Steven Paul Rannard

Dendrimers: a new class of nanoscopic containers and delivery devices

Abstract Dendrimers and hyperbranched polymers are a relatively new class of materials with unique molecular architectures and dimensions in comparison to traditional linear polymers. This review details recent notable advances in the application of these new polymers in terms of the development of new polymeric delivery systems. Although comparatively young, the developing field of hyperbranched drug delivery devices is a rapidly maturing area and the key discoveries in drug-conjugate systems amongst others are highlighted. As a consequence of their ideal hyperbranched architectures, the utilisation of host–guest chemistries in dendrimers has been included within the scope of this review.

Formation and enhanced biocidal activity of water-dispersable organic nanoparticles

Water-insoluble organic compounds are often used in aqueous environments in various pharmaceutical and consumer products. To overcome insolubility, the particles are dispersed in a medium during product formation, but large particles that are formed may affect product performance and safety. Many techniques have been used to produce nanodispersions-dispersions with nanometre-scale dimensions-that have properties similar to solutions. However, making nanodispersions requires complex processing, and it is difficult to achieve stability over long periods. Here we report a generic method for producing organic nanoparticles with a combination of modified emulsion-templating and freeze-drying. The dry powder composites formed using this method are highly porous, stable and form nanodispersions upon simple addition of water. Aqueous nanodispersions of Triclosan (a commercial antimicrobial agent) produced with this approach show greater activity than organic/aqueous solutions of Triclosan.

pH-Responsive branched polymer nanoparticles

We describe a new one-pot, single-step route for the preparation of pH-responsive branched polymer nanoparticles. These polymers, which are based on the pH-responsive monomer 2-(diethylamino)ethyl methacrylate (DEA) and hydrophilic macromonomer poly(ethyleneglycol) methacrylate (PEGMA), are synthesised using a modified conventional free-radical polymerisation. Consequently, their preparation is generic, scaleable and tolerant of functionality. In aqueous solution the branched copolymers form core-shell structures at basic pH and on reducing the solution pH they become hydrated and swell, displaying similar characteristics to those of pH-responsive shell cross-linked micelles and microgels. We demonstrate good control over the hydrodynamic particle size, polymer chain-end, and the uptake and release of a model hydrophobe and also the ability to tune the apparent pKa of the DEA residues by varying the degree of branching. These results augur well for commercially viable tunable release applications.

Antiretroviral solid drug nanoparticles with enhanced oral bioavailability: production, characterization, and in vitro-in vivo correlation.

Nanomedicine strategies have produced many commercial products. However, no orally dosed HIV nanomedicines are available clinically to patients. Although nanosuspensions of drug particles have demonstrated many benefits, experimentally achieving >25 wt% of drug relative to stabilizers is highly challenging. In this study, the emulsion-templated freeze-drying technique for nanoparticles formation is applied for the first time to optimize a nanodispersion of the leading non-nucleoside reverse transcriptase inhibitor efavirenz, using clinically acceptable polymers and surfactants. Dry monoliths containing solid drug nanoparticles with extremely high drug loading (70 wt% relative to polymer and surfactant stabilizers) are stable for several months and reconstitute in aqueous media to provide nanodispersions with z-average diameters of 300 nm. The solid drug nanoparticles exhibit reduced cytoxicity and increased in vitro transport through model gut epithelium. In vivo studies confirm bioavailability benefits with an approximately four-fold higher pharmacokinetic exposure after oral administration to rodents, and predictive modeling suggests dose reduction with the new formulation may be possible.

Hyperbranched polydendrons: a new controlled macromolecular architecture with self-assembly in water and organic solvents

A new macromolecular architecture (hyperbranched polydendrons) is presented. Combining aspects of linear-dendritic hybrids, controlled radical polymerisation and branched vinyl polymerisation, the materials have very high molecular weight (Mw > 1 MDa) and surface functionality. Although dispersities are broad (Đ up to 25) the structures behave with remarkable uniformity upon manipulation of solvent environment. Comparisons of conventional linear-dendritic hybrids and hyperbranched polydendrons are presented, including aspects of their synthesis. Under solvent exchange in organic media, a reversible self-assembly to form monodispersed nanoparticles (PDI as low as 0.013) is observed. Self-assembly and encapsulation is also observed during aqueous nanoprecipitation of the hyperbranched materials, with nanoparticle size (diameters from 60–140 nm) controlled through modification of precipitation conditions and the generation of the ideally branched dendrons at one end of each primary chain. The aqueous nanoparticles are highly stable and offer considerable opportunities for tailored functionality and future advanced applications.

