Design and synthesis of PEGylated amphiphilic block oligomers as membrane anchors for stable binding to lipid bilayer membranes

Polymer Journal volume 50, pages787–797(2018)Cite this article

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Abstract

Cell surface engineering is a potentially powerful method for manipulating living cells by decorating the cell membrane with specific molecules. Possible applications include cell therapy, drug delivery systems, bio-imaging, and tissue engineering. The stable binding of synthetic molecules to serve as artificial membrane protein anchors is a promising approach for appending functional molecules to the cell surface. However, such synthetic molecules have previously shown limitations, including cytotoxicity and low cell surface affinity. We synthesized amphiphilic block oligomers, using ruthenium-catalyzed living radical polymerization, as novel membrane anchors for stable binding to lipid bilayer membranes. AB and ABA-type amphiphilic block oligomers were synthesized with poly(ethylene glycol) methacrylate (PEGMA) and varying butyl methacrylate (BMA) contents (PEGMA/BMA ratios of 25/5–25/50). These PEGylated oligomers showed high binding efficiencies (up to 92%) for liposomes, which served as model cell membranes, and low cytotoxicity in K562 cells. Both the BMA content and the block segment sequence in the copolymers strongly affected their binding efficiencies. Oligomers with an ABA-type block structure were much more effective than AB-type block oligomers, random oligomers, or PEGMA homo-oligomers for stable membrane binding. Thus, precise control of the primary structures of the amphiphilic oligomers enabled tuning of their binding efficiencies. These amphiphilic block oligomers hold promise as novel membrane anchors in many biomedical applications.

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References

  1. 1.

    Custódio CA, Mano JF. Cell surface engineering to control cellular interactions. Chem Nano Mat. 2016;2:376–84.

    Google Scholar 

  2. 2.

    Capicciotti CJ, Zong C, Sheikh MO, Sun T, Wells L, Boons G-J. Cell-surface glyco-engineering by exogenous enzymatic transfer using a bifunctional CMP-Neu5Ac derivative. J Am Chem Soc. 2017;139:13342–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Niu J, Lunn DJ, Pusuluri A, Yoo JI, Malley MAO, Mitragotri S, Soh HT, Hawker CJ. Engineering live cell surfaces with functional polymers via cytocompatible controlled radical polymerization. Nat Chem. 2017;9:537–45.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Mastuda M, Hatanaka W, Takeo M, Kim CW, Niidome T, Yamamoto T, Kishimura A, Mori T, Katayama Y. Short peptide motifs for long-lasting anchoring to the cell surface. Bioconjug Chem. 2014;25:2134–43.

    Article  CAS  Google Scholar 

  5. 5.

    Hoffecker IT, Takemoto N, Arima Y, Iwata H. Sequence-specific nuclease-mediated release of cells tethered by oligonucleotide phospholipids. Biomaterials. 2015;53:318–29.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Liu Q, Lyu Z, Yu Y, Zhao Z-A, Hu S, Yuan L, Chen G, Chen H. Synthetic glycopolymers for highly efficient differentiation of embryonic stem cells into neurons: lipo- or not? ACS Appl Mater. 2017;9:11518–27.

    Article  CAS  Google Scholar 

  7. 7.

    D’Souza S, Murata H, Jose MV, Askarova S, Yantsen Y, Andersen JD, Edington CDJ, Clafshenkel WP, Koepsel RR, Russell AJ. Engineering of cell membranes with a bisphosphonate-containing polymer using ATRP synthesis for bone targeting. Biomaterials. 2014;35:9447–58.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Muraoka T, Endo T, Tabata KV, Noji H, Nagatoishi S, Tsumoto K, Li R, Kinbara K. Reversible ion transportation switch by a ligand-gated synthetic supramolecular ion channel. J Am Chem Soc. 2014;136:15584–95.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Shi P, Ju E, Wang E, Yan Z, Ren J, Qu X. Host–guest recognition on photo-responsive cell surfaces directs cell–cell contacts. J Method. 2016;12:16–21.

    Google Scholar 

  10. 10.

    Shi P, Ju E, Yan Z, Gao N, Wang J, Hou J, Zhang Y, Ren J, Qu X. Spatiotemporal control of cell–cell reversible interactions using molecular engineering. Nat Commun. 2016;7:1–9.

    Google Scholar 

  11. 11.

    Langton MJ, Keymeulen F, Ciaccia M, Williams NH, Hunter CA. Controlled membrane translocation provides a mechanism for signal transduction and amplification. Nat Chem. 2017;9:426–30.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Lister FGA, Le Bailly BAF, Webb SJ, Clayden J. Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor. Nat Chem. 2017;9:420–5.

    Article  CAS  Google Scholar 

  13. 13.

    Jia H-R, Wang H-Y, Yu Z-W, Chen Z, Wu F-G. Long-time plasma membrane imaging based on a two-step synergistic cell surface modification strategy. Bioconjug Chem. 2016;27:782–9.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Chen X, Zhang X, Wang H-Y, Chen Z, Wu F-G. Subcellular fate of a fluorescent cholesterol-poly(ethylene glycol) conjugate: an excellent plasma membrane imaging reagent. Langmuir. 2016;32:10126–35.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Kobayashi S, Terai T, Yoshikawa Y, Ohkawa R, Ebihara M, Hayashi M, Takiguchi K, Nemoto N. In vitro selection of random peptides against artificial lipid bilayers: A potential tool to immobilize molecules on membranes. Chem Commun. 2017;53:3458–61.

    Article  CAS  Google Scholar 

  16. 16.

