Effect of Bottlebrush Poloxamer Architecture on Binding to Liposomes

Joseph F. Hassler, Adelyn Crabtree, Lucy Liberman, Frank S. Bates, Benjamin J. Hackel, Timothy P. Lodge

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Poloxamers triblock copolymers consisting of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) have demonstrated cell membrane stabilization efficacy against numerous types of stress. However, the mechanism responsible for this stabilizing effect remains elusive, hindering engineering of more effective therapeutics. Bottlebrush polymers have a wide parameter space and known relationships between architectural parameters and polymer properties, enabling their use as a tool for mechanistic investigations of polymer-lipid bilayer interactions. In this work, we utilized a versatile synthetic platform to create novel bottlebrush analogues to poloxamers and then employed pulsed-field-gradient NMR and an in vitro osmotic stress assay to explore the effect of bottlebrush architectural parameters on binding to, and protection of, model phospholipid bilayers. We found that the binding affinity of a bottlebrush poloxamer (BBP) (B-E1043P515, Mn ≈ 26 kDa) is about 3 times higher than a linear poloxamer with a similar composition and number of PPO units (L-E93P54E93, Mn ≈ 11 kDa). Furthermore, BBP binding is sensitive to overall molecular weight, side-chain length, and architecture (statistical versus block). Finally, all tested BBPs exhibit a protective effect on cell membranes under stress at sub-μM concentrations. As the factors controlling membrane affinity and protection efficacy of bottlebrush poloxamers are not understood, these results provide important insight into how they adhere to and stabilize a lipid bilayer surface.

Original languageEnglish (US)
Pages (from-to)449-461
Number of pages13
JournalBiomacromolecules
Volume24
Issue number1
DOIs
StatePublished - Jan 9 2023

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (R01 HL122323 and R01 AR071349). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The cryo-TEM images were taken using resources in the Characterization Facility, College of Science and Engineering, University of Minnesota, which receives partial support from the NSF through the MRSEC (Award Number DMR-2011401) and the NNCI (Award Number ECCS-2025124) programs. The authors acknowledge Dr. Thomas Smith for helpful discussions regarding NMR acquisition and analysis. They thank Dr. Michael Sims, Joanna White, and Benjamin Rudzinski for careful review of the manuscript.

Publisher Copyright:
© 2023 American Chemical Society. All rights reserved.

MRSEC Support

  • Shared

PubMed: MeSH publication types

  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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