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Biopolymers, Bio-related Polymer Materials

Polyion complex micelle formation from double-hydrophilic block copolymers composed of charged and non-charged segments in aqueous media


Polymeric micelles are representative self-assembly structures of block copolymers and have widely been investigated from both fundamental and applied aspects. In 1995, we discovered polyion complex (PIC) micelles formed from a pair of oppositely charged block copolymers with poly(ethylene glycol) segments through electrostatic interactions in aqueous media, which expanded the concept of polymeric micelle formation in selective solvents. Hereafter, extensive studies have been carried out on PIC micelles, for example, fundamental characterizations as a novel class of self-assembly systems and applications as nanocarrier systems for the delivery of charged molecules with therapeutic efficacies, including nucleic acids and proteins. This review mainly focuses on physicochemical studies on the formation of PIC micelles, particularly the critical molecular factors that have a role to determine the self-assembly scheme of charged block copolymers for micelle structures.

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  1. 1

    Verduzco, R, Li, X, Pesek, SL & Stein, GE Structure, function, self-assembly, and applications of bottlebrush copolymers. Chem. Soc. Rev. 44, 2405–2420 (2015).

    CAS  Article  Google Scholar 

  2. 2

    Tritschler, U, Pearce, S, Gwyther, J, Whittell, GR & Manners, I 50th Anniversary Perspective: Functional Nanoparticles from the Solution Self-Assembly of Block Copolymers. Macromolecules 50, 3439–3463 (2017).

    CAS  Article  Google Scholar 

  3. 3

    Cabral, H & Kataoka, K Progress of drug-loaded polymeric micelles into clinical studies. J. Controlled Release 190, 465–476 (2014).

    CAS  Article  Google Scholar 

  4. 4

    Gohy, JF & Zhao, Y Photo-responsive block copolymer micelles: design and behavior. Chem. Soc. Rev. 42, 7117–7129 (2013).

    CAS  Article  Google Scholar 

  5. 5

    Soleymani, AH, Vakili, MR, Shafaati, A & Lavasanifar, A Block Copolymer Stereoregularity and Its Impact on Polymeric Micellar Nanodrug Delivery. Mol. Pharm. 14, 2487–2502 (2017).

    Article  Google Scholar 

  6. 6

    Gohy, J.F. Block Copolymer Micelles. Adv. Polym. Sci. 190, 65–136 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Hamley, IW Nanotechnology with Soft Materials. Angew. Chem., Int. Ed. 42, 1692–1712 (2003).

    CAS  Article  Google Scholar 

  8. 8

    Schacher, FH, Rupar, PA & Manners, I Functional Block Copolymers: Nanostructured Materials with Emerging Applications. Angew. Chem., Int. Ed. 51, 7898–7921 (2012).

    CAS  Article  Google Scholar 

  9. 9

    Harada, A & Kataoka, K Formation of polyion complex micelles in an aqueous milieu from a pair of oppositely-charged block copolymers with poly(ethylene glycol) segments. Macromolecules 28, 5294–5299 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Kataoka, K, Togawa, H, Harada, A, Yasugi, K, Matsumoto, T & Katayose, S Spontaneous formation of polyion complex micelles with narrow distribution from antisense oligonucleotide and cationic block copolymer in physiological saline. Macromolecules 29, 8556–8557 (1996).

    CAS  Article  Google Scholar 

  11. 11

    Katayose, S & Kataoka, K Water-Soluble Polyion Complex Associates of DNA and Poly(ethylene glycol)-Poly(L-lysine) Block Copolymer. Bioconjugate Chem 8, 702–707 (1997).

