks the National Council for Scientific and Technological Development (CNPq – 465259/2014-6). IMC and HC thank the Coordination for the Improvement of Higher Education Personnel (CAPES), the National Institute of Science and Technology Complex Fluids (INCT-FCx) and NAP-FCx (Núcleo de Apoio à Pesquisa de Fluidos Complexos da Universidade de São Paulo). G.P.B.Carretero thanks the Programa CAPES: INCT -Institutos Nacionais de Ciência e Tecnologia (Proc. 88887.137085/2017-00) and FAPESP (2018/15230-5). FHF thanks CNPq (Universal 457733/2014-4), and GKVS acknowledges the Projeto Biocomputacional/CAPES (proc. no. 23038.004630/2014-35) and CNPq (proc. 457733/2014-4).


Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP (Grants 2013/08166–5 and 2018/15230–5). National Council for Scientific and Technological Development. CNPq (Grants 465259/2014–6 and 457733/2014–4). Coordination for the Improvement of Higher Education Personnel (CAPES). The National Institute of Science and Technology Complex Fluids (INCT-FCx) and NAP-FCx (Núcleo de Apoio à Pesquisa de Fluidos Complexos da Universidade de São Paulo). CAPES: INCT -Institutos Nacionais de Ciência e Tecnologia (Proc. 88887.137085/2017–00). Projeto Biocomputacional/CAPES (proc. no. 23038.004630/2014–35).

Author information



Corresponding author

Correspondence to Fabio H. Florenzano.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Availability of data and material

Data are available under request.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

de Souza, V.V., Carretero, G.P.B., Vitale, P.A.M. et al. Stimuli-responsive polymersomes of poly [2-(dimethylamino) ethyl methacrylate]-b-polystyrene. Polym. Bull. (2021).

Download citation


  • Polymersome
  • RAFT
  • PDMAEMA-b-polystyrene
  • LCST