    Rosen BM, Percec V. Single-electron transfer and single-electron transfer degenerative chain transfer living radical polymerization. Chem Rev. 2009;109:5069–119.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Anastasaki A, Nikolaou V, Nurumbetov G, Wilson P, Kempe K, Quinn JF, Davis TP, Whittaker MR, Haddleton DM. Cu(0)-mediated living radical polymerization: a versatile tool for materials synthesis. Chem Rev. 2016;116:835–77.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Matyjaszewski K, Tsarevsky NV. Macromolecular engineering by atom transfer radical polymerization. J Am Chem Soc. 2014;136:6513–33.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Keddie DJ, Moad G, Rizzard E, Thang SH. RAFT agent design and synthesis. Macromolecules. 2012;45:5321–42.

    Article  CAS  Google Scholar 

  20. 20.

    Koda Y, Terashima T, Sawamoto M, Maynard HD. Amphiphilic/fluorous random copolymers as a new class of non-cytotoxic polymeric materials for protein conjugation. Polym Chem. 2015;6:240–7.

    Article  CAS  Google Scholar 

  21. 21.

    Koda Y, Terashima T, Maynard HD, Sawamoto M. Protein storage with perfluorinated PEG compartments in a hydrofluorocarbon solvent. Polym Chem. 2016;7:6694–8.

    Article  CAS  Google Scholar 

  22. 22.

    Pelegri-O’Day EM, Lin E-W, Maynard HD. Therapeutic protein-polymer conjugates: advancing beyond PEGylation. J Am Chem Soc. 2014;136:14323–32.

    Article  CAS  Google Scholar 

  23. 23.

    Nguyen TH, Kim S-H, Decker CG, Wong DY, Loo JA, Maynard HD. A heparin-mimicking polymer conjugate stabilizes basic fibroblast growth factor. Nat Chem. 2013;5:221–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bat E, Lee J, Lau UY, Maynard HD. Trehalose glycopolymer resists allow direct writing of protein patterns by electron-beam lithography. Nat Commun. 2015;6:6654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Lau UY, Saxer SS, Lee J, Bat E, Maynard HD. Direct write protein patterns for multiplexed cytokine detection from live cells using electron beam lithography. ACS Nano. 2016;10:723–9.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Delplace V, Nicolas J. Degradable vinyl polymers for biomedical applications. Nat Chem. 2015;7:771–84.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Boyer C, Corrigan NA, Jung K, Nguyen D, Nguyen T-K, Adnan NNM, Oliver S, Shanmugan S, Yeow J. Copper-mediated living radical polymerization (atom transfer radical polymerization and copper(0) mediated polymerization): from fundamentals to bioapplications. Chem Rev. 2016;116:1803–949.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Tu Y, Peng F, Adawy A, Men Y, Abdelmohsen LKEA, Wilson DA. Mimicking the cell: bio-inspired functions of supramolecular assemblies. Chem Rev. 2016;116:2023–78.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Palivan C, Goers R, Najer A, Zhang X, Car A, Meier W. Bioinspired polymer vesicles and membranes for biological and medical applications. Chem Soc Rev. 2016;45:377–411.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Ouchi M, Terashima T, Sawamoto M. Transition metal-catalyzed living radical polymerization: toward perfection in catalysis and precision polymer synthesis. Chem Rev. 2006;109:4963–5050.

    Article  CAS  Google Scholar 

  31. 31.

    Yoda H, Nakatani K, Terashima T, Ouchi M, Sawamoto M. Ethanol-mediated living radical homo- and copolymerizations with Cp*-ruthenium catalysts: active, robust, and universal for functionalized methacrylates. Macromolecules. 2010;43:5595–601.

    Article  CAS  Google Scholar 

  32. 32.

    Koda Y, Terashima T, Sawamoto M. Fluorous microgel star polymers: selective recognition and separation of polyfluorinated surfactants and compounds in water. J Am Chem Soc. 2014;136:15742–8.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Koda Y, Terashima T, Sawamoto M. Multimode self-folding polymers via reversible and thermoresponsive self-assembly of amphiphilic/fluorous random copolymers. Macromolecules. 2016;49:4534–43.

    Article  CAS  Google Scholar 

  34. 34.

    Weissig V. Liposomes. 2nd ed. In: Torchilin VP, editor. Oxford: Oxford Univ. Press; 2003.

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Acknowledgements

This work was supported by a Grant for Exploratory Research for Advanced Technology from the Japan Science and Technology Agency (JST-ERATO). This work was also supported by Grants-in-Aid from the Japan Society for the Promotion of Science (JSPS), KAKENHI grant numbers JP16H06313 (K.A.) and JP16H03842 (Y.S.). We thank Professor M. Sawamoto (Kyoto University) for support in performing the SEC analysis. We also thank S.R. Doctrow, PhD, from the Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

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  1. Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto, 615-8510, Japan

    Daiki Takahashi, Yuta Koda, Yoshihiro Sasaki & Kazunari Akiyoshi

  2. ERATO Akiyoshi Bio-Nanotransporter Project, Japan Science and Technology Agency (JST), Katsura Int’tech Center, Katsura, Nishikyo-ku, Kyoto, 615-8530, Japan

    Yuta Koda & Kazunari Akiyoshi

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  1. Daiki Takahashi
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Correspondence to Kazunari Akiyoshi.

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Takahashi, D., Koda, Y., Sasaki, Y. et al. Design and synthesis of PEGylated amphiphilic block oligomers as membrane anchors for stable binding to lipid bilayer membranes. Polym J 50, 787–797 (2018). https://doi.org/10.1038/s41428-018-0055-5

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