Polyelectrolyte Complexation of Oligonucleotides by Charged Hydrophobic-Neutral Hydrophilic Block Copolymers.

Alexander E Marras,Matthew V Tirrell,Jeffrey M Ting,Jack D Rubien,Jeffrey R Vieregg

doi:10.3390/polym11010083

Alexander E Marras, Matthew V Tirrell + Show 3 more

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https://doi.org/10.3390/polym11010083

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Abstract

Polyelectrolyte complex micelles (PCMs, core-shell nanoparticles formed by complexation of a polyelectrolyte with a polyelectrolyte-hydrophilic neutral block copolymer) offer a solution to the critical problem of delivering therapeutic nucleic acids, Despite this, few systematic studies have been conducted on how parameters such as polycation charge density, hydrophobicity, and choice of charged group influence PCM properties, despite evidence that these strongly influence the complexation behavior of polyelectrolyte homopolymers. In this article, we report a comparison of oligonucleotide PCMs and polyelectrolyte complexes formed by poly(lysine) and poly((vinylbenzyl) trimethylammonium) (PVBTMA), a styrenic polycation with comparatively higher charge density, increased hydrophobicity, and a permanent positive charge. All of these differences have been individually suggested to provide increased complex stability, but we find that PVBTMA in fact complexes oligonucleotides more weakly than does poly(lysine), as measured by stability versus added salt. Using small angle X-ray scattering and electron microscopy, we find that PCMs formed from both cationic blocks exhibit very similar structure-property relationships, with PCM radius determined by the cationic block size and shape controlled by the hybridization state of the oligonucleotides. These observations narrow the design space for optimizing therapeutic PCMs and provide new insights into the rich polymer physics of polyelectrolyte self-assembly.

Highlights

Developing effective non-viral methods for delivery of nucleic acids and other macromolecular therapeutics is one of the most pressing challenges for nanomedicine and polymer science [1,2,3,4].The potential power of engineered nucleic acids as therapeutic agents is severely limited by the difficulty of overcoming the physical and biological barriers to using them as practical drugs
PCMs using poly((vinylbenzyl) trimethylammonium) (PVBTMA)-PEG block copolymers and single-stranded DNA oligonucleotides and compared them to PCMs assembled from PLys-PEG block copolymers of similar lengths using
The block copolymer with the shortest PVBTMA polycation (PVBTMA(8)-PEG(5k) did not phase separate when mixed with DNA, and block copolymers with the shortest PEG

Summary

Introduction

Developing effective non-viral methods for delivery of nucleic acids and other macromolecular therapeutics is one of the most pressing challenges for nanomedicine and polymer science [1,2,3,4].The potential power of engineered nucleic acids as therapeutic agents is severely limited by the difficulty of overcoming the physical and biological barriers to using them as practical drugs. Developing effective non-viral methods for delivery of nucleic acids and other macromolecular therapeutics is one of the most pressing challenges for nanomedicine and polymer science [1,2,3,4]. Therapeutic applications to date have required extensive chemical modification and/or encapsulation of the nucleic acids, most commonly by liposomes and other lipid nanoparticles assembled by hydrophobic interactions [5,6,7,8]. These approaches have demonstrated the effectiveness of nucleic acid therapeutics but come with significant drawbacks, including toxicity, Polymers 2019, 11, 83; doi:10.3390/polym11010083 www.mdpi.com/journal/polymers

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