Article pubs.acs.org/Macromolecules
Conformation of Hydrophobically Modified Thermoresponsive Poly(OEGMA-co-TFEA) across the LCST Revealed by NMR and Molecular Dynamics Studies Cheng Zhang,†,∥ Hui Peng,†,∥ Simon Puttick,†,∥ James Reid,† Stefano Bernardi,† Debra J. Searles,†,‡ and Andrew K. Whittaker*,†,§,∥ †
Australian Institute for Bioengineering and Nanotechnology, ‡School of Chemistry and Molecular Biosciences, and §Centre for Advanced Imaging, The University of Queensland, Brisbane, Qld 4072, Australia ∥ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, Brisbane, Qld 4072, Australia S Supporting Information *
ABSTRACT: High-resolution NMR measurements and molecular dynamics (MD) simulations have been applied to the study of thermoresponsive copolymers of poly(ethylene glycol) methyl ether methacrylate (OEGMA) and 2,2,2trifluoroethyl acrylate (TFEA) (poly(OEGMA-co-TFEA)) synthesized via reversible addition−fragmentation chain transfer (RAFT) polymerization. The detailed chemical microstructure of poly(OEGMA-co-TFEA) was investigated by means of various high-resolution NMR techniques. The polymer in aqueous solution possesses a lower critical solution temperature (LCST) at which significant changes in conformation are apparent. 1H 2D NOESY spectra were collected at temperatures below and above the LCST and demonstrated closer association of the exterior segments of the OEGMA side chains with the TFEA units above the LCST. MD simulations provided additional information on the changes in conformation and were consistent with the experimental findings. The combination of MD simulations with a detailed experimental study of poly(OEGMA-co-TFEA) in water leads to a clearer understanding of conformation occurring at the phase transition.
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°C, depending on the balance of hydrophilic and hydrophobic moieties within the polymer structure. Most simply this can be controlled by adjusting the length of OEG side chain.3,26 Copolymerization of OEGMA with other monomers can also be used to vary the LCST and at the same time to endow the polymers with additional properties of interest.6,27−31 Of relevance to this study, hydrophobic monomers have been used to adjust the thermal properties of a number of thermoresponsive polymers.32−34 For example, An et al. showed that the LCST of microgels of NIPAAm and hexafluorobutyl methacrylate (HFMA) decreased on incorporation of the fluorinated monomer.33 Recently, we reported the synthesis of a series of thermoresponsive copolymers, poly(poly(ethylene glycol) methyl ether methacrylate-co-2,2,2trifluoroethyl acrylate) (poly(OEGMA-co-TFEA)), and found that the temperature of the LCST decreased linearly with the weight fraction of the hydrophobic TFEA segments. In that series of polymers the addition of TFEA segments provides the possibility of the copolymer to be used as stimuli-responsive 19F MRI contrast agents.34
INTRODUCTION Polymers that undergo a change in properties in response to an external stimulus, for example temperature,1−5 pH,6,7 or ionic strength,8,9 have received much attention recently, particularly in the biomedical fields. The most thoroughly investigated of these so-called “smart” materials are the thermoresponsive polymers with a lower critical solution temperature (LCST) in aqueous solution. At temperatures below the LCST, the polymers are fully soluble in water, and when the temperature is raised above the LCST, they become partially or completely phase separated.10,11 As a consequence of their interesting properties, such thermoresponsive polymers have found many applications, such as in drug and gene delivery,6,12,13 within sensing devices,14 and in tissue engineering.15 Over the past several years, the thermoresponsive properties of polymers of oligo(ethylene glycol) methacrylates (POEGMAs) have attracted the interest of a number of researchers.3,11,16−25 This class of materials is becoming more widely employed as biomaterials since they have well-established properties of biocompatibility and nontoxicity. Furthermore, the versatility of the chemistry available to control thermal properties is making them an attractive alternative to the extensively studied thermoresponsive polymer poly(N-isopropylacrylamide) (PNIPAAm).16,19 The POEGMAs are reported to exhibit LCST behavior across a temperature range of 26−90 © XXXX American Chemical Society
Received: March 27, 2015 Revised: April 26, 2015
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DOI: 10.1021/acs.macromol.5b00641 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
the experimental findings reported previously49,51−54 and amply demonstrate that the combination of experimental and theoretical work is crucial for understanding the phase transition properties of thermoresponsive polymers. In this study, we have prepared statistical copolymers of OEGMA and TFEA (poly(OEGMA-co-TFEA)) through reversible addition−fragmentation chain-transfer (RAFT) copolymerization and examined their thermoresponsive behavior in detail. The structure and sequence distribution of OEGMA and TFEA segments in the copolymer were studied by solution-state NMR techniques. By conducting 1H 2D NOESY experiments as a function of temperature, we investigated the changes in conformation experienced by poly(OEGMA-co-TFEA) when the temperature is increased through the LCST. To assist the interpretation of the experimental results, molecular dynamics (MD) simulations were performed using both single and multiple polymer chains at two different temperatures (below and above the LCST). The solution behavior of poly(OEGMA-co-TFEA) at different temperatures below and above its LCST is discussed. The results of this work provide detailed information on the changes in conformation in hydrophobically modified thermoresponsive polymers and furthermore are expected to provide direction in the design of thermoresponsive 19F MRI contrast agents.
Although a large number of thermoresponsive polymers with different potential applications have been described, to date these studies have mainly focused on the design of new polymers and the measurements of phase transition properties. In the majority of these publications the volume phase transition has been examined through changes in optical density (turbidimetry) or molecular size, most usually by dynamic light scattering (DLS) measurements.35−37 As such, the observed behavior is that of the whole molecule or is due to molecular association. A more complete understanding of the processes responsible for the phase transition requires a detailed study on the structure and dynamics of thermoresponsive polymers at a molecular level. High-resolution NMR is a key method for the analysis of polymer structure and the dynamics of chain segments and has emerged as a powerful tool for the study of the phase transitions of thermoresponsive polymers. Changes in NMR spectra (primarily peak intensity, line width, and chemical shift), NMR relaxation times, and diffusion coefficients as a function of temperature can be used to systematically investigate the changes in conformation experienced by thermoresponsive polymers.38−40 In particular, two-dimensional nuclear Overhauser effect spectroscopy (2D NOESY) can provide detailed information on the interactions between segments of the polymers over short distances in space (typically
