Nano Research

, Volume 10, Issue 9, pp 2905–2922 | Cite as

A series of nanoparticles with phase-separated structures by 1,1-diphenylethene controlled one-step soap-free emulsion copolymerization and their application in drug release

  • Xinlong Fan
  • Jin Liu
  • Xiangkun Jia
  • Yin Liu
  • Hao Zhang
  • Shenqiang Wang
  • Baoliang Zhang
  • Hepeng Zhang
  • Qiuyu Zhang
Research Article


A facile one-step approach to synthesize various phase-separated porous, raspberry-like, flower-like, core–shell and anomalous nanoparticles and nanocapsules via 1,1-diphenylethene (DPE) controlled soap-free emulsion copolymerization of styrene (S) with glycidyl methacrylate (GMA), or acrylic acid (AA) is reported. By regulating the mass ratio of S/GMA, transparent polymer solution, porous and anomalous P(S-GMA) particles could be produced. The P(S-GMA) particles turn from flower-like to raspberry-like and then to anomalous structures with smooth surface as the increase of divinylbenzene (DVB) crosslinker. Transparent polymer solution, nanocapsules and core–shell P(S-AA) particles could be obtained by altering the mole ratio of S/AA; anomalous and raspberry-like P(S-AA) particles are produced by adding DVB. The unpolymerized S resulted from the low monomer conversion in the presence of DPE aggregates to form nano-sized droplets, and migrates towards the external surfaces of the GMA-enriched P(S-GMA) particles and the internal bulk of the AA-enriched P(S-AA) particles. The nano-sized droplets function as in situ porogen, porous P(S-GMA) particles and P(S-AA) nanocapsules are produced when the porogen is removed. This novel, facile, one-step method with excellent controllability and reproducibility will inspire new strategies for creating hierarchical phase-separated polymeric particles with various structures by simply altering the species and ratio of comonomers. The drug loading and release experiments on the porous particles and nanocapsules demonstrate that the release of doxorubicin hydrochloride is very slow in weakly basic environment and quick in weakly acidic environment, which enables the porous particles and nanocapsules with promising potential in drug delivery applications.


phase separation 1,1-diphenylethene controlled polymerization porous nanocapsules controlled release 


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This work was supported by the National High-tech R&D Program of China (No. 2012AA02A404), the Key Program of the National Natural Science Foundation of China (No. 51433008), the Basic Research of Northwestern Polytechnical University (Nos. 3102014JCQ01094, JC20120248 and 3102014ZD) and the 2015 Sino-Germany (CSC-DAAD) Postdoc Scholarship.

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A series of nanoparticles with phase-separated structures by 1,1-diphenylethene controlled one-step soap-free emulsion copolymerization and their application in drug release


  1. [1]
    Schulze, M. W.; McIntosh, L. D.; Hillmyer, M. A.; Lodge, T. P. High-modulus, high-conductivity nanostructured polymer electrolyte membranes via polymerization-induced phase separation. Nano Lett. 2014, 14, 122–126.CrossRefGoogle Scholar
