Chemical End Group Modified Diblock Copolymers Elucidate Anchor and Chain Mechanism of Membrane Stabilization

Evelyne M. Houang; Karen J. Haman; Mihee Kim; Wenjia Zhang; Dawn A. Lowe; Yuk Y. Sham; Timothy P. Lodge; Benjamin J. Hackel; Frank S. Bates; Joseph M. Metzger

doi:10.1021/acs.molpharmaceut.7b00197

Chemical End Group Modified Diblock Copolymers Elucidate Anchor and Chain Mechanism of Membrane Stabilization

Evelyne M. Houang, Karen J. Haman, Mihee Kim, Wenjia Zhang, Dawn A. Lowe, Yuk Y. Sham, Timothy P. Lodge, Benjamin J. Hackel, Frank S. Bates, Joseph M. Metzger

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Block copolymers can be synthesized in an array of architectures and compositions to yield diverse chemical properties. The triblock copolymer Poloxamer 188 (P188), the family archetype, consisting of a hydrophobic poly(propylene oxide) core flanked by hydrophilic poly(ethylene oxide) chains, can stabilize cellular membranes during stress. However, little is known regarding the molecular basis of membrane interaction by copolymers in living organisms. By leveraging diblock architectural design, discrete end-group chemistry modifications can be tested. Here we show evidence of an anchor and chain mechanism of interaction wherein titrating poly(propylene oxide) block end group hydrophobicity directly dictates membrane interaction and stabilization. These findings, obtained in cells and animals in vivo, together with molecular dynamics simulations, provide new insights into copolymer-membrane interactions and establish the diblock copolymer molecular architecture as a valuable platform to inform copolymer-biological membrane interactions. These results have implications for membrane stabilizers in muscular dystrophy and for other biological applications involving damaged cell membranes.

Original language	English (US)
Pages (from-to)	2333-2339
Number of pages	7
Journal	Molecular pharmaceutics
Volume	14
Issue number	7
DOIs	https://doi.org/10.1021/acs.molpharmaceut.7b00197
State	Published - Jul 3 2017

Bibliographical note

Funding Information:
This work was supported by grants from National Institutes of Health (NIH grant HL122323), the Lillehei Heart Institute (to J.M.M.) American Heart Association predoctoral fellowship (to E.M.H.) the Muscular Dystrophy Association (to J.M.M.), and NIH P30 grant AR057220 (to D.A.L). The University of Minnesota Supercomputing Institute provided all the necessary computational resources for the MD simulations.

Publisher Copyright:
© 2017 American Chemical Society.

Keywords

Duchenne muscular dystrophy
block copolymer
materials science
striated muscle

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648059

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abstract = "Block copolymers can be synthesized in an array of architectures and compositions to yield diverse chemical properties. The triblock copolymer Poloxamer 188 (P188), the family archetype, consisting of a hydrophobic poly(propylene oxide) core flanked by hydrophilic poly(ethylene oxide) chains, can stabilize cellular membranes during stress. However, little is known regarding the molecular basis of membrane interaction by copolymers in living organisms. By leveraging diblock architectural design, discrete end-group chemistry modifications can be tested. Here we show evidence of an anchor and chain mechanism of interaction wherein titrating poly(propylene oxide) block end group hydrophobicity directly dictates membrane interaction and stabilization. These findings, obtained in cells and animals in vivo, together with molecular dynamics simulations, provide new insights into copolymer-membrane interactions and establish the diblock copolymer molecular architecture as a valuable platform to inform copolymer-biological membrane interactions. These results have implications for membrane stabilizers in muscular dystrophy and for other biological applications involving damaged cell membranes.",

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N2 - Block copolymers can be synthesized in an array of architectures and compositions to yield diverse chemical properties. The triblock copolymer Poloxamer 188 (P188), the family archetype, consisting of a hydrophobic poly(propylene oxide) core flanked by hydrophilic poly(ethylene oxide) chains, can stabilize cellular membranes during stress. However, little is known regarding the molecular basis of membrane interaction by copolymers in living organisms. By leveraging diblock architectural design, discrete end-group chemistry modifications can be tested. Here we show evidence of an anchor and chain mechanism of interaction wherein titrating poly(propylene oxide) block end group hydrophobicity directly dictates membrane interaction and stabilization. These findings, obtained in cells and animals in vivo, together with molecular dynamics simulations, provide new insights into copolymer-membrane interactions and establish the diblock copolymer molecular architecture as a valuable platform to inform copolymer-biological membrane interactions. These results have implications for membrane stabilizers in muscular dystrophy and for other biological applications involving damaged cell membranes.

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Chemical End Group Modified Diblock Copolymers Elucidate Anchor and Chain Mechanism of Membrane Stabilization

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