Probing nanoparticle interactions with biological system for drug delivery applications

Before any drug administered to the gastro-intestinal tract reaches the epithelium, it must traverse a layer of mucus. The main polymeric component of mucus is the glycoproteins collectively called mucins. These are complex gel-forming polymers which exhibit electrostatic, hydrophobic and H-bonding interactions and are responsible for the viscous and elastic gel-like properties of the mucus layer. The efficacy of nanoparticles (NPs) to penetrate this layer, and deliver macromolecular drugs in therapeutic concentrations to the epithelium will depend on the surface chemistry (decoration) of the NPs. Quantifying the interactions between these NPs and the mucin gel is essential for designing successful drug delivery systems. In this project various decorations were fabricated, including zeta potential changing, slippery, and proteolytic enzymes. Figure 1 illustrates slippery and proteolytic enzyme decorated NPs penetrating a mucus layer that would stop conventional NPs. Please click Additional Files below to see the full abstract

Controlling competitive and synergistic interactions in formulations

Amphiphilic block copolymers of the poly (ethylene oxide)–poly (propylene oxide) (PEO–PPO) group (commercially available as Pluronic or Poloxamers) are widely used in numerous applications, especially the pharmaceutical, consumer, technological and formulation areas. Whilst mixtures of small molecule surfactants and Pluronics have previously been examined, as has the effect of alcohols on Pluronic behavior, there are far fewer studies of the quaternary systems; Pluronic/small molecule surfactants/alcohol/water. Against this background, we have employed a range of techniques including surface tension, pulsed gradient spin-echo nuclear magnetic resonance (PGSE-NMR) and small- angle neutron scattering (SANS) to quantify the interaction between these small molecule surfactants (sodium dodecyl sulphate, dodecyltrimethylammonium bromide and polyoxyethylene (23) lauryl ether) and short, medium and long chain alcohols (ethanol, hexanol and decanol respectively) on the critical micelle concentration (CMC) and subsequently the micellar structure. SANS data for aqueous Pluronic solutions with added alcohols fitted to a charged spherical core/shell model for the micelle. The addition of the surfactants led to significantly smaller, oblate elliptical mixed micelles in the absence of alcohols. Addition of ethanol to the system led to a decrease in the micelle size, whereas larger micelles were observed upon addition of longer chain alcohols. NMR studies provided a complementary estimate of the micelle composition using average diffusion coefficients. These observations extend our understanding of the synergistic interactions between the Pluronic and small molecule surfactants when the partitioning of the added alcohol perturbs the interaction between the two types of surfactants. Please click Additional Files below to see the full abstract

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

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

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