  2. [2]
    Seo, M.; Hillmyer, M. A. Reticulated nanoporous polymers by controlled polymerization-induced microphase separation. Science 2012, 336, 1422–1425.CrossRefGoogle Scholar
  3. [3]
    Wu, Q. Y.; Liu, B. T.; Li, M.; Wan, L. S.; Xu, Z. K. Polyacrylonitrile membranes via thermally induced phase separation: Effects of polyethylene glycol with different molecular weights. J. Membrane Sci. 2013, 437, 227–236.CrossRefGoogle Scholar
  4. [4]
    Wu, Q. Y.; Wan, L. S.; Xu, Z. K. Structure and performance of polyacrylonitrile membranes prepared via thermally induced phase separation. J. Membrane Sci. 2012, 409-410, 355–364.CrossRefGoogle Scholar
  5. [5]
    Xue, L. J.; Zhang, J. L.; Han, Y. C. Phase separation induced ordered patterns in thin polymer blend films. Prog. Polym. Sci. 2012, 37, 564–594.CrossRefGoogle Scholar
  6. [6]
    Lagerwall, J. P. F.; Schütz, C.; Salajkova, M.; Noh, J.; Park, J. H.; Scalia, G.; Bergström, L. Cellulose nanocrystal-based materials: From liquid crystal self-assembly and glass formation to multifunctional thin films. NPG Asia Mater. 2014, 6, e80.CrossRefGoogle Scholar
  7. [7]
    Sai, H.; Tan, K. W.; Hur, K.; Asenath-Smith, E.; Hovden, R.; Jiang, Y.; Riccio, M.; Muller, D. A.; Elser, V.; Estroff, L. A. et al. Hierarchical porous polymer scaffolds from block copolymers. Science 2013, 341, 530–534.CrossRefGoogle Scholar
  8. [8]
    Urban, J.; Svec, F.; Fréchet, J. M. J. A monolithic lipase reactor for biodiesel production by transesterification of triacylglycerides into fatty acid methyl esters. Biotechnol. Bioeng. 2012, 109, 371–380.CrossRefGoogle Scholar
  9. [9]
    Tan, J. J.; Li, C. M.; Zhou, J.; Yin, C. J.; Zhang, B. L.; Gu, J. W.; Zhang, Q. Y. Fast and facile fabrication of porous polymer particles via thiol-ene suspension photopolymerization. RSC Adv. 2014, 4, 13334–13339.CrossRefGoogle Scholar
  10. [10]
    Gokmen, M. T.; Du Prez, F. E. Porous polymer particles—A comprehensive guide to synthesis, characterization, functionalization and applications. Prog. Polym. Sci. 2012, 37, 365–405.CrossRefGoogle Scholar
  11. [11]
    Kowalczuk, A.; Trzcinska, R.; Trzebicka, B.; Müller, A. H. E.; Dworak, A.; Tsvetanov, C. B. Loading of polymer nanocarriers: Factors, mechanisms and applications. Prog. Polym. Sci. 2014, 39, 43–86.CrossRefGoogle Scholar
  12. [12]
    Lee, W. L.; Guo, W. M.; Ho, V. H. B.; Saha, A.; Chong, H. C.; Tan, N. S.; Widjaja, E.; Tan, E. Y.; Loo, S. C. J. Inhibition of 3-D tumor spheroids by timed-released hydrophilic and hydrophobic drugs from multilayered polymeric microparticles. Small 2014, 10, 3986–3996.CrossRefGoogle Scholar
  13. [13]
    Lee, W. L.; Widjaja, E.; Loo, S. C. J. One-step fabrication of triple-layered polymeric microparticles with layer localization of drugs as a novel drug-delivery system. Small 2010, 6, 1003–1011.CrossRefGoogle Scholar
  14. [14]
