Tailored silyl ether monomers enable backbone-degradable polynorbornene-based linear, bottlebrush and star copolymers through ROMP

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Abstract

Ring-opening metathesis polymerization of norbornene-based (macro)monomers is a powerful approach for the synthesis of macromolecules with diverse compositions and complex architectures. Nevertheless, a fundamental limitation of polymers prepared by this strategy is their lack of facile degradability, limiting their utility in a range of applications. Here we describe a class of readily available bifunctional silyl ether-based cyclic olefins that copolymerize efficiently with norbornene-based (macro)monomers to provide copolymers with backbone degradability under mildly acidic aqueous conditions and degradation rates that can be tuned over several orders of magnitude, depending on the silyl ether substituents. These monomers can be used to manipulate the in vivo biodistribution and clearance rate of polyethylene glycol-based bottlebrush polymers, as well as to synthesize linear, bottlebrush and brush-arm star copolymers with degradable segments. We expect that this work will enable preparation of degradable polymers by ROMP for biomedical applications, responsive self-assembly and improved sustainability.

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Fig. 1: The study design and initial results.
Fig. 2: Norbornene monomer scope.
Fig. 3: Bifunctional silyl ether monomer scope.
Fig. 4: Bottlebrush copolymer degradation studies as a function of time, pH and bifunctional silyl ether composition.
Fig. 5: Regioselective degradation of bifunctional silyl ether-containing BASPs.
Fig. 6: Biological studies of fluorescently labelled bottlebrush (co)polymers.

Data availability

All data that support the findings of this study are available within the Article and its Supplementary Information, and/or from the corresponding author on reasonable request.

References

  1. 1.

    Mortell, K. H., Weatherman, R. V. & Kiessling, L. L. Recognition specificity of neoglycopolymers prepared by ring-opening metathesis polymerization. J. Am. Chem. Soc. 118, 2297–2298 (1996).

  2. 2.

    Kiessling, L. L., Gestwicki, J. E. & Strong, L. E. Synthetic multivalent ligands as probes of signal transduction. Angew. Chem. Int. Ed. 45, 2348–2368 (2006).

  3. 3.

    Blum, A. P. et al. Peptides displayed as high density brush polymers resist proteolysis and retain bioactivity. J. Am. Chem. Soc. 136, 15422–15437 (2014).

  4. 4.

    James, C. R. et al. Poly(oligonucleotide). J. Am. Chem. Soc. 136, 11216–11219 (2014).

  5. 5.

    Buchmeiser, M. R., Sinner, F., Mupa, M. & Wurst, K. Ring-opening metathesis polymerization for the preparation of surface-grafted polymer supports. Macromolecules 33, 32–39 (2000).

  6. 6.

    Rule, J. D. & Moore, J. S. ROMP reactivity of endo- and exo-dicyclopentadiene. Macromolecules 35, 7878–7882 (2002).

  7. 7.

    Kalow, J. A. & Swager, T. M. Synthesis of Miktoarm branched conjugated copolymers by ROMPing in and out. ACS Macro Lett. 4, 1229–1233 (2015).

  8. 8.

    Xia, Y., Olsen, B. D., Kornfield, J. A. & Grubbs, R. H. Efficient synthesis of narrowly dispersed brush copolymers and study of their assemblies: the importance of side chain arrangement. J. Am. Chem. Soc. 131, 18525–18532 (2009).

  9. 9.

    Johnson, J. A. et al. Drug-loaded, bivalent-bottle-brush polymers by graft-through ROMP. Macromolecules 43, 10326–10335 (2010).

  10. 10.

    Johnson, J. A. et al. Core-clickable peg-branch-azide bivalent-bottle-brush polymers by ROMP: grafting-through and clicking-to. J. Am. Chem. Soc. 133, 559–566 (2011).

  11. 11.

    Liu, J. et al. ‘Brush-first’ method for the parallel synthesis of photocleavable, nitroxide-labeled poly(ethylene glycol) star polymers. J. Am. Chem. Soc. 134, 16337–16344 (2012).

  12. 12.

    Sowers, M. A. et al. Redox-responsive branched-bottlebrush polymers for in vivo MRI and fluorescence imaging. Nat. Commun. 5, 5460 (2014).

