Ring-opening polymerisation of alkyl-substituted ε-caprolactones:kinetic effects of substitution position†

Ring-opening polymerisation (ROP) of lactones has been proven as a powerful technique to generate polyesters with high levels of control over molar mass and polymer dispersity. However, the introduction of functional groups on the monomer ring structure can dramatically influence the ability of a monomer to undergo ROP. Therefore, understanding the structure–reactivity relationship of functional monomers is essential to gain access to materials with chemical functionality via direct polymerisation. Herein, we report how structural modifications of alkyl-substituted ε-caprolactones affected their reactivity towards the ring-opening of the functional monomer. We observed that the reactivity was strongly influenced by the substituent position, wherein the δ-substituted monomer exhibited the fastest polymerisation kinetics. In contrast, a substituent placement in the ε-position significantly reduced polymerisation time compared to other substituent positions. Moreover, the thermal properties of the resultant functional ε-polycaprolactones were investigated and showed no significant change in the thermal transitions. This demonstrates that functional caprolactone monomers with sterically demanding functional groups can still undergo direct ring-opening polymerisation and that careful positioning of these functional groups enables control of the rate of polymerisation, a crucial parameter to be considered for the design of new prospective functional monomers and their industrial applications

Nanoparticle diffusion within intestinal mucus: Three-dimensional response analysis dissecting the impact of particle surface charge, size and heterogeneity across polyelectrolyte, pegylated and viral particles

Multiple particle tracking (MPT) methodology was used to dissect the impact of nanoparticle surface charge and size upon particle diffusion through freshly harvested porcine jejunum mucus. The mucus was characterised rheologically and by atomic force microscopy. To vary nanoparticle surface charge we used a series of self-assembly polyelectrolyte particles composed of varying ratios of the negatively charged polyacrylic acid polymer and the positively charged chitosan polymer. This series included a neutral or near-neutral particle to correspond to highly charged but near-neutral viral particles that appear to effectively permeate mucus. In order to negate the confounding issue of self-aggregation of such neutral synthetic particles a sonication step effectively reduced particle size (to less than 340 nm) for a sufficient period to conduct the tracking experiments. Across the polyelectrolyte particles a broad and meaningful relationship was observed between particle diffusion in mucus (×1000 difference between slowest and fastest particle types), particle size (104–373 nm) and particle surface charge (−29 mV to +19.5 mV), where the beneficial characteristic promoting diffusion was a neutral or near-neutral charge. The diffusion of the neutral polyelectrolyte particle (0.02887 cm S−1 × 10−9) compared favourably with that of a highly diffusive PEGylated-PLGA particle (0.03182 cm2 S−1 × 10−9), despite the size of the latter (54 nm diameter) accommodating a reduced steric hindrance with the mucin network. Heterogeneity of particle diffusion within a given particle type revealed the most diffusive 10% sub-population for the neutral polyelectrolyte formulation (5.809 cm2 S−1 × 10−9) to be faster than that of the most diffusive 10% sub-populations obtained either for the PEGylated-PLGA particle (4.061 cm2 S−1 × 10−9) or for a capsid adenovirus particle (1.922 cm2 S−1 × 10−9). While this study has used a simple self-assembly polyelectrolyte system it has substantiated the pursuance of other polymer synthesis approaches (such as living free-radical polymerisation) to deliver stable, size-controlled nanoparticles possessing a uniform high density charge distribution and yielding a net neutral surface potential. Such particles will provide an additional strategy to that of PEGylated systems where the interactions of mucosally delivered nanoparticles with the mucus barrier are to be minimised

In vitro evaluation of the interaction of dextrin-colistin conjugates with bacterial lipopolysaccharide.

Dextrin-colistin conjugates have been developed with the aim of reducing clinical toxicity associated with colistin and improving targeting to sites of bacterial infection. This study investigated the in vitro ability of these dextrin-colistin conjugates to bind and modulate bacterial lipopolysaccharide (LPS), and how this binding affects its biological activity. These results showed that colistin, and ‘amylase-activated’ dextrin-colistin conjugate to a lesser extent, bound to LPS and induced significant conformational changes to its structure. In biological studies, both colistin and dextrin-colistin conjugate effectively inhibited LPS-induced hemolysis and TNFα secretion in a concentration-dependent manner, but only dextrin-colistin conjugate did not cause additive toxicity at higher concentrations. This study provides the first direct structural experimental evidence for the binding of dextrin-colistin conjugates and LPS, providing insight into the mode of action of dextrin-colistin conjugates