    Hofmeister, I.; Landfester, K.; Taden, A. Controlled formation of polymer nanocapsules with high diffusionbarrier properties and prediction of encapsulation efficiency. Angew. Chem., Int. Ed. 2015, 54, 327–330.CrossRefGoogle Scholar
  15. [15]
    Zhao, Y.; Berger, R.; Landfester, K.; Crespy, D. Double redox-responsive release of encoded and encapsulated molecules from patchy nanocapsules. Small 2015, 11, 2995–2999.CrossRefGoogle Scholar
  16. [16]
    Vecchione, R.; Iaccarino, G.; Bianchini, P.; Marotta, R.; D’autilia, F.; Quagliariello, V.; Diaspro, A.; Netti, P. A. Ultrastable liquid–liquid interface as viable route for controlled deposition of biodegradable polymer nanocapsules. Small 2016, 12, 3005–3013.CrossRefGoogle Scholar
  17. [17]
    Wajs, E.; Nielsen, T. T.; Larsen, K. L.; Fragoso, A. Preparation of stimuli-responsive nano-sized capsules based on cyclodextrin polymers with redox or light switching properties. Nano Res. 2016, 9, 2070–2078.CrossRefGoogle Scholar
  18. [18]
    Li, L. Y.; Cui, C. Y.; Su, W. Y.; Wang, Y. X.; Wang, R. H. Hollow click-based porous organic polymers for heterogenization of [Ru(bpy)3]2+ through electrostatic interactions. Nano Res. 2016, 9, 779–786.CrossRefGoogle Scholar
  19. [19]
    Gröschel, A. H.; Walther, A.; Löbling, T. I.; Schmelz, J.; Hanisch, A.; Schmalz, H.; Müller, A. H. E. Facile, solutionbased synthesis of soft, nanoscale Janus particles with tunable Janus balance. J. Am. Chem. Soc. 2012, 134, 13850–13860.CrossRefGoogle Scholar
  20. [20]
    Nisisako, T. Recent advances in microfluidic production of Janus droplets and particles. Curr. Opin. Colloid Interface Sci. 2016, 25, 1–12.CrossRefGoogle Scholar
  21. [21]
    Wang, X. Y.; Feng, X. Y.; Ma, G. P.; Yao, L.; Ge, M. F. Amphiphilic Janus particles generated via a combination of diffusion-induced phase separation and magnetically driven dewetting and their synergistic self-assembly. Adv. Mater. 2016, 28, 3131–3137.CrossRefGoogle Scholar
  22. [22]
    Fan, X. L.; Jia, X. K.; Zhang, H. P.; Zhang, B. L.; Li, C. M.; Zhang, Q. Y. Synthesis of raspberry-like poly(styrene-glycidyl methacrylate) particles via a one-step soap-free emulsion polymerization process accompanied by phase separation. Langmuir 2013, 29, 11730–11741.CrossRefGoogle Scholar
  23. [23]
    Fan, X. L.; Jia, X. K.; Liu, Y.; Zhang, B. L.; Li, C. M.; Liu, Y. L.; Zhang, H. P.; Zhang, Q. Y. Tunable wettability of hierarchical structured coatings derived from one-step synthesized raspberry-like poly(styrene-acrylic acid) particles. Polym. Chem. 2015, 6, 703–713.CrossRefGoogle Scholar
  24. [24]
    Lu, C. L.; Urban, M. Rationally designed gibbous stimuliresponsive colloidal nanoparticles. ACS Nano 2015, 9, 3119–3124.CrossRefGoogle Scholar
  25. [25]
    Yabu, H.; Sato, S.; Higuchi, T.; Jinnai, H.; Shimomura, M. Creating suprapolymer assemblies: Nanowires, nanorings, and nanospheres prepared from symmetric block-copolymers confined in spherical particles. J. Mater. Chem. 2012, 22, 7672–7675.CrossRefGoogle Scholar
  26. [26]
