Polymer Bulletin

, Volume 75, Issue 3, pp 1149–1169 | Cite as

Synthesis and micellization of block copolymer based on host–guest recognition and double disulphide linkage for intracellular drug delivery

  • Zhen Zhang
  • Changyu He
  • Lianjiang Tan
  • Bingya Liu
  • Zhenggang Zhu
  • Bing Gong
  • Yu-Mei ShenEmail author
Original Paper


Block copolymer CSO2500-β-CD-PLA3000 and CSO2500-β-CD-PLA5000 were synthesized via H-bonding-instructed double disulfide linkage and host–guest recognition between adamantane and β-cyclodextrin. Transmission electron microscopy and dynamic light scattering results further confirmed the formation of self-assembled micelles with an average size of 45 and 96 nm, and a polydispersity index of 0.178 and 0.161 for blank micelles, respectively. The copolymers CSO2500-β-CD-PLA3000 and CSO2500-β-CD-PLA5000 exhibited a low critical micellization concentration of 0.041 and 0.027 mg/mL, respectively, suggesting that the micelles are highly stable in dilute solution. Doxorubicin (DOX), a hydrophobic model anticancer drug, was loaded in the micelles, and the drug release can be triggered and significantly accelerated in reductive environment. The blank micelles had fairly low cytotoxicity, but the DOX-loaded micelles exhibited great proliferation inhibition against HeLa cells, which was confirmed by MTT assay. The experimental results demonstrated that these copolymeric micelles are promising carriers for the redox-responsive intracellular delivery of hydrophobic anticancer drugs. Due to the noncovalent interactions between the host and guest, which endowed supramolecular block copolymer with the ability of reversible assembling and disassembling, dual stimuli responsiveness can be expected for this novel supramolecular block copolymer CSO2500-β-CD-PLA5000 favorable in efficient anticancer drug delivery.


Disulfide bond Block copolymer Self-assembly micelles β-CD 



This work was financially supported by the Natural Science Foundation of China (No. 81671802).

Supplementary material

289_2017_2086_MOESM1_ESM.docx (1.1 mb)
Supplementary material 1 (DOCX 1126 kb)