    CAS  Article  Google Scholar 

  12. 12

    Harada, A & Kataoka, K Novel polyion complex micelles entrapping enzyme molecules in the core: Preparation of narrowly-distributed micelles from lysozyme and poly(ethylene glycol)-poly(aspartic acid) block copolymer in aqueous medium. Macromolecules 31, 288–294 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Harada, A & Kataoka, K On-off control of enzymatic activity synchronizing with reversible formation of supramolecular assembly from enzyme and charged block copolymers. J. Am. Chem. Soc. 121, 9241–9242 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Kakizawa, Y, Harada, A & Kataoka, K Environment-sensitive stabilization of core-shell structured polyion complex micelle by reversible cross-linking of the core through disulfide bond. J. Am. Chem. Soc. 121, 11247–11248 (1999).

    CAS  Article  Google Scholar 

  15. 15

    Kataoka, K, Harada, A & Nagasaki, Y Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv. Drug Del. Rev 47, 113–131 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Harada, A & Kataoka, K Supramolecular assemblies of block copolymers in aqueous media as nanocontainers relevant to biological applications. Prog. Polym. Sci. 31, 949–982 (2006).

    CAS  Article  Google Scholar 

  17. 17

    Cabral, H, Nishiyama, N & Kataoka, K Supramolecular nanodevices: From design validation to theranostic Nanomedicine. Acc. Chem. Res. 44, 999–1008 (2011).

    CAS  Article  Google Scholar 

  18. 18

    Itaka, K & Kataoka, K Progress and prospects of polyplex nanomicelles for plasmid DNA delivery. Current Gene Therapy 11, 457–465 (2011).

    CAS  Article  Google Scholar 

  19. 19

    Gohy, JF, Varshney, SK, Antoun, S & Jerome, R Water-Soluble Complexes Formed by Sodium Poly(4-styrenesulfonate) and a Poly(2-vinylpyridinium)-block-poly(ethyleneoxide) Copolymer. Macromolecules 33, 9298–9305 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Gohy, JF, Varshney, SK & Jerome, R Water-Soluble Complexes Formed by Poly(2-vinylpyridinium)-block-poly(ethylene oxide) and Poly(sodium methacrylate)-block-poly(ethylene oxide) Copolymers. Macromolecules 34, 3361–3366 (2001).

    CAS  Article  Google Scholar 

  21. 21

    Li, Y, Bronich, TK, Chelushkin, PS & Kabanov, AV Dynamic Properties of Block Ionomer Complexes with Polyion Complex Cores. Macromolecules 41, 5863–5868 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Luo, K, Yin, J, Song, Z, Cui, L, Cao, B & Chen, X Biodegradable Interpolyelectrolyte Complexes Based on Methoxy Poly(ethylene glycol)-b-poly(α, L-glutamic acid) and Chitosan. Biomacromolecules 9, 2653–2661 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Yusa, S, Yokoyama, Y & Morishima, Y Synthesis of Oppositely Charged Block Copolymers of Poly(ethylene glycol) via Reversible Addition-Fragmentation Chain Transfer Radical Polymerization and Characterization of Their Polyion Complex Micelles in Water. Macromolecules 42, 376–383 (2009).

    CAS  Article  Google Scholar 

  24. 24

    Novoa-Carballal, R, Pergushov, DV & Muller, AHE Interpolyelectrolyte complexes based on hyaluronic acid-block-poly(ethylene glycol) and poly-L-lysine. Soft Matter 9, 4297–4303 (2013).

    CAS  Article  Google Scholar 

  25. 25

    van der Burgh, S, Keizer, A & Stuart, MAC Complex Coacervation Core Micelles. Colloidal Stability and Aggregation Mechanism. Langmuir 20, 1073–1084 (2004).

    CAS  Article  Google Scholar 

  26. 26

    Liu, Y, Li, C, Wang, HY, Zhang, XZ & Zhuo, RX Synthesis of Thermo- and pH-Sensitive Polyion Complex Micelles for Fluorescent Imaging. Chem. Eur. J 18, 2297–2304 (2012).

    CAS  Article  Google Scholar 

  27. 27

    Nakai, K, Nishiuchi, M, Inoue, M, Ishihara, K, Sanada, Y, Sakurai, K & Yusa, S Preparation and Characterization of Polyion Complex Micelles with Phosphobetaine Shells. Langmuir 29, 9651–9661 (2013).

