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This review outlines the importance of improving the treatment of preterm birth, summarises the use of nanomedicines for the delivery of active pharmaceutical ingredients and discusses the opportunities/challenges for enhancing future patient outcomes.

Core–shell nanogels with a poly(N-isopropylmethacrylamide) core and poly(N-isopropylacrylamide) shell display tuneable thermoresponsive behaviour and high degradability.

Transfer-dominated Branching Radical Telomerisation (TBRT) enables the production of branched polymers with step-growth backbones using radical telomerisation chemistry. By conducting identical TBRTs over a broad temperature range, the role of temperature in telomer formation and branching has been evaluated. Elevated temperature limits telomer length, thereby allowing a10% reduction in the amount of telogen required to produce near identical high molecular weight branched polymers.

Amine functionality offers the modification of polymer properties to enable stimuli-responsive behaviour, and this feature has been utilised in numerous studies of self-assembly and disassembly. The ability to place amines as pendant groups along linear polymer backbones within distinct blocks, at chain ends or as statistical mixtures with other functionalities, has allowed fine tuning of responses to pH. Here we study and compare the placement of amines within the backbones or as pendant groups within polyesters synthesised by the newly reported transfer-dominated branching radical telomerisation (TBRT). Branched polymers with backbone amines are clearly shown to undergo dissolution that is determined by pH and telogen selection; they undergo nanoprecipitation only when hydrophilic telogens are present within their structure and provide nanoprecipitates that are highly sensitive to the addition of acid. In contrast, TBRT polymers with pendant amines form uniform nanoparticles with remarkable stability to pH changes, under identical nanoprecipitation conditions. The behaviour differences shown here open new avenues of synthetic flexibility for pH-responsive polymer design using TBRT.

New branched polymerisations offer previously inaccessible macromolecules and architectural understanding is important as it provides insight into the branching mechanism and enables the determination of structure–property relationships. Here we present a detailed inverse gated 13C NMR characterisation of materials derived from the very recently reported Transfer-dominated Branching Radical Telomerisation (TBRT) approach to quantify branching and provide an insight into cyclisation.

A significant number of new chemical entities in the drug development pipeline are poorly soluble, therefore routes that facilitate effective administration is of considerable value. Lipid nanoparticles have proved an attractive approach for drug delivery; however, challenges that include optimising drug loading and understanding the impact of drug physiochemical parameters on nanoparticle properties have limited progression. In this work, we investigate the effect of modifying the LogP of a model drug on the formation and stability of lipid-based nanoparticles. A range of model drug analogues with systematically varying alkyl chains were produced using a lamivudine (nucleoside analog reverse transcriptase inhibitor) scaffold and processed into lipid nanoparticles by nanoprecipitation. Characterisation included evaluation of particle diameter, size distribution, drug loading and nanoformulation stability. A distinct correlation with the LaMer model of nucleation was observed and LogP appeared to stongly influence rates of nucleation. Model drugs with high LogP were uniform in particle size and distribution and offered enhanced stability. In addition, various model drug/lipid blends were produced and their physical properties were investigated using dynamic light scattering (DLS) and differential scanning calorimetry (DSC). Complex mixtures of lipids were shown to influence formulation crystallinity and strategies to form unifrom and stable lipid based nanoparticles of high drug loading- through manipulation of LogP are discussed.

Curcumin is widely used as a nutraceutical ingredient in food and beverage products. It has been reported that curcumin has a broad spectrum of biological activities such as anticancer, anti-inflammatory, antioxidant, and antibacterial effects. Despite the potent therapeutic effect of curcumin, its low aqueous solubility, stability, and oral bioavailability limits its effectiveness. In order to improve the physical and chemical properties of curcumin, we have formulated curcumin as a nanosuspension by using the emulsion templated freeze-drying technique. This approach produces a solid that can be dispersed as required to form a nanosuspension. The formulations were investigated in a screening process using various excipients, resulting in the identification of one curcumin nanosuspension sample which contained only polyethylene glycol (PEG) as the excipient. This formulation exhibited a small diameter (211 nm), low polydispersity (0.06) and zeta potential of −25 mV and was therefore chosen for further in vitro investigations. Various experimental parameters such as active agent and excipient concentrations, and sonication time were varied to tune the size and polydispersity of the chosen formulation. The resulting nanosuspension showed an improved chemical stability at pH values that mimic the gastrointestinal tract. An in vitro bioaccessibility experiment showed that the nanosuspension formulation resulted in more dissolution of the curcumin but this was also coupled with reduced stability. Cytotoxicity studies showed that the nanosuspension offered a reduced cytotoxicity profile compared to the solubilised curcumin on both cell lines investigated. This redispersible curcumin nanosuspension formulation may provide new opportunities for the oral dosing of curcumin.