  1. 1.
    Rinaudo M (2006) Chitin and chitosan: properties and applications. Prog Polym Sci 31:603–632CrossRefGoogle Scholar
  2. 2.
    Tan L, Huang R, Li X, Liu S, Shen Y-M, Shao Z (2017) Chitosan-based core-shell nanomaterials for pH-triggered release of anticancer drug and near-infrared bioimaging. Carbohydr Polym 157:325–334CrossRefGoogle Scholar
  3. 3.
    Du YZ, Wang L, Yuan H, Hu FQ (2011) Linoleic acid-grafted chitosan oligosaccharide micelles for intracellular drug delivery and reverse drug resistance of tumor cells. Int J Biol Macromol 48:215–222CrossRefGoogle Scholar
  4. 4.
    Du YZ, Cai LL, Liu P, You J, Yuan H, Hu FQ (2012) Tumor cells-specific targeting delivery achieved by A54 peptide functionalized polymeric micelles. Biomaterials 33:8858–8867CrossRefGoogle Scholar
  5. 5.
    Köping-Höggård M, Mel’nikova YS, Vårum KM, Lindman B, Artursson P (2003) Relationship between the physical shape and the efficiency of oligomeric chitosan as a gene delivery system in vitro and in vivo. J Gene Med 5:130–141CrossRefGoogle Scholar
  6. 6.
    Chae SY, Jang MK, Nah JW (2005) Influence of molecular weight on oral absorption of water soluble chitosans. J Control Release 102:383–394CrossRefGoogle Scholar
  7. 7.
    You J, Hu FQ, Du YZ, Yuan H (2007) Polymeric micelles with glycolipid-like structure and multiple hydrophobic domains for mediating molecular target delivery of paclitaxel. Biomacromolecules 8:2450–2456CrossRefGoogle Scholar
  8. 8.
    Du YZ, Wang L, Yuan H, Wei XH, Hu F (2009) Preparation and characteristics of linoleic acid-grafted chitosan oligosaccharide micelles as a carrier for doxorubicin. Colloid Q Surf B Biointerfaces 69(2):257–263CrossRefGoogle Scholar
  9. 9.
    Hu FQ, Liu LN, Du YZ, Yuan H (2009) Synthesis and antitumor activity of doxorubicin conjugated stearic acid-g-chitosan oligosaccharide polymeric micelles. Biomaterials 30(36):6955–6963CrossRefGoogle Scholar
  10. 10.
    Huang X, Jiang XH, Hu FQ, Du YZ, Zhu QF, Jin CS (2012) In vitro antitumour activity of stearic acid-g-chitosan oligosaccharide polymeric micelles loading podophyllotoxin. J Microencapsul 29(1):1–8CrossRefGoogle Scholar
  11. 11.
    Yan J, Du YZ, You FY, Yuan H, Hu FQ (2013) Effect of proteins with different isoelectric points on the gene transfection efficiency mediated by stearic acid grafted chitosan oligosaccharide micelles. Mol Pharm 10(7):2568–2577CrossRefGoogle Scholar
  12. 12.
    Jia LJ, Li ZY, Zhang DR, Zhang QJ, Shen Y, Guo HJ, Tian XN, Liu GP, Zheng DD, Qi LS (2013) Redox-responsive catiomer based on PEG-ss-chitosan oligosaccharide-ss-polyethylenimine copolymer for effective gene delivery. Polym Chem 49(1):156–165CrossRefGoogle Scholar
  13. 13.
    Harada A, Kamachi M (1990) Complex formation between poly(ethylene glycol) and α-cyclodextrin. Macromolecules 23:2821–2823CrossRefGoogle Scholar
  14. 14.
    Eftink MR, Andy ML, Bystrom K, Perlmutter HD, Kristol DS (1989) Cyclodextrin inclusion complexes: studies of the variation in the size of alicyclic guests. J Am Chem Soc 111:6722–6756CrossRefGoogle Scholar
  15. 15.
    Shuai X, Porbeni FE, Wei M, Bullions T, Tonelli AE (2002) Stereoselectivity in the formation of crystalline inclusion complexes of poly(3-hydroxybutyrate)s with cyclodextrins. Macromolecules 35:3778–3780CrossRefGoogle Scholar
  16. 16.
    Kang MH, Ooya T, Shintaro Sasaki A, Yui N (2001) Polymer inclusion complex consisting of poly(ε-lysine) and α-cyclodextrin. Macromolecules 34(8):2402–2404CrossRefGoogle Scholar
  17. 17.
    Michishita T, Takashima Y, Harada A (2004) Complex formation between polyisoprene and cyclodextrins. Macromol Rapid Commun 25(12):1159–1162CrossRefGoogle Scholar
  18. 18.
    Hasegawa Y, Miyauchi M, Takashima Y, Yamaguchi H, Harada A (2005) Supramolecular polymers formed from β-cyclodextrins dimer linked by poly(ethylene glycol) and guest dimers. Macromolecules 38:3724–3730CrossRefGoogle Scholar
  19. 19.
    Zhang ZX, Liu X, Xu FJ, Loh XJ, Kang ET, Neoh KG, Li J (2008) Pseudo-block copolymer based on star-shaped poly (N-isopropylacrylamide) with a β-cyclodextrin core and guest-bearing PEG: controlling thermoresponsivity through supramolecular self-assembly. Macromolecules 41:5967–5970CrossRefGoogle Scholar
  20. 20.
    Li L, Guo X, Wang J, Liu P, Prud’homme RK, May BL, Lincoln SF (2008) Polymer networks assembled by host–guest Inclusion between adamantyl and β-cyclodextrin substituents on poly(acrylic acid) in aqueous solution. Macromolecules 41:8677–8681CrossRefGoogle Scholar
  21. 21.
    Kretschmann OS, Choi W, Miyauchi M, Tomatsu I, Harada A, Ritter H (2006) Switchable hydrogels obtained by supramolecular cross-linking of adamantyl-containing LCST copolymers with cyclodextrin dimers. Angew Chem Int Ed 45:4361–4365CrossRefGoogle Scholar
