Polycation Architecture Affects Complexation and Delivery of Short Antisense Oligonucleotides: Micelleplexes Outperform Polyplexes

Christian J. Grimme; McKenna G. Hanson; Louis G. Corcoran; Theresa M. Reineke

doi:10.1021/acs.biomac.2c00338

Polycation Architecture Affects Complexation and Delivery of Short Antisense Oligonucleotides: Micelleplexes Outperform Polyplexes

Christian J. Grimme, McKenna G. Hanson, Louis G. Corcoran, Theresa M. Reineke

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

8 Scopus citations

Abstract

Herein, we examine the complexation and biological delivery of a short single-stranded antisense oligonucleotide (ASO) payload with four polymer derivatives that form two architectural variants (polyplexes and micelleplexes): a homopolymer poly(2-dimethylaminoethyl methacrylate) (D), a diblock polymer poly(ethylene glycol)methylether methacrylate-block-poly(2-dimethylaminoethyl methacrylate) (O_bD), and two micelle-forming variants, poly(2-dimethylaminoethyl methacrylate)-block-poly(n-butyl methacrylate) (DB) and poly(ethylene glycol)methylether methacrylate-block-poly(2-dimethylaminoethyl methacrylate)-block-poly(n-butyl methacrylate) (O_bDB). Both polyplexes and micelleplexes complexed ASOs, and the incorporation of an O_bbrush enhances colloidal stability. Micellplexes are templated by the size and shape of the unloaded micelle and that micelle-ASO complexation is not sensitive to formulation/mixing order, allowing ease, versatility, and reproducibility in packaging short oligonucleotides. The DB micelleplexes promoted the largest gene silencing, internalization, and tolerable toxicity while the O_bDB micelleplexes displayed enhanced colloidal stability and highly efficient payload trafficking despite having lower cellular uptake. Overall, this work demonstrates that cationic micelles are superior delivery vehicles for ASOs denoting the importance of vehicle architecture in biological performance.

Original language	English (US)
Pages (from-to)	3257-3271
Number of pages	15
Journal	Biomacromolecules
Volume	23
Issue number	8
DOIs	https://doi.org/10.1021/acs.biomac.2c00338
State	Published - Aug 8 2022
Externally published	Yes

Bibliographical note

Funding Information:
The project was funded by Genentech. M.G.H. also acknowledges support from the National Science Foundation Graduate Research Fellowship Program (DGE-1839286). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.

Funding Information:
We thank Genentech for funding of this work and Dr. Karthik Nagapudi and Dr. Apoorva Sarode for their helpful discussion and insight. The authors would like to express their gratitude toward Cristiam F. Santa Chalarca for performing the dn/dc measurements for the poly( n-butyl methacrylate) block and Wei Zhang for her insightful discussions about TEM. Additionally, parts of this work were carried out in the Characterization Facility, 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. Some of this work’s figures were adapted or created with BioRender.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

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Journal Article
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Research Support, U.S. Gov't, Non-P.H.S.

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title = "Polycation Architecture Affects Complexation and Delivery of Short Antisense Oligonucleotides: Micelleplexes Outperform Polyplexes",

abstract = "Herein, we examine the complexation and biological delivery of a short single-stranded antisense oligonucleotide (ASO) payload with four polymer derivatives that form two architectural variants (polyplexes and micelleplexes): a homopolymer poly(2-dimethylaminoethyl methacrylate) (D), a diblock polymer poly(ethylene glycol)methylether methacrylate-block-poly(2-dimethylaminoethyl methacrylate) (ObD), and two micelle-forming variants, poly(2-dimethylaminoethyl methacrylate)-block-poly(n-butyl methacrylate) (DB) and poly(ethylene glycol)methylether methacrylate-block-poly(2-dimethylaminoethyl methacrylate)-block-poly(n-butyl methacrylate) (ObDB). Both polyplexes and micelleplexes complexed ASOs, and the incorporation of an Obbrush enhances colloidal stability. Micellplexes are templated by the size and shape of the unloaded micelle and that micelle-ASO complexation is not sensitive to formulation/mixing order, allowing ease, versatility, and reproducibility in packaging short oligonucleotides. The DB micelleplexes promoted the largest gene silencing, internalization, and tolerable toxicity while the ObDB micelleplexes displayed enhanced colloidal stability and highly efficient payload trafficking despite having lower cellular uptake. Overall, this work demonstrates that cationic micelles are superior delivery vehicles for ASOs denoting the importance of vehicle architecture in biological performance.",

author = "Grimme, {Christian J.} and Hanson, {McKenna G.} and Corcoran, {Louis G.} and Reineke, {Theresa M.}",

note = "Funding Information: The project was funded by Genentech. M.G.H. also acknowledges support from the National Science Foundation Graduate Research Fellowship Program (DGE-1839286). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. Funding Information: We thank Genentech for funding of this work and Dr. Karthik Nagapudi and Dr. Apoorva Sarode for their helpful discussion and insight. The authors would like to express their gratitude toward Cristiam F. Santa Chalarca for performing the dn/dc measurements for the poly( n-butyl methacrylate) block and Wei Zhang for her insightful discussions about TEM. Additionally, parts of this work were carried out in the Characterization Facility, 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. Some of this work{\textquoteright}s figures were adapted or created with BioRender. Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",

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Polycation Architecture Affects Complexation and Delivery of Short Antisense Oligonucleotides: Micelleplexes Outperform Polyplexes

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