Brush copolymers from 2-oxazoline and acrylic monomers via an inimer approach

Brush-shaped macromolecular architectures provide unique material properties because of their dense branched structures. However, there are major challenges in obtaining brush-shaped macromolecules when the required functional monomers are not compatible for copolymerization using the same synthetic technique. Herein, we present an inimer molecule structure that has both an initiating group for Cu-mediated radical polymerization and a 2-oxazoline monomer ring for cationic ring-opening polymerization. Thus, various combinations of poly(2-oxazoline-brush-acrylate/acrylamide) copolymers could be obtained by grafting from a poly(2-oxazoline) backbone bearing radical initiator units. A simple two-step synthesis method for a novel 2-oxazoline inimer was established and used in the homo and block copolymerization with 2-ethyl-2-oxazoline to yield the brush initiator structure. Moreover, selected acrylates and acrylamides were utilized for Cu(0)-mediated reversible deactivation radical polymerization (RDRP) initiated through the brush initiator. Finally, because of the understanding obtained via optimization reactions, high/low density, block, and amphiphilic brush copolymers with narrow molecular weight distributions were successfully obtained

Segregation versus interdigitation in highly dynamic polymer/surfactant layers

Many polymer/surfactant formulations involve a trapped kinetic state that provides some beneficial character to the formulation. However, the vast majority of studies on formulations focus on equilibrium states. Here, nanoscale structures present at dynamic interfaces in the form of air-in-water foams are explored, stabilised by mixtures of commonly used non-ionic, surface active block copolymers (Pluronic®) and small molecule ionic surfactants (sodium dodecylsulfate, SDS, and dodecyltrimethylammonium bromide, C12TAB). Transient foams formed from binary mixtures of these surfactants shows considerable changes in stability which correlate with the strength of the solution interaction which delineate the interfacial structures. Weak solution interactions reflective of distinct coexisting micellar structures in solution lead to segregated layers at the foam interface, whereas strong solution interactions lead to mixed structures both in bulk solution, forming interdigitated layers at the interface

The effect of self-sorting and co-assembly on the mechanical properties of low molecular weight hydrogels

Self-sorting in low molecular weight hydrogels can be achieved using a pH triggered approach. We show here that this method can be used to prepare gels with different types of mechanical properties. Cooperative, disruptive or orthogonal assembled systems can be produced. Gels with interesting behaviour can be also prepared, for example self-sorted gels where delayed switch-on of gelation occurs. By careful choice of gelator, co-assembled structures can also be generated, which leads to synergistic strengthening of the mechanical properties

Assembly of small molecule surfactants at highly dynamic air-water interfaces

Small-angle neutron scattering has been used to probe the interfacial structure of foams stabilised by small molecule surfactants at concentrations well below their critical micelle concentration. The data for wet foams showed a pronounced Q−4 dependence at low Q and noticeable inflexions over the mid Q range. These features were found to be dependent on the surfactant structure (mainly the alkyl chain length) with various inflexions across the measured Q range as a function of the chain length but independent of factors such as concentration and foam age/height. By contrast, foam stability (for C < CMC) was significantly different at this experimental range. Drained foams showed different yet equally characteristic features, including additional peaks attributed to the formation of classical micellar structures. Together, these features suggest the dynamic air–water interface is not as simple as often depicted, indeed the data have been successfully described by a model consisting paracrystalline stacks (multilayer) of adsorbed surfactant layers; a structure that we believe is induced by the dynamic nature of the air–water interface in a foam

The effect of thiamine-coating nanoparticles on their biodistribution and fate following oral administration

Thiamine-coated nanoparticles were prepared by two different preparative methods and evaluated to compare their mucus-penetrating properties and fate in vivo. The first method of preparation consisted of surface modification of freshly poly(anhydride) nanoparticles (NP) by simple incubation with thiamine (T-NPA). The second procedure focused on the preparation and characterization of a new polymeric conjugate between the poly(anhydride) backbone and thiamine prior the nanoparticle formation (T-NPB). The resulting nanoparticles displayed comparable sizes (about 200 nm) and slightly negative surface charges. For T-NPA, the amount of thiamine associated to the surface of the nanoparticles was 15 µg/mg. For in vivo studies, nanoparticles were labeled with either 99mTc or Lumogen® Red. T-NPA and T-NPB moved faster from the stomach to the small intestine than naked nanoparticles. Two hours post-administration, for T-NPA and T-NPB, more than 30% of the given dose was found in close contact with the intestinal mucosa, compared with a 13.5% for NP. Interestingly, both types of thiamine-coated nanoparticles showed a greater ability to cross the mucus layer and interact with the surface of the intestinal epithelium than NP, which remained adhered in the mucus layer. Four hours post-administration, around 35% of T-NPA and T-NPB were localized in the ileum of animals. Overall, both preparative processes yielded thiamine decorated carriers with similar physico-chemical and biodistribution properties, increasing the versatility of these nanocarriers as oral delivery systems for a number of biologically active compounds