Adam Limer

Dexamethasone-pDMAEMA polymeric conjugates reduce inflammatory biomarkers in human intestinal epithelial monolayers.

The mucoadhesive polymer, poly(dimethylamino)ethyl methacrylate, (pDMAEMA), was synthesised by living radical polymerisation and subsequently conjugated by quaternisation reaction to a functionalised anti-inflammatory corticosteroid dexamethasone, to separately yield two conjugates with either 9:1 or 18:1 molar ratios of dexamethasone:polymer respectively. The hypothesis was to test whether the active agent maintained in vitro bioactivity when exposed to the apical side of human intestinal epithelial monolayers, Caco-2 and mucus-covered HT29-MTX-E12 (E12). HPLC analysis indicated high conjugate purity. Similar to pDMAEMA, fluorescently-labelled dexamethasone-pDMAEMA conjugates were bioadhesive to Caco-2 and mucoadhesive to E12. Apical addition of conjugates suppressed mRNA expression of the inflammatory markers, NURR1 and ICAM-1 in E12 following stimulation by PGE(2) and TNF-alpha, respectively. Conjugates also suppressed TNF-alpha stimulated cytokine secretion to the basolateral side of Caco-2 monolayers. Measurement of dexamethasone permeability from conjugates across monolayers suggested that conjugation reduced permeability compared to free dexamethasone. LDH assay indicated that conjugates were not cytotoxic to monolayers. Anti-inflammatory agents can therefore be successfully conjugated to polymers and they retain adhesion and bioactivity and have potential to be formulated for topical administration.

Transition metal mediated living radical polymerisation

Living radical polymerisation has witnessed an unprecedented interest from polymer and materials scientists. Traditionally, polymers tended to replace natural materials such as wood, cotton and glass, and were used primarily for their structural features and performance and cost advantages. New functional polymers are essential for the manufacture of cell phones, lap-top computers, new cosmetics, and many pharmaceuticals. It is important to be able to control how monomers are put together within the macromolecule for the design at the molecular level for specific applications. Living polymerisation allows for end group control, polymer chain length and relatively narrow polydispersity polymers. In nature, the ability to control monomer distribution and chain length is obvious with approximately 20 amino acids being the monomers for polymers as diverse as hair, insulin and haemoglobin. Living radical polymerisation solves many of the problems in the use of monomers that contain heteroatoms and functional groups. These tend to be reactive towards strong nucleophiles and electrophiles which are required in ionic polymerisation. Protecting group chemistry as used in small molecule organic synthesis is not practical in polymer synthesis. Thus radicals that are inert to most functional groups and in particular protic species seem to be the answer. The mechanism of the transition metal mediate systems is extremely complicated with a range of organometallic species present in the reaction mixture. Solvents and coordinating monomers drastically affect the ideal reaction conditions and it is impossible to predict the optimum conditions for each synthesis without certain experiments being carried out. Nevertheless, catalyst systems are available which are acceptable and work well enough to be able to make a plethora of different macromolecules for a diverse range of applications /properties.

Synthesis of functional polymers by living radical polymerisationBasis of a presentation given at Materials Discussion No. 6, 12?14th September 2003, Durham, UK.Electronic supplementary information (ESI) available: synthesis and characterization of initiators 2, 3 and 5?7. See http://www.rsc.org/suppdata/jm/b3/b303759b/

The use of copper(I) halides in conjunction with pyridine imine ligands is reported to lead to a range of controlled molecular weight and architecture polymers. The use of multifunctional initiators leads to di-, tri- and tetra-functional star polymers based on pentaerythritol cores. The polymerisations all follow excellent first order kinetics with Mn increasing linearly with conversion. The polymerisation is first order in copper halide. A range of α-functional polymers with 4-[(4-chloro-6-methoxy-1,3,5-triazin-2-yl)amino]phenyl 2-bromo-2-methylpropionate, N-hydroxysuccinimide and phthalimide have been prepared which introduce terminal functionality into polymers for subsequent coupling and potential synthesis of conjugates for biologically active compounds. Finally block/graft amphiphilic copolymers are demonstrated via the preparation of a statistical copolymer macroinitiator containing a hydroxy functionality which is used for the polymerisation of dimethylaminoethyl methacrylate prior to esterification of the hydroxy functionality to give living radical polymerisation initiators which are used subsequently in the polymerisation of methyl methacrylate. Copper(I) mediated living radical polymerisation is shown to be an effective method for the synthesis of a range of functional synthetic polymers.

Synthesis of microcapsules via reactive surfactants

A statistical library of well-defined ionic and non-ionic amphiphilic block copolymers of P(MMA/HEMA)-b-PDMAEMA and PEG-b-P(MMA/HEMA) were synthesised via living radical polymerisation employing the macroinitiator technique. All the block copolymers show monomodal peaks and narrow weight distributions, indicating they were obtained in controlled manner. Those copolymers were further modified in order to prepare inisurfs and surfmers. This yielded a selection of active surfactants of desired molecular weight and low polydispersity. Soap-free miniemulsion polymerisations of butyl methacrylate were carried out using the obtained active surfactants to prepare core–shell microcapsules in which various concentrations of inert oil, hexadecane, as a model system were encapsulated. The influence of the block copolymer structure on the particle formation was studied. The core–shell nature of the particles could be confirmed using scanning electron microscopy. Up to 66% of hexadecane could be incorporated in PBMA microcapsules.