Ultra-fast microwave enhanced reversible addition-fragmentation chain transfer (RAFT) polymerization: monomers to polymers in minutes

Microwave mediated RAFT polymerization leads to ultra-fast polymerizations, whilst keeping excellent control over molecular weights and molecular weight distributions; this is the first example of such a dramatic effect of microwaves on living radical polymerization kinetics, and it shows the potential for chemists to produce very well controlled polymers in a matter of minutes.

Investigation of the Experimental Factors Affecting the Trithiocarbonate-Mediated RAFT Polymerization of Methyl Acrylate

The reversible addition–fragmentation chain transfer polymerization of acrylates, using methyl acrylate (MA) as a monomer model, mediated by a trithiocarbonate was tested under several conditions where the experimental parameters were systematically altered. The most significant parameter in controlling the rate and control of the polymerization was found to be the ratio of chain transfer agent (CTA) to initiator. Decreasing this ratio increased the rate of polymerization and had little noticeable effect on the control over molecular weight distribution. A ratio of CTA to initiator of unity was shown to give the best compromise between rate and control of the polymerization. Targeted degrees of polymerization (equivalent to ratios of monomer to CTA) had negligible effect on the rate of polymerization and polydispersity index (PDI). Performing the polymerization in the presence of solvent (up to 41.2% (w/w) in toluene) had no negative effect on the rate of polymerization. Indeed, marginally higher conversions and lower PDIs than for bulk polymerization were achieved for similar reaction times. A higher amount of toluene (66.6% (w/w)) induced a lower rate of polymerization, but the evolution of molecular weight and PDI were unaffected. Polymerizations performed in the presence of toluene, N,N′-dimethylformamide, and methyl ethyl ketone showed that solvent polarity and aromaticity had no observable effect on the rate of polymerization and over the control of molecular weight distribution. The optimum conditions for the polymerization of MA, mediated by 2-ethylthiocarbonylsulfanyl-propionic acid ethyl ester at 50°C were found to be [CTA]/[AIBN] = 1/1 and ~40% solvent (w/w).

Mediation of in Vitro Cytochrome P450 Activity by Common Pharmaceutical Excipients

Polymers and surfactants are commonly used as excipients in oral formulations and are generally considered to be inert. However, relatively few studies have assessed their interaction with enzymes involved in the absorption, distribution, metabolism, and elimination of drugs. We have investigated the impact of twenty-three commonly used excipients (ten polymers and thirteen surfactants) on seven cytochrome P450 (CYP450) isoforms using baculosome-derived CYP450 enzymes across a range of concentrations. Time-course fluorescent readings were then taken to generate IC50 (inhibition) or EC50 (activation) values for excipient effects on CYP450 activity. All excipients had an observable effect activity of at least one CYP450 isoform with the majority of excipients altering substrate metabolism of at least 57% of CYP450s studied. In addition, most excipients were capable of inhibiting and increasing activity of several different CYP450 isoforms. Although the majority of these effects required concentrations outside those achievable therapeutically (>100 μM), almost 20% were seen at concentrations below 100 μM, and these results indicate that several excipients have the potential to modify the pharmacokinetics of administered drugs.

‘One-pot’ sequential deprotection/functionalisation of linear-dendritic hybrid polymers using a xanthate mediated thiol/Michael addition

Thiol–Michael addition chemistry is a powerful tool for the preparation of functional materials. In this first report of xanthate-functional linear-dendritic polymer hybrids, the preparation of four generations of xanthate-functionalised dendron atom transfer radical polymerisation macroinitiators is described using an orthogonal chemical strategy. The controlled polymerisation of tertiary butyl methacrylate is demonstrated to high conversion and without interference from the xanthate surface groups. Modification of the peripheral xanthate groups of dendrons at the hybrid polymer chain-end has been studied using a one-pot deprotection/functionalisation strategy and a range of commercially available and bespoke acrylate monomers to form complex polymer architectures from feedstock polymers, differing in the number of modified end groups and the surface chemistry of the dendron chain end.

Synthesis of well-defined Locust Bean Gum-graft-copolymers using ambient aqueous atom transfer radical polymerisation

The first atom transfer radical graft copolymerisation at ambient temperature in water from a soluble polysaccharide is demonstrated for a range of monomer types.