    Klinger, D.; Wang, C. X.; Connal, L. A.; Audus, D. J.; Jang, S. G.; Kraemer, S.; Killops, K. L.; Fredrickson, G. H.; Kramer, E. J.; Hawker, C. J. A facile synthesis of dynamic, shape-changing polymer particles. Angew. Chem., Int. Ed. 2014, 53, 7018–7022.CrossRefGoogle Scholar
  27. [27]
    Chen, L. X.; Xu, S. F.; Li, J. H. Recent advances in molecular imprinting technology: Current status, challenges and highlighted applications. Chem. Soc. Rev. 2011, 40, 2922–2942.CrossRefGoogle Scholar
  28. [28]
    Liang, S.; Liu, Y.; Jin, X.; Liu, G.; Wen, J.; Zhang, L. L.; Li, J.; Yuan, X. B.; Chen, I. S. Y.; Chen, W. et al. Phosphorylcholine polymer nanocapsules prolong the circulation time and reduce the immunogenicity of therapeutic proteins. Nano Res. 2016, 9, 1022–1031.CrossRefGoogle Scholar
  29. [29]
    Hu, R.; Yang, C. B.; Wang, Y. C.; Lin, G. M.; Qin, W.; Ouyan, Q. L.; Law, W. C.; Nguyen, Q. T.; Yoon, H. S.; Wang, X. M. et al. Aggregation-induced emission (AIE) dye loaded polymer nanoparticles for gene silencing in pancreatic cancer and their in vitro and in vivo biocompatibility evaluation. Nano Res. 2015, 8, 1563–1576.CrossRefGoogle Scholar
  30. [30]
    Zhang, L. L.; Liu, Y.; Liu, G.; Xu, D.; Liang, S.; Zhu, X. Y.; Lu, Y. F.; Wang, H. Prolonging the plasma circulation of proteins by nano-encapsulation with phosphorylcholinebased polymer. Nano Res. 2016, 9, 2424–2432.CrossRefGoogle Scholar
  31. [31]
    Gaitzsch, J.; Huang, X.; Voit, B. Engineering functional polymer capsules toward smart nanoreactors. Chem. Rev. 2016, 116, 1053–1093.CrossRefGoogle Scholar
  32. [32]
    Zulian, L.; Emilitri, E.; Scavia, G.; Botta, C.; Colombo, M.; Destri, S. Structural iridescent tuned colors from selfassembled polymer opal surfaces. ACS Appl. Mater. Interfaces 2012, 4, 6071–6079.CrossRefGoogle Scholar
  33. [33]
    von Freymann, G.; Kitaev, V.; Lotsch, B. V.; Ozin, G. A. Bottom-up assembly of photonic crystals. Chem. Soc. Rev. 2013, 42, 2528–2554.CrossRefGoogle Scholar
  34. [34]
    Li, C. M.; Tan, J. J.; Liu, Y. L.; Zhang, B. L.; Fan, X. L.; Zhang, Q. Y. Facile fabrication of multihollow polymer microspheres via novel two-step assembly of P(St-co-nBA-co-AA) particles. Colloid Polym. Sci. 2015, 293, 993–1001.CrossRefGoogle Scholar
  35. [35]
    Zhang, B. L.; Zhang, H. P.; Tian, L.; Li, X. J.; Li, W.; Fan, X. L.; Ali, N.; Zhang, Q. Y. Magnetic microcapsules with inner asymmetric structure: Controlled preparation, mechanism, and application to drug release. Chem. Eng. J. 2015, 275, 235–244.CrossRefGoogle Scholar
  36. [36]
    Tian, L.; Zhang, B. L.; Li, W.; Li, X. J.; Fan, X. L.; Jia, X. K.; Zhang, H. P.; Zhang, Q. Y. Facile fabrication of Fe3O4@PS/PGMA magnetic Janus particles via organic–inorganic dual phase separation. RSC Adv. 2014, 4, 27152–27158.CrossRefGoogle Scholar
  37. [37]
    Fan, X. L.; Zhang, Q. Y.; Zhang, H. P.; Zhang, B. L.; Li, C. M.; Li, X. J.; Lei, X. F. Synthesis of PS/Ag asymmetric hybrid particles via phase separation and self-assembly. Particuology 2013, 11, 768–775.CrossRefGoogle Scholar
  38. [38]
    Kim, B.; Lee, T. Y.; Abbaspourrad, A.; Kim, S. H. Perforated microcapsules with selective permeability created by confined phase separation of polymer blends. Chem. Mater. 2014, 26, 7166–7171.CrossRefGoogle Scholar