Solid lipid nanoparticles (SLNs) have proved to be effective nanocarriers with many advantages over other non-lipid-based systems. The development of new SLN formulations is often hindered through poor drug loading capacity and time-consuming optimisation of lipid/stabiliser combinations. One challenge in the development of new SLN formulations is understanding the complex interactions between amphiphilic stabilisers and hydrophobic lipids; the nature of these interactions can significantly impact SLN properties, including the internal polarity within the nanoparticle core. Herein, we report the use of pyrene to probe the internal lipid microenvironment inside SLNs. We investigate the effect of using different poloxamer stabilisers on the internal polarity of SLNs formed using the common solid lipid, Compritol 888 ATO. We show that the polarity of the internal lipid environment is modified by the length of the poly(propylene oxide) (PPO) block of the poloxamer stabiliser, with longer PPO blocks producing SLNs with less polar lipid cores. Blending of stabilisers could also be used to tune the polarity of the core lipid environment, which may allow for adjusting the polarity of the lipid to assist the loading of different therapeutics.

The synthesis of complex polymer architectures using relatively facile experimental protocols provides access to materials with the opportunity to control functionality and physical behaviour. The scope of hyperbranched-polydendron chemistries has been expanded here to include primary chains comprising amine-functional ‘homopolymer’, ‘statistical copolymer’ and amphiphilic ‘block copolymer’ analogues using 2-(diethyl amino)ethyl methacrylate, 2-hydroxy propyl methacrylate and t-butyl methacrylate. The different primary chain chemistry and architectures leads to a marked variation in nanoprecipitation behaviour and the response of the resulting amine-functional nanoparticles to varying pH. When acid-sensitive and acid-stable branchers, 1,4-butanediol di(methacryoyloxy)-ethyl ether and ethylene glycol dimethacrylate respectively, are utilised, nanoparticles with encapsulation properties are formed and may be triggered to either release-and-disassemble or release-disassemble-degrade to form a solution of lower molecular weight constituent primary chains.

Poly(N-isopropylacrylamide) (pNIPAM) nanogels are a highly researched type of colloidal material. In this work, we establish a versatile asymmetric-flow field-flow fractionation (AF4) method that can provide high resolution particle sizing and also structural information on nanogel samples from 65–310 nm in hydrodynamic diameter and so different chemical compositions. To achieve this online multi-angle light scattering and dynamic light scattering detectors were used to provide measurement of the radius of gyration (Rg) and hydrodynamic radius (Rh) respectively. Two different eluents and a range of cross-flows were evaluated in order to provide effective fractionation and high recovery for the different nanogel samples. We found that using 0.1 M NaNO3 as the eluent and an initial cross-flow of 1 mL min−1 provided optimal separation conditions for all samples tested. Using this method, we analysed two types of samples, pNIPAM nanogels prepared by free radical dispersion polymerisation with increasing diameters and analysed poly(acrylic acid)-b-pNIPAM crosslinked nanogels prepared by reversible addition–fragmentation chain transfer dispersion polymerisation. We could determine that the differently sized free radical nanogels possessed differing internal structures; shape factors (Rg/Rh) ranged from 0.58–0.73 and revealed that the smallest nanogel had a homogeneous internal crosslinking density, while the larger nanogels had a more densely crosslinked core compared to the shell. The poly(acrylic acid)-b-pNIPAM crosslinked nanogels displayed clear core–shell structures due to all the crosslinking being contained in the core of the nanogel.

Mucus lines the moist cavities throughout the body, acting as barrier by protecting the underlying cells against the external environment, but it also hinders the permeation of drugs and drug delivery systems. As the rate of diffusion is low, the development of a system which could increase retention time at the mucosal surface would prove beneficial. Here, we have designed a range of branched copolymers to act as functional mucus-responsive oil-in-water emulsifiers comprising the hydrophilic monomer oligo(ethylene glycol) methacrylate and a hydrophobic dodecyl initiator. The study aimed to investigate the importance of chain end functionality on successful emulsion formation, by systematically replacing a fraction of the hydrophobic chain ends with a secondary poly(ethylene glycol) based hydrophilic initiator in a mixed-initiation strategy; a decrease of up to 75 mole percent of hydrophobic chain ends within the branched polymer emulsifiers was shown to maintain comparative emulsion stability. These redundant chain ends allowed for functionality to be incorporated into the polymers via a xanthate based initiator containing a masked thiol group; thiol groups are known to have mucoadhesive character, due to their ability to form disulfide bonds with the cysteine rich areas of mucus. The mucoadhesive nature of emulsions stabilised by thiol-containing branched copolymers was compared to non-functional emulsions in the presence of a biosimilar mucosal substrate and enhanced adherence to the mucosal surface was observed. Importantly, droplet rupture and mucus triggered release of dye-containing oil was seen from previously highly-stable thiol-functional emulsions; this observation was not mirrored by non-functional emulsions where droplet integrity was maintained even in the presence of mucus.