  13. 13.

    Kawamoto, K. et al. Graft-through synthesis and assembly of janus bottlebrush polymers from A-branch -B diblock macromonomers. J. Am. Chem. Soc. 138, 11501–11504 (2016).

  14. 14.

    Cheng, L.-C. et al. Templated self-assembly of a PS-branch -PDMS bottlebrush copolymer. Nano Lett. 18, 4360–4369 (2018).

  15. 15.

    Rokhlenko, Y., Kawamoto, K., Johnson, J. A. & Osuji, C. O. Sub-10 nm self-assembly of mesogen-containing grafted macromonomers and their bottlebrush polymers. Macromolecules 51, 3680–3690 (2018).

  16. 16.

    Guo, Z.-H. et al. Janus graft block copolymers: design of a polymer architecture for independently tuned nanostructures and polymer properties. Angew. Chem. Int. Ed. 57, 8493–8497 (2018).

  17. 17.

    Golder, M. R. et al. Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs. Nat. Biomed. Eng. 2, 822–830 (2018).

  18. 18.

    Fishman, J. M. & Kiessling, L. L. Synthesis of functionalizable and degradable polymers by ring-opening metathesis polymerization. Angew. Chem. Int. Ed. 52, 5061–5064 (2013).

  19. 19.

    Gutekunst, W. R. & Hawker, C. J. A general approach to sequence-controlled polymers using macrocyclic ring opening metathesis polymerization. J. Am. Chem. Soc. 137, 8038–8041 (2015).

  20. 20.

    Mallick, A. et al. Oxadiazabicyclooctenone as a versatile monomer for the construction of pH sensitive functional polymers via ROMP. Polym. Chem. 9, 372–377 (2018).

  21. 21.

    Moatsou, D., Nagarkar, A., Kilbinger, A. F. M. & O’Reilly, R. K. Degradable precision polynorbornenes via ring-opening metathesis polymerization. J. Polym. Sci. A 54, 1236–1242 (2016).

  22. 22.

    Yasir, M., Liu, P., Tennie, I. K. & Kilbinger, A. F. M. Catalytic living ring-opening metathesis polymerization with Grubbs’ second- and third-generation catalysts. Nat. Chem. 11, 488–494 (2019).

  23. 23.

    Parrott, M. C. et al. Tunable bifunctional silyl ether cross-linkers for the design of acid-sensitive biomaterials. J. Am. Chem. Soc. 132, 17928–17932 (2010).

  24. 24.

    Szychowski, J. et al. Cleavable biotin probes for labeling of biomolecules via azide-alkyne cycloaddition. J. Am. Chem. Soc. 132, 18351–18360 (2010).

  25. 25.

    Shibuya, Y., Nguyen, H. V.-T. & Johnson, J. A. Mikto-brush-arm star polymers via cross-linking of dissimilar bottlebrushes: synthesis and solution morphologies. ACS Macro Lett. 6, 963–968 (2017).

  26. 26.

    Sveinbjornsson, B. R. et al. Rapid self-assembly of brush block copolymers to photonic crystals. Proc. Natl Acad. Sci. USA 109, 14332–14336 (2012).

  27. 27.

    Radzinski, S. C., Foster, J. C., Chapleski, R. C., Troya, D. & Matson, J. B. Bottlebrush polymer synthesis by ring-opening metathesis polymerization: the significance of the anchor group. J. Am. Chem. Soc. 138, 6998–7004 (2016).

  28. 28.

    Gillard, J. W. et al. Symmetrical alkoxysilyl ethers. A new class of alcohol-protecting groups. Preparation of tert-butoxydiphenylsilyl ethers. J. Org. Chem. 53, 2602–2608 (1988).

  29. 29.

    Davies, J. S., Higginbotham, C. L., Tremeer, E. J., Brown, C. & Treadgold, R. C. Protection of hydroxy groups by silylation: use in peptide synthesis and as lipophilicity modifiers for peptides. J. Chem. Soc. Perkin Trans. 1, 3043 (1992).

  30. 30.

