Fine-tuning of the polymer structure-property relationship is a desirable feature when it comes to the design of macromolecules, especially for biomedical applications. Homo- and copolymers of 2-substituted-2-oxazolines, called sometimes pseudopeptides, are known as biomimicking polymers of good biocompatibility. These are obtained via cationic ring opening polymerization of a five-membered cyclic imino ethers, with alkyl substituent R in the position 2 of oxazoline ring.
The nature of alkyl substituent R determines the behavior of 2-oxazoline homo- and copolymers, both in solution (for instance, solubility and thermoresponsive behavior) and in the condensed state. 2-oxazoline homopolymers containing in the side chain less than 4 carbon atoms are soluble in water. Poly(2-ethyl-2-oxazoline), poly(2-isopropyl-2-oxazoline), poly(2-cyclopropyl-2-oxazoline) and poly(2-n-propyl-2-oxazoline) have limited solubility dependent on temperature. These homopolymers, above a certain temperature called the cloud point temperature (TCP) undergo a coil-to-globule transition and precipitate from the solution. In case of 2-oxazoline copolymers, their phase transition in solution is dependent on the type, content and distribution of comonomers in the polymer chain (random or gradient composition). The gradient 2-oxazoline copolymers due to their specific comonomer distribution within the chain may organize in the solution to form micelles or structures similar to micelles.
The phase transition of thermoresponsive poly(2-substituted-2-oxazoline)s is reversible when the temperature is changed to the initial state (unless crystallization occurs). It is described, that 2-oxazoline homo- and copolymers show only a minor or no transition hysteresis for sufficiently high polymer concentration and/or heating rate.
In this work, we discuss the behavior of gradient and random copolymers of 2-oxazolines that undergo a coil-to-globule transition in aqueous solution. The influence of the copolymer structure and composition on the phase transition, the hysteresis of phase transition and aggregation is discussed.
Three groups of 2-substituted-2-oxazoline copolymers built of monomers with different affinity to water were obtained via cationic ring opening polymerization. As a 1st comonomer in case of all obtained copolymers, 2-n-propyl-2-oxazoline was used (nPrOx). As a 2nd comonomer 2-methyl-2-oxazoline (MOx), 2-ethyl-2-oxazoline (EOx) or 2-isopropyl-2-oxazoline (iPrOx) were used. By using different monomers as 2nd reactant we expected the copolymers of different microstructure and affinity to water. Copolymerization of nPrOx with EOx led to random copolymers while for nPrOx with MOx or iPrOx gradient copolymers were obtained, due to greater difference of monomers reactivity. The reactivity ratios for the studied systems were calculated while Monte Carlo simulations yielded visual data about the copolymer structure and distribution of units along the chain.
All obtained copolymers showed the phase transition in water. For random copolymers no hysteresis of the phase transition was observed. Gradient copolymers at concentration 5mg mL-1 showed the hysteresis of the phase transition. This was most evident for the gradient copolymers with MOx units. The solutions of gradient copolymers at lower concentration 0.5 mg mL-1 did not exhibit hysteresis.
The polymer under heating and cooling behaved different as compared to systems described in the literature. Usually, the phase transition during heating occurs at a higher temperature than the transition when cooling the system. In our systems we observed a reversed behavior: transition when cooling occurred at a higher temperature. This is unusual as in most cases diffusion of water into dehydrated globules formed above the phase transition is considered to delay the hydration and dissolution of the polymer during cooling of the system.
Although in the literature the hysteresis of phase transition is often explained by the correlation of Tg with TCP, in case of gradient copolymers of nPrOx this correlation seems to be unjustified as both TCP and Tg are depended on the copolymer composition.
To further investigate the origin of hysteresis of phase transition for gradient copolymers, we studied their organization in water. Based on spectrometric studies using a fluorescent probe, it was observed that the obtained gradient copolymers could associate in water to form complex structure: a systems consisting of hydrophilic and hydrophobic domains (not necessary single or well defined micelles). For selected copolymers the critical aggregation concentration (cac) was estimated and it was dependent on the composition (at 25°C). To confirm the formation of structures in the solution above cac, aqueous solutions of copolymers of different concentrations were visualized by atomic force microscopy. Also, to investigate the organization of structures in water, dynamic light scattering measurements were carried out in wide temperature range.
Based on these studies we confirmed that the process of thermally induced aggregation of gradient copolymers is complex and influenced by concentration of polymer chains. The presence of hysteresis of the phase transition observed for gradient copolymers for certain concentrations may result from the organization of the polymer chains into specific structures. In general, above cac aggregates consisting of structures with more or less hydrophobic interior (fluorescent probe results), kept in solution by the hydrophilic shell, are formed. The sizes of particles are equal to several nanometers. Single assemblies are present in the solution till temperature of 50% of transmittance is reached. Then a small amount of a larger, rather loose particles, most probably consisting of an agglomerates of micelle-like structures are formed. During cooling an agglomerates are not stable and their disintegration to single assemblies occurs at higher temperatures that their formation during heating. Conversely, below cac mostly unimers and very small amount of aggregates with a size of several dozen nanometers are present in the solution even when temperature of 50% of transmittance is reached. During cooling dissociation of structures to unimers proceeds without hysteresis.
Organization of thermoresponsive 2-oxazoline gradient copolymers in water however still requires more detailed studies and is the subject of further investigations.
Natalia Oleszko-Torbus, Alicja Utrata-Wesołek, Wojciech Wałach, and Andrzej Dworak. Solution behavior of thermoresponsive random and gradient copolymers of 2-n-propyl-2-oxazoline. European Polymer Journal, volume 88 (2017), pages 613–622.
Centre of Polymer and Carbon Materials, Polish Academy of Sciences, ul. M. Curie-Skłodowskiej 34, 41-819 Zabrze, Poland.Go To European Polymer Journal