The facile formation of drug nanoparticles in injectable/ingestible oils, of water-soluble antiretroviral tenofovir disoproxil fumarate, using a novel nanoprecipitation is presented with studies showing drug release into relevant aqueous media.

Enhancing the activity of existing antimicrobial agents may help to address the emergence of resistant bacteria. Nanoparticles of antimicrobial agents have previously been shown to provide potential activity enhancements and here we report a high-throughput nanoprecipitation approach to identify viable nanosuspensions of the antimicrobial compound triclosan. Through careful choice of the components of the nanoprecipitation, amorphous nanosuspensions were created, freeze-dried and redispersed in water with z-average diameters varying from 170–290 nm. Particle size was shown to be controlled by a series of factors including polymer/surfactant concentration and concentration of triclosan solution prior to nanoprecipitation. A ten-fold decrease (i.e. higher activity) in the Escherichia coli (E. coli) inhibitory concentration (IC50) of triclosan, compared to an aqueous control, was observed for nanoparticles prepared using Pluronic® F68 and the cationic surfactant Hyamine. This overall approach offers a rapid route for identifying viable nanosuspensions and enhancing the properties of commercially available biologically active compounds with poor water-solubility.

Chemoprophylaxis is currently the best available prevention from malaria, but its efficacy is compromised by non-adherence to medication. Here we develop a long-acting injectable formulation of atovaquone solid drug nanoparticles that confers long-lived prophylaxis against Plasmodium berghei ANKA malaria in C57BL/6 mice. Protection is obtained at plasma concentrations above 200 ng ml-1 and is causal, attributable to drug activity against liver stage parasites. Parasites that appear after subtherapeutic doses remain atovaquone-sensitive. Pharmacokinetic–pharmacodynamic analysis indicates protection can translate to humans at clinically achievable and safe drug concentrations, potentially offering protection for at least 1 month after a single administration. These findings support the use of long-acting injectable formulations as a new approach for malaria prophylaxis in travellers and for malaria control in the field., Long-acting antimalarials could provide improved prophylaxis and treatment options in the field. Here, Bakshi et al. develop a long-acting injectable atovaquone nanomedicine that prevents malaria infection prophylactically for up to 4 weeks in mice with no evidence for generation of resistant parasites.

The new macromolecular architecture, hyperbranched polydendrons, are composed of a broad distribution of molecular weights and architectural variation; however, nanoprecipitation of these materials yields highly uniform, dendron-functional nanoparticles. By isolating different fractions of the diverse samples, the key role of the most highly branched structures in directing nucleation and growth has been explored and determined.

A new convergent synthesis for polyurethane dendrons to generation 4, and dendrimers to generation 3, is presented with control of surface functionality. The systematic synthesis of twenty-six new dendritic materials has led to a study of the factors affecting Tg using widely accepted approaches. The established understanding of dendritic polymerTg behaviour is that the Flory–Fox models, used for linear polymers, are unsuitable as the high number of chain ends and globular nature of dendrimers requires special consideration. In our review of the accepted understanding we have shown that the conventional Flory–Fox models predict Tg∞ accurately and generate identical values to the established modifications of the Flory–Fox equation that consider ‘dendrimer-relevant’ aspects such as the non-zero values of ne/M at infinite molecular weight. We also present a new approach using the geometric parameters of dendrimer mass evolution suggesting that the Flory–Fox equation is indeed appropriate for determination of dendrimerTg∞.

Despite the large volume of academic literature on the synthesis and physico-chemical characterization of block copolymers and their potential for application in a wide variety of products, relatively few of these materials have been commercialized. More often than not the main obstacle to this is the high cost of synthesis versus the extra value added to potential products. Devising more cost-effective routes to block copolymers therefore remains an important challenge to polymer chemists. Using conventional solution free radical polymerization we have now synthesized, each in one-pot, architecturally complex ‘branched diblock copolymers’ and compositionally related ‘grafted branched copolymers’, exploiting a generic branching synthetic methodology developed in our own laboratory. In each case blocks of poly(methacrylic acid) and poly(ethylene glycol) (PEG) are involved. The first group was obtained by copolymerization of methacrylic acid with a PEG dimethacrylate with branching favoured in competition with crosslinking by use of appropriate levels of free radical chain transfer agent. For the second series methacrylic acid has been copolymerized with a PEG monomethacrylate and ethylene glycol dimethacrylate, again with crosslinking inhibited by use of a chain transfer agent. Good yields of products are obtained and typically the polymerization mole feed compositions have been chosen to yield an even mass balance of poly(methacrylic acid) and PEG blocks in the copolymers, though this parameter is readily adjustable. The molecular composition of the products has been characterized by elemental microanalysis and 1H NMR spectroscopy, with the latter also combining with multi-angle light scattering size exclusion chromatographic (MALS/SEC) molar mass data to provide information on the branching architecture. The products are complex mixtures in terms of both architecture and molar mass, but the synthetic strategy is far simpler, more practical and more cost-effective than alternative routes to structurally more uniform analogues via multi-step living polymerization procedures are likely to be. The materials are therefore complementary to, rather than competitive with, these analogues. The present approach lends itself to efficient scale-up, and could make significant quantities of materials readily available for further physico-chemical characterization and applications evaluation.