    Xia, Y. et al. EPR study of spin labeled brush polymers in organic solvents. J. Am. Chem. Soc. 133, 19953–19959 (2011).

  31. 31.

    Burts, A. O. et al. Using EPR to compare PEG-branch-nitroxide “bivalent-brush polymers” and traditional PEG bottle–brush polymers: branching makes a difference. Macromolecules 45, 8310–8318 (2012).

  32. 32.

    Elling, B. R. & Xia, Y. Living alternating ring-opening metathesis polymerization based on single monomer additions. J. Am. Chem. Soc. 137, 9922–9926 (2015).

  33. 33.

    Alonso-Villanueva, J. et al. ROMP of functionalized cyclooctene and norbornene derivatives and their copolymerization with cyclooctene. J. Macromol. Sci. A 48, 211–218 (2011).

  34. 34.

    Gringolts, M. L. et al. Synthesis of norbornene–cyclooctene copolymers by the cross-metathesis of polynorbornene with polyoctenamer. RSC Adv. 5, 316–319 (2015).

  35. 35.

    Bang, J. et al. Defect-free nanoporous thin films from ABC triblock copolymers. J. Am. Chem. Soc. 128, 7622–7629 (2006).

  36. 36.

    Zhao, H., Sterner, E. S., Coughlin, E. B. & Theato, P. O-nitrobenzyl alcohol derivatives: opportunities in polymer and materials science. Macromolecules 45, 1723–1736 (2012).

  37. 37.

    Zhang, W. et al. Tuning microdomain spacing with light using ortho-nitrobenzyl-linked triblock copolymers. J. Polym. Sci. B 56, 355–361 (2018).

  38. 38.

    Gao, A. X., Liao, L. & Johnson, J. A. Synthesis of acid-labile PEG and PEG-doxorubicin-conjugate nanoparticles via brush-first ROMP. ACS Macro Lett 3, 854–857 (2014).

  39. 39.

    Nguyen, H. V.-T. et al. Nitroxide-based macromolecular contrast agents with unprecedented transverse relaxivity and stability for magnetic resonance imaging of tumors. ACS Cent. Sci. 3, 800–811 (2017).

  40. 40.

    Nguyen, H. V.-T. et al. Triply loaded nitroxide brush-arm star polymers enable metal-free millimetric tumor detection by magnetic resonance imaging. ACS Nano 12, 11343–11354 (2018).

  41. 41.

    Li, S.-D. & Huang, L. Pharmacokinetics and biodistribution of nanoparticles. Mol. Pharm. 5, 496–504 (2008).

  42. 42.

    Demoy, M. et al. Splenic trapping of nanoparticles: complementary approaches for in situ studies. Pharm. Res. 14, 463–468 (1997).

  43. 43.

    Cataldi, M., Vigliotti, C., Mosca, T., Cammarota, M. & Capone, D. Emerging role of the spleen in the pharmacokinetics of monoclonal antibodies, nanoparticles and exosomes. Int. J. Mol. Sci. 18, E1249 (2017).

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Acknowledgements

The authors thank the National Institutes of Health (grant no. 1R01CA220468-01) for supporting this work. P.S. was supported by a fellowship from the American Cancer Society. H.V.-T.N was supported by the National Science Foundation (Graduate Research Fellowship).

Author information

P.S. and J.A.J. conceived the idea. P.S. conducted all synthesis and characterization studies. P.S. and H.V.-T.N. conducted cell culture and in vivo studies. P.S. and J.A.J. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Correspondence to Jeremiah A. Johnson.

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Competing interests

P.S. and J.A.J. are named inventors on a patent application (US Patent application no. 16/542824) filed by the Massachusetts Institute of Technology on the monomers and copolymers described in this work.

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Supplementary information

Supplementary Information

Procedures for the synthesis and characterization of the materials described in the main text, procedures for all in vitro and in vivo biological experiments, and Supplementary Scheme 1, Table 1 and Figs. 1–40

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Shieh, P., Nguyen, H.V. & Johnson, J.A. Tailored silyl ether monomers enable backbone-degradable polynorbornene-based linear, bottlebrush and star copolymers through ROMP. Nat. Chem. (2019) doi:10.1038/s41557-019-0352-4

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