    CAS  Article  Google Scholar 

  28. 28

    Voets, IK, Moll, PM, Aqil, A, Jerome, C, Detrembleur, C, de Waard, P, de Keizer, A & Cohen, SMA Temperature Responsive Complex Coacervate Core Micelles With a PEO and PNIPAAm Corona. J. Phys. Chem. B 112, 10833–10840 (2008).

    CAS  Article  Google Scholar 

  29. 29

    De Santis, S, Diana, LR, Diociaiuti, M & Masci, G Pegylated and Thermosensitive Polyion Complex Micelles by Self-Assembly of Two Oppositely and Permanently Charged Diblock Copolymers. Macromolecules 43, 1992–2001 (2010).

    CAS  Article  Google Scholar 

  30. 30

    Voets, IK, de Keizer, A, Cohen S, MA, Justynska, J & Schlaad, H Irreversible Structural Transitions in Mixed Micelles of Oppositely Charged Diblock Copolymers in Aqueous Solution. Macromolecules 40, 2158–2164 (2007).

    CAS  Article  Google Scholar 

  31. 31

    Harada, A & Kataoka, K Effect of charged segment length on physicochemical properties of core-shell type polyion complex micelles from block ionomers. Macromolecules 36, 4995–5001 (2003).

    CAS  Article  Google Scholar 

  32. 32

    Koide, A, Kishimura, A, Osada, K, Jang, WD, Yamasaki, Y & Kataoka, K Semipermeable Polymer Vesicle (PICsome) Self-Assembled in Aqueous Medium from a Pair of Oppositely Charged Block Copolymers: Physiologically Stable Micro-/Nanocontainers of Water-Soluble Macromolecules. J. Am. Chem. Soc. 128, 5988–5989 (2006).

    CAS  Article  Google Scholar 

  33. 33

    Anraku, Y, Kishimura, A, Yamasaki, Y & Kataoka, K Living Unimodal Growth of Polyion Complex Vesicles via Two-Dimensional Supramolecular Polymerization. J. Am. Chem. Soc. 135, 1423–1429 (2013).

    CAS  Article  Google Scholar 

  34. 34

    Harada, A & Kataoka, K Chain length recognition: Core-shell supramolecular assembly from oppositely charged block copolymers. Science 283, 65–67 (1999).

    CAS  Article  Google Scholar 

  35. 35

    Hayashi, K, Chaya, H, Fukushima, S, Watanabe, S, Takemoto, H, Osada, K, Nishiyama, N, Miyata, K & Kataoka, K Influence of RNA Strand Rigidity on Polyion Complex Formation with Block Catiomers. Macromol. Rapid Commun. 37, 486–493 (2016).

    CAS  Article  Google Scholar 

  36. 36

    Yi, Y, Kim, H-J, Mi, P, Zheng, M, Takemoto, H, Toh, K, Kim, B-S, Hayashi, K, Naito, M, Matsumoto, Y, Miyata, K & Kataoka, K Targeted systemic delivery of siRNA to cervical cancer model using cyclic RGD-installed unimer polyion complex-assembled gold nanoparticles. J. Control. Release 244, 247–256 (2016).

    CAS  Article  Google Scholar 

  37. 37

    Kim, H-J, Takemoto, H, Yi, Y, Zheng, M, Maeda, Y, Chaya, H, Hayashi, K, Mi, P, Pittella, F, Christie, RJ, Toh, K, Matsumoto, Y, Nishiyama, N, Miyata, K & Kataoka, K Precise engineering of siRNA delivery vehicles to tumors using polyion complexes and gold nanoparticles. ACS Nano 8, 8979–8991 (2014).

    CAS  Article  Google Scholar 

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Correspondence to Atsushi Harada or Kazunori Kataoka.

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Harada, A., Kataoka, K. Polyion complex micelle formation from double-hydrophilic block copolymers composed of charged and non-charged segments in aqueous media. Polym J 50, 95–100 (2018).

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