  22. 22.
    Koopmans C, Ritter H (2008) Formation of physical hydrogels via host–guest interactions of β-cyclodextrin polymers and copolymers bearing adamantyl groups. Macromolecules 41:7418–7422CrossRefGoogle Scholar
  23. 23.
    Wang J, Jiang M (2006) Polymeric self-assembly into micelles and hollow spheres with multiscale cavities driven by inclusion complexation. J Am Chem Soc 128:3703–3708CrossRefGoogle Scholar
  24. 24.
    Yang X, Hua F, Yamato K, Ruckenstein E, Gong B, Kim W, Ryu CY (2004) Supramolecular AB diblock copolymers. Angew Chem Int Ed 43:6471–6474CrossRefGoogle Scholar
  25. 25.
    Yang X, Gong B (2005) Template-assisted cross olefin metathesis. Angew Chem Int Ed 44:1352–1356CrossRefGoogle Scholar
  26. 26.
    Gong B (2007) Engineering hydrogen-bonded duplexes. Polym Int 56:436–443CrossRefGoogle Scholar
  27. 27.
    Li M, Yamato K, Ferguson JS, Singarapu KK, Szyperski T, Gong B (2008) Sequence-specific, dynamic covalent crosslinking in aqueous media. J Am Chem Soc 130:491–500CrossRefGoogle Scholar
  28. 28.
    Li M, Yamato K, Ferguson JS, Gong B (2006) Sequence-specific association in aqueous media by integrating hydrogen bonding and dynamic covalent interactions. J Am Chem Soc 128:12628–12629CrossRefGoogle Scholar
  29. 29.
    Gong B (2012) Molecular duplexes with encoded sequences and stabilities. Acc Chem Res 45:2077–2087CrossRefGoogle Scholar
  30. 30.
    Yang QL, Bai L, Zhang YQ, Zhu FX, Xu YH, Shao ZF, Shen YM, Gong B (2014) Dynamic covalent diblock copolymers: instructed coupling, micellation and redox responsiveness. Macromolecules 47:7431–7441CrossRefGoogle Scholar
  31. 31.
    Yang QL, Tan LJ, He CY, Liu BY, Xu YH, Zhu ZG, Shao ZF, Gong B, Shen YM (2015) Redox-responsive micelles self-assembled from dynamic covalent block copolymers for intracellular drug delivery. Acta Biomater 17:193–200CrossRefGoogle Scholar
  32. 32.
    Yang QL, He CY, Xu YH, Liu BY, Shao ZF, Zhu ZG, Hou Y, Gong B, Shen YM (2015) Chitosan oligosaccharide copolymer micelles with double disulphide linkage in the backbone associated by H-bonding duplexes for targeted intracellular drug delivery. Polym Chem 6:1454–1464CrossRefGoogle Scholar
  33. 33.
    Yang QL, He CY, Zhang Z, Tan LJ, Liu BY, Zhu ZG, Hou Y, Gong B, Shen YM (2016) Redox-responsive flower-like micelles of poly(l-lactic acid)-bpoly(ethylene glycol)-b-poly(l-lactic acid) for intracellular drug delivery. Polymer 90:351–362CrossRefGoogle Scholar
  34. 34.
    He CY, Zhang Z, Yang QL, Shao ZF, Gong B, Shen YM, Liu BY, Zhu ZG (2016) Reductive triblock copolymer micelles with a dynamic covalent linkage deliver antimiR-21 for gastric cancer therapy. Polym Chem 7:4352–4366CrossRefGoogle Scholar
  35. 35.
    Hu W, He CY, Tan LJ, Liu BY, Zhu ZG, Gong B, Shen YM, Shao ZF (2016) Synthesis and micellization of redox-responsive dynamic covalent multi-block copolymers. Polym Chem 7:3145–3155CrossRefGoogle Scholar
  36. 36.
    Malmsten M, Lindman B (1992) Self-assembly in aqueous block copolymer solutions. Macromolecules 25:5440–5447CrossRefGoogle Scholar
  37. 37.
    You J, Li X, De CF, Du YZ, Yuan H, Hu FQ (2008) Folate-conjugated polymer micelles for active targeting to cancer cells: preparation, in vitro evaluation of targeting ability and cytotoxicity. Nanotechnology 19(4):045102CrossRefGoogle Scholar
  38. 38.
    Liu J, Pang Y, Huang W, Huang X, Meng L, Zhu X, Zhou Y, Yan D (2011) Redox-responsive polyphosphate nanosized assemblies: a smart drug delivery platform for cancer therapy. Biomacromolecules 12(6):2407–2415CrossRefGoogle Scholar
  39. 39.
    Liu J, Pang Y, Huang W, Huang X, Meng L, Zhu X, Zhou Y, Yan D (2011) Bioreducible micelles self-assembled from amphiphilic hyperbranched multiarm copolymer for glutathione-mediated intracellular drug delivery. Biomacromolecules 12(5):1567–1577CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Zhen Zhang
    • 1
  • Changyu He
    • 2
  • Lianjiang Tan
    • 1
  • Bingya Liu
    • 2
  • Zhenggang Zhu
    • 2
  • Bing Gong
    • 3
    • 4
  • Yu-Mei Shen
    • 1
    Email author
  1. 1.Key Laboratory of Systems Biomedicine, Shanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Shanghai Key Laboratory of Gastric Neoplasms, Department of SurgeryRuijin Hospital, Shanghai Institute of Digestive Surgery, Shanghai Jiao Tong University School of MedicineShanghaiChina
  3. 3.College of ChemistryBeijing Normal UniversityBeijingChina
  4. 4.Department of ChemistryUniversity at Buffalo, State University of New YorkBuffaloUSA

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