Cationic Bottlebrush Copolymers from Partially Hydrolyzed Poly(oxazoline)s

Abstract

Cationically charged bottlebrush copolymers were produced by hydrolysis of poly­(2-ethyl-2-oxazoline) (PEtOx). The cationic ring-opening polymerization of EtOx was initiated using a styrene derivative to produce PEtOx macromonomers with two different lengths. After detailed characterization, these macromonomers were polymerized via reversible addition-fragmentation chain transfer (RAFT) polymerization in a grafting-through process. The length of the bottlebrush backbone was varied, and it was found that a good control over the polymerization could be retained up to backbone DP 50. Hydrolysis of PEtOx repeating units under acidic conditions afforded cationic bottlebrushes, with a defined charge content that could be adjusted by changing the hydrolysis reaction time. Bottlebrush copolymers were analyzed in detail using size-exclusion chromatography, small-angle neutron scattering, and atomic force microscopy indicating a cylindrical topology and an increasing flexibility with increasing chain length.

Bottlebrush copolymers for gene delivery: influence of architecture, charge density, and backbone length on transfection efficiency

“…The synthesis and characterization of cationic bottlebrush polymers has recently been reported by our group. 39 Briefly, a poly(2-ethyl-2-oxazoline) (PEtOx) macromonomer was synthesized via the cationic ring-opening polymerization of 2-ethyl-2-oxazoline (EtOx), initiated by 4-vinylbenzyl chloride. This installs a styrenic end-group on the α-terminus of the polymer, capable of undergoing subsequent polymerization to synthesize bottlebrush copolymers.…”

“…Full synthetic details and characterization reported in literature. 39 polymers with the same charge density and different molecular weight were compared (Fig. 1B).…”

“…In a previous study we established a protocol for the efficient production of P(Ox- co -EI) bottle brushes by a combination of cationic ring-opening polymerization (CROP), reversible addition–fragmentation chain-transfer (RAFT) polymerization, and acidic hydrolysis. 39 Within the present study, these cationic bottle brush copolymers are probed regarding their potential as transfection agents. Their ability to condense pDNA into polyplexes and then transfect mammalian cells in vitro is extensively studied, with the aim of drawing conclusions on the effect of introducing a bottlebrush architecture.…”

Polymer-based non-viral vectors for gene therapy in the skin

“…87 Branched PEI is not the only PEI derivative studied as a gene delivery platform, with studies of hybrid chains of PEI with non-hydrolyzed polyoxazoline units also providing encouraging results. 88,89 The polyoxazoline groups in the polymer chain add biocompatibility to the system; furthermore, they can provide thermoresponsive behavior, as some polyoxazoline family members can undergo a reversible soluble-to-insoluble state transition in response to small changes in temperature and exhibit a lower critical solution temperature in water. 90 Despite these challenges, combined with high toxicity, nonspecific interactions, and non-biodegradability, the clinical evaluation of PEI remains in progress.…”

Enabling Reversible Addition-Fragmentation Chain-Transfer Polymerization for Brush Copolymers with a Poly(2-oxazoline) Backbone

“…33 Similarly, Floyd et al synthesized cationic bottlebrush copolymers by grafting through vinyl groups present in poly(2-ethyl-2-oxazoline)-based macromonomers via RAFT. 34 It must be noted that while there are literature reports of CROP brush copolymers, there are only a few studies where the oxazoline is on the backbone, not on the brush, and no previous studies on poly(2-oxazoline) backbonebased graft copolymers with RAFT on the side chain to date.…”