The combination of linear polymers with dendritic chain-ends has led to numerous studies of linear–dendritic polymer hybrid materials. Interchain branching within the linear segment of these materials has recently extended this concept to the formation of soluble hyperbranched-polydendrons. Here, the introduction of amphiphilicity into hyperbranched-polydendrons has been achieved for the first time through the use of tertiary amine functional dendritic chain-ends and branched hydrophobic polymer segments. The synthesis and aqueous nanoprecipitation of these branched materials is compared with their linear–dendritic polymer analogues, showing that chain-end chemistry/generation, precipitation medium pH and polymer architecture are all capable of influencing the ability to generate nanoparticles, the resulting nanoparticle diameter and dispersity, and subsequent response to changes in pH.

Hyperbranched aliphatic polyesters derived from the AB2 monomer diethyl 3-hydroxyglutarate in the presence of titanium(iv) butoxide are reported. The oligomeric products were characterised by GPC, NMR spectroscopy and MALDI-TOF mass spectrometry. The degree of branching, molecular weights and the possibility of intramolecular cyclisation reactions have been evaluated. MALDI-TOF mass spectrometry was used to quantify the extent of possible side reactions, particularly those resulting from alkoxide exchange with the catalyst.

Oligomers of poly(diethyl 3-hydroxyglutarate), an aliphatic hyperbranched polyester, have been prepared via a titanium(IV) butoxide catalysed step growth condensation process. The characterisation of the products depends on MALDI-TOF mass spectrometry; this study establishes that the incident laser power has a marked effect on the distribution of peak intensities in the spectra observed for these systems. High laser powers can initiate scissions in the polymer structure, whilst at lower incident laser power it is very difficult to define what constitutes a “representative spectrum”.

Multi-purpose amphiphilic branched copolymer surfactants can be used to simultaneously stabilise and cross-link emulsion droplets to produce encapsulated spheres and hollow capsules.

(14)C-radio-initiated atom transfer radical polymerisations allow direct monitoring of the fate of initiating species.

Subtle changes in copolymer surfactant architecture and chain-end functionality can induce diverse behaviours in pH-responsive branched copolymer-stabilized emulsions.

Remarkable changes of properties result from systematically varying the surface functionality of polyamide dendrimers within a single generation.

Well-defined dumbbell and tripartite organic nanoparticles (30−60 nm) were produced via a one-pot direct synthesis of branched amphiphilic block copolymers, avoiding the need for postsynthesis self-assembly steps. We show the mechanism of dumbbell formation is largely a concerted process of particle growth during polymerization, although data suggest that particle−particle linking also occurs, particularly at higher monomer conversions. Dumbbell particles formed using a disulfide bifunctional initiator lead to cleavable structures, underlining the role of initiator functionality in shape control and the potential for functionality placement. Trifunctional initiators allow the direct one-pot synthesis of “tripartite” clover-leaf shaped nanoparticles which would be difficult to achieve through conventional synthesis/self-assembly/cross-linking strategies.

The first nanoprecipitation study of hydrophobic branched vinyl polymers is presented with control across a wide range of particle diameters (approximately 60–800 nm) from control of degree of polymerisation and precipitation parameters. In contrast to linear polymers of identical primary chain length, the formation of stable nanoparticles in aqueous media appears to be architecture driven with a contribution from oligomeric chain-ends with measureable water-solubility. The aqueous nanoparticles dispersions are robust and stable to dilution, solvent addition, sonication and temperature. The addition of small amounts of NaCl led to a destabilisation indicating charge stabilisation is also a major contributor to stability.

Freezing and its combination with emulsion-templating are investigated to systematically tune pore morphologies and volumes in macroporous materials. Macroporous structures with controllable pore morphologies are formed under defined freezing conditions. Oil-in-water emulsions are processed to produce porous polymeric materials with a controlled proportion of ice-templated pores and emulsion-templated pores by systematically changing the volume ratio of the internal oil droplet phase to aqueous continuous phase in the emulsions. Pore morphology, bulk density, and pore volumes of these macroporous materials can thus be systematically tuned. Chemical crosslinking and sol–gel processing are further employed to produce porous polymeric and inorganic materials (silica, silica–alumina, and zirconia) with enhanced mechanical stability and hierarchical porosity.