  39. [39]
    Motoyoshi, K.; Tajima, A.; Higuchi, T.; Yabu, H.; Shimomura, M. Static and dynamic control of phase separation structures in nanoparticles of polymer blends. Soft Matter 2010, 6, 1253–1257.CrossRefGoogle Scholar
  40. [40]
    Yabu, H.; Koike, K.; Motoyoshi, K.; Higuchi, T.; Shimomura, M. A novel route for fabricating metal-polymer composite nanoparticles with phase-separated structures. Macromol. Rapid Commun. 2010, 31, 1267–1271.CrossRefGoogle Scholar
  41. [41]
    Jin, Z. X.; Fan, H. L. Self-assembly of nanostructured block copolymer nanoparticles. Soft Matter 2014, 10, 9212–9219.CrossRefGoogle Scholar
  42. [42]
    Skelhon, T. S.; Chen, Y. H.; Bon, S. A. F. Synthesis of “hard-soft” janus particles by seeded dispersion polymerization. Langmuir 2014, 30, 13525–13532.CrossRefGoogle Scholar
  43. [43]
    Kim, J. W.; Cho, J.; Cho, J.; Park, B. J.; Kim, Y. J.; Choi, K. H.; Kim, J. W. Synthesis of monodisperse bicompartmentalized amphiphilic Janus microparticles for tailored assembly at the oil–water interface. Angew. Chem., Int. Ed. 2016, 55, 4509–4513.CrossRefGoogle Scholar
  44. [44]
    Tu, F. Q.; Lee, D. Shape-changing and amphiphilicityreversing Janus particles with pH-responsive surfactant properties. J. Am. Chem. Soc. 2014, 136, 9999–10006.CrossRefGoogle Scholar
  45. [45]
    Kobayashi, C.; Watanabe, T.; Murata, K.; Kureha, T.; Suzuki, D. Localization of polystyrene particles on the surface of poly(N-isopropylacrylamide-co-methacrylic acid) microgels prepared by seeded emulsion polymerization of styrene. Langmuir 2016, 32, 1429–1439.CrossRefGoogle Scholar
  46. [46]
    Wen, F.; Zhang, W. Q.; Zheng, P. W.; Zhang, X.; Yang, X. L.; Wang, Y.; Jiang, X. W.; Wei, G. W.; Shi, L. Q. One-stage synthesis of narrowly dispersed polymeric core–shell microspheres. J. Polym. Sci. Part A: Polym. Chem. 2008, 46, 1192–1202.CrossRefGoogle Scholar
  47. [47]
    Serrano-Medina, A.; Cornejo-Bravo, J.; Licea-Claveríe, A. Synthesis of pH and temperature sensitive, core–shell nano/microgels, by one pot, soap-free emulsion polymerization. J. Colloid Interface Sci. 2012, 369, 82–90.CrossRefGoogle Scholar
  48. [48]
    Landfester, K.; Rothe, R.; Antonietti, M. Convenient synthesis of fluorinated latexes and core–shell structures by miniemulsion polymerization. Macromolecules 2002, 35, 1658–1662.CrossRefGoogle Scholar
  49. [49]
    Yan, R.; Zhang, Y. Y.; Wang, X. H.; Xu, J. X.; Wang, D.; Zhang, W. Q. Synthesis of porous poly(styrene-co-acrylic acid) microspheres through one-step soap-free emulsion polymerization: Whys and wherefores. J. Colloid Interface Sci. 2012, 368, 220–225.CrossRefGoogle Scholar
  50. [50]
    Liu, Y. Y.; Liu, W.; Ma, Y. H.; Liu, L. Y.; Yang, W. T. Direct one-pot synthesis of chemically anisotropic particles with tunable morphology, dimensions, and surface roughness. Langmuir 2015, 31, 925–936.CrossRefGoogle Scholar
  51. [51]
