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Bottlebrush polymers with flexible enantiomeric side chains display differential biological properties

Abstract

Chirality and molecular conformation are central components of life: biological systems rely on stereospecific interactions between discrete (macro)molecular conformers, and the impacts of stereochemistry and rigidity on the properties of small molecules and biomacromolecules have been intensively studied. Nevertheless, how these features affect the properties of synthetic macromolecules has received comparably little attention. Here we leverage iterative exponential growth and ring-opening metathesis polymerization to produce water-soluble, chiral bottlebrush polymers (CBPs) from two enantiomeric pairs of macromonomers of differing rigidity. Remarkably, CBPs with conformationally flexible, mirror image side chains show several-fold differences in cytotoxicity, cell uptake, blood pharmacokinetics and liver clearance; CBPs with comparably rigid, mirror image side chains show no differences. These observations are rationalized with a simple model that correlates greater conformational freedom with enhanced chiral recognition. Altogether, this work provides routes to the synthesis of chiral nanostructured polymers and suggests key roles for stereochemistry and conformational rigidity in the design of future biomaterials.

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Fig. 1: Conceptual design of this work.
Fig. 2: Scheme for two-atom IEG synthesis.
Fig. 3: Chemical structures of two-atom versus five-atom MMs and CBPs and comparison of their CD spectra.
Fig. 4: Analysis of conformational flexibility of 2A-R-OH-MM and 5A-R-OH-MM using molecular dynamics simulations.
Fig. 5: Cytotoxicity and uptake of CBPs in three different cell lines.
Fig. 6: Blood compartment pharmacokinetics and ex vivo biodistribution for CBPs in healthy BALB/c mice (n = 3 mice per treatment group).

Data availability

All data supporting the findings of this study are available within the article and its Supplementary Information and can also be obtained from the corresponding author upon reasonable request.

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Acknowledgements

We thank the Army Research Office (W911NF-17-1-0521) and the National Institutes of Health (R01-CA220468-01 and postdoctoral fellowships for M.R.G. and N.J.O.) for supporting this work. We thank the National Science Foundation (graduate research fellowship for H.V.-T.N.). This work was supported in part by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute. We acknowledge the support of the National Institute of Standards and Technology, US Department of Commerce, in providing the neutron research facilities used in this work. We also thank J. Zhao for assistance with Fig. 1. We thank S.E. Denmark and A.F. Zahrt for helpful discussions.

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J.A.J., H.V.-T.N., J.C.B. and Y.J. conceived the idea. H.V.-T.N., Y.J., J.C.B., W.W., K.K.C., Z.H. and K.Y. performed the chemical syntheses and characterizations. H.V.-T.N., Y.J. J.C.B., N.J.O., Q.C., W.W. and M.R.G. performed biological studies. S.M., S.A. and R.G.-B. conducted simulations. M.J.A.H. conducted SANS studies. D.S., Y.S., A.P.W. and J.A.J. designed and conducted coarse-grained simulations. J.A.J., H.V.-T.N. and Y.J. wrote the manuscript. All authors discussed the results and edited the manuscript.

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Correspondence to Rafael Gómez-Bombarelli or Jeremiah A. Johnson.

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Peer review information Nature Chemistry thanks Arthi Jayaraman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1–90, Tables 1–3, discussion, materials/general experimental methods/instrumentations and synthetic protocols.

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Nguyen, H.VT., Jiang, Y., Mohapatra, S. et al. Bottlebrush polymers with flexible enantiomeric side chains display differential biological properties. Nat. Chem. 14, 85–93 (2022). https://doi.org/10.1038/s41557-021-00826-8

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