Regular ArticlePhase behaviour, micellar structure and linear rheology of tetrablock copolymer Tetronic 908
Graphical abstract
Introduction
Polyethylene oxide (PEO)/polypropylene oxide (PPO) block copolymers have been extensively studied over the last decades [1], [2]. The presence of PEO and PPO moieties, of a hydrophilic and hydrophobic nature, respectively, enables their self-assembly in aqueous solutions, where they form mostly spherical micelles, and more elongated structures close to phase boundaries [3], [4], [5]. Temperature, concentration, molecular weight of the blocks and their configuration can be tuned to provide a wide span of properties. The synthesis, chemical analysis, aggregation and structure, foaming and surface properties, toxicology and biological activity, as well as applications of this family of block copolymers have been described in a number of classic and recent reviews [1], [6], [7]. In addition to their use as solubilizing agents, these amphiphilic block copolymers have also been shown to overcome multidrug resistance, a major obstacle for effective cancer therapy, by inhibiting ATP-binding cassette transporters [2], [8].
The first PEO/PPO surfactants studied and most widely used are the linear PEO-PPO-PEO triblock copolymers, known as poloxamers or Pluronic® (BASF). The full characterization of these copolymers [9] and important applications have been reported, including detergency, foaming, emulsification, lubrication, cosmetics [10], [11], and their use as vehicles for drug delivery [2], [8], [12], [13], [14] more complex architectures, such as non-linear block copolymers and multiblock copolymers, have also been investigated, expanding the number of accessible morphologies [15], [16]. These non-linear polymer backbones can be obtained by linking PEO and PPO blocks to a central functional group, forming for instance the category of X-shaped tetrablock copolymers referred to as poloxamines or Tetronic® (BASF). Each of the four arms comprises a PPO and a PEO block, which are connected by a central ethylene diamine spacer. Different Tetronics are obtained by varying the number of PO and EO monomers, offering a wide range of hydrophilic-lipophilic balances (HLB) and molecular weights, and hence a rich phase behaviour [17], dependent on both temperature and pH, due to the protonation of the central diamine group [18], [19], which can also be exploited for further chemical modification to attain other properties [20]. The micellization and gelation at high concentration and temperature of some Tetronics have been reported by us [19], [21], [22], [23] mainly from a structural point of view, and by other groups [24]. However, the full characterization of this attractive class of polymers is only starting to emerge, while their applications as biomaterials are expanding [25], [26].
In this work, we report for the first time the nanostructure of Tetronic 908 micelles, and its gels in the concentrated regime. Tetronic 908 is a very large and hydrophilic poloxamine (21 PO and 114 EO units per arm, HLB > 24), which shows the ability to form gels, with values of the elastic modulus similar to those of other Tetronics reported to date. Its long PEO chains make it particularly attractive to impart stealth properties to nanoparticles, namely, to prolong their circulation time by suppressing opsonization, while achieving optimum stabilization [27], [28]. It has also been used as a biomaterial, for instance in scaffolds to promote the differentiation of mesenchymal stem cells into osteoblasts [25], as well as in implant for the sustained delivery of ciprofloxacin to treat osteomyelitis [26]. In addition, its structure is reminiscent of its Pluronic counterpart, F127 (triblock with a central 60 PO units, flanked by 100 EO on each side), extensively studied as a drug carrier and for its role against multidrug resistance [2]. With approximately the same block length and double the molecular weight, T908 is broadly equivalent to two F127 which would be connected in the middle; it is therefore interesting to compare and contrast the micellar structures and gelation behaviour of these two related amphiphilic copolymers. While previous SANS studies on this Tetronic have been reported in the literature, they were specifically focused on the structure of the gel phase under flow [29], [30], [31], [32]. This is the first structural study covering the micelles from the dilute to the concentrated regime including the gel phase, through the combined use of dynamic light scattering (DLS), small-angle neutron scattering (SANS), steady-state and time-resolved fluorescence, Fourier transform infrared attenuated total reflectance (FTIR-ATR) and oscillatory rheology. We explore specifically the impact of pH and temperature on micellar structure and phase behaviour, with the aim to develop formulations responsive to these two environmental parameters. We also examine the effect of switching H2O for D2O, which is necessary to obtain contrast in SANS, an effect which is often overlooked in the literature.
Section snippets
Materials
Tetronic 908 (hereafter, T908) was a gift from BASF, and used without further purification, with a reported composition of 21 PO and 114 EO units per arm, HLB > 24 and average molecular weight of 25,000 g mol−1. The reported pKas for this poloxamine are 5.2 and 7.9 for pKa1 and pKa2, respectively [18]. With the concentrations used in this work, the solutions are slightly alkaline, with typical pH values ranging from 8.0 to 10.0. The solutions were prepared either in deionized water or in D2O
Phase behaviour of T908 and self-aggregation at the dilute regime
The phase behaviour of T908 in water at natural pH (non-buffered) is shown in Fig. 1 the threshold concentration for gel formation in water is 20%, when heated up to 55 °C. At higher concentrations, the onset of gelation occurs at lower temperatures and the gel phase extends over a wider span of temperatures, and at 40% the samples are gels at room temperature. At pH < 2, below pKa1, gelation is fully suppressed at concentrations as high as 40%, and up to 70 °C. This effect results from the
Conclusions
This work reports the micellization and gelation process of the large, highly hydrophilic tetrablock copolymer Tetronic 908 (T908), as a function of temperature, concentration and pH. At low concentration of the amphiphile, a minimum temperature is required for its aggregation in the form of micelles, which display a core-shell architecture with a dehydrated core and a highly hydrated corona (94% D2O), with relatively small aggregation numbers at low surfactant concentration (Nagg ≈ 13), lower
Acknowledgments
The authors are grateful to JCNS at the Heinz Maier-Leibnitz Zentrum (MLZ), Garching, Germany, for financial support and beam-time and to G. Mangiapia for his assistance with the SANS experiments and data reduction. Financial support from project MAT2014-59116-C2-2-R of the Spanish MINECO and the Asociación de Amigos de la Universidad de Navarra for the doctoral grant of J.P.-R. and P.M.-P. is acknowledged.
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