    Sun, Y. Y.; Yin, Y. Y.; Chen, M.; Zhou, S. X.; Wu, L. M. One-step facile synthesis of monodisperse raspberry-like P(S-MPS-AA) colloidal particles. Polym. Chem. 2013, 4, 3020–3027.CrossRefGoogle Scholar
  52. [52]
    Fan, X. L.; Jia, X. K.; Liu, J.; Liu, Y.; Zhang, H. P.; Zhang, B. L.; Zhang, Q. Y. Morphology evolution of poly(glycidyl methacrylate) colloids in the 1,1-diphenylethene controlled soap-free emulsion polymerization. Eur. Polym. J. 2017, 92, 220–232.CrossRefGoogle Scholar
  53. [53]
    Soundararajan, S.; Reddy, B. S. R.; Rajadurai, S. Synthesis and characterization of glycidyl methacrylate-styrene copolymers and determination of monomer reactivity ratios. Polymer 1990, 31, 366–370.CrossRefGoogle Scholar
  54. [54]
    Zůrková, E.; Bouchal, K.; Zdeňková, D.; Pelzbauer, Z.; Svec, F.; Kálal, J.; Batz, H. G. Preparation of monodisperse reactive styrene-glycidyl methacrylate latexes by the emulsifier- free dispersion copolymerization technique. J. Polym. Sci.: Polym. Chem. Ed. 1983, 21, 2949–2960.Google Scholar
  55. [55]
    Chapin, E. C.; Ham, G. E.; Mills, C. L. Copolymerization. VII. Relative rates of addition of various monomers in copolymerization. J. Polym. Sci. 1949, 4, 597–604.CrossRefGoogle Scholar
  56. [56]
    Hastings, G. W. Synthesis and copolymerisation of α-acrylic acids and esters. J. Chem. Soc. D: Chem. Commun. 1969, 18, 1039.CrossRefGoogle Scholar
  57. [57]
    Huang, H.; Yuan, Q.; Shah, J. S.; Misra, R. D. K. A new family of folate-decorated and carbon nanotube-mediated drug delivery system: Synthesis and drug delivery response. Adv. Drug Deliver. Rev. 2011, 63, 1332–1339.CrossRefGoogle Scholar
  58. [58]
    Meng, H.; Liong, M.; Xia, T.; Li, Z. X.; Ji, Z. X.; Zink, J. I.; Nel, A. E. Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line. ACS Nano 2010, 4, 4539–4550.CrossRefGoogle Scholar
  59. [59]
    Gerweck, L. E.; Seetharaman, K. Cellular pH gradient in tumor versus normal tissue: Potential exploitation for the treatment of cancer. Cancer Res. 1996, 56, 1194–1198.Google Scholar
  60. [60]
    Kim, B.; Lee, E.; Kim, Y.; Park, S.; Khang, G.; Lee, D. Dual acid-responsive micelle-forming anticancer polymers as new anticancer therapeutics. Adv. Funct. Mater. 2013, 23, 5091–5097.CrossRefGoogle Scholar
  61. [61]
    Dan, K.; Ghosh, S. One-pot synthesis of an acid-labile amphiphilic triblock copolymer and its pH-responsive vesicular assembly. Angew. Chem., Int. Ed. 2013, 52, 7300–7305.CrossRefGoogle Scholar
  62. [62]
    Liu, R.; Zhang, Y.; Zhao, X.; Agarwal, A.; Mueller, L. J.; Feng, P. Y. pH-responsive nanogated ensemble based on gold-capped mesoporous silica through an acid-labile acetal linker. J. Am. Chem. Soc. 2010, 132, 1500–150.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Xinlong Fan
    • 1
  • Jin Liu
    • 1
  • Xiangkun Jia
    • 1
  • Yin Liu
    • 1
  • Hao Zhang
    • 1
  • Shenqiang Wang
    • 1
  • Baoliang Zhang
    • 1
  • Hepeng Zhang
    • 1
  • Qiuyu Zhang
    • 1
  1. 1.Department of Applied Chemistry, School of Natural and Applied SciencesNorthwestern Polytechnical UniversityXi’anChina

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