Strontium-based initiator system for ring-opening polymerization of cyclic esters

An amino isopropoxyl strontium (Sr-PO) initiator, which was prepared by the reaction of propylene oxide with liquid strontium ammoniate solution, was used to carry out the ring-opening polymerization (ROP) of cyclic esters to obtain aliphatic polyesters, such as poly(epsilon-caprolactone) (PCL) and poly(L-lactide) (PLLA). The Sr-PO initiator demonstrated an effective initiating activity for the ROP of epsilon-caprolactone (epsilon-CL) and L-lactide (LLA) under mild conditions and adjusted the molecular weight by the ratio of monomer to Sr-PO initiator. Block copolymer PCL-b-PLLA was prepared by sequential polymerization of epsilon-CL and LLA, which was demonstrated by H-1 NMR, C-13 NMR, and gel permeation chromatography. The chemical structure of Sr-PO initiator was confirmed by elemental analysis of Sr and N, H-1 NMR analysis of the end groups in epsilon-CL oligomer, and Fourier transform infrared (FTIR) spectroscopy. The end groups of PCL were hydroxyl and isopropoxycarbonyl, and FTIR spectroscopy showed the coordination between Sr-PO initiator and model monomer gamma-butyrolactone. These experimental facts indicated that the ROP of cyclic esters followed a coordination-insertion mechanism, and cyclic esters exclusively inserted into the Sr-O bond.

Stereoselective polymerization of rac-lactide using a monoethylaluminum Schiff base complex

A monoethylaluminum Schiff base complex (2) with formula LA1Et (L = N,N'-(2,2-dimethylpropylene)bis(3,5-di-tei-t-butylsalicylideneimine) was synthesized and employed for the stercoselective ring-opening polymerization of rac-lactide (rac-LA). The complex 2 was characterized by nuclear magnetic resonance, crystal structure, and elemental analysis. It contains a five-coordinate aluminum atom with distorted trigonal bipyramidal geornetry in the solid state. In the presence of 2-propanol, 2 showed high stereoselectivity for the polymerization of rac-LA. The polymerization yielded crystalline poly(rac-LA) with a high melting temperature (193-201 degreesC). NMR, differential scanning calorimetry, and wide-angle X-ray diffraction indicated that the poly(rac-LA) was highly isotactic, and a stereocomplex was formed between poly-L- and poly-D-lactide block sequences. By the analysis of electrospray-ionization mass spectrometry and H-1 NMR, the polymer was demonstrated to be endcapped in both terminals with an isopropyl ester and a hydroxy group, respectively. The polymerization was of first order in rac-LA concentration. The relationship between the rac-LA conversion and molecular weights of the polymer was linear so that the polymerization could be well controlled.

Synthesis of a novel structural triblock copolymer of poly(gamma-benzyl-L-glutamic acid)-b-poly(ethylene oxide)-b-poly(epsilon-caprolactone)

A novel structural triblock copolymer of poly(gamma-benzyl-L-glutamic acid)-b-poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PBLG-PEO-PCL) was synthesized by a new approach in the following three steps: (1) sequential anionic ring opening polymerization (ROP) of ethylene oxide and epsilon-caprolactone with an acetonitrile/potassium naphthalene initiator system to obtain a diblock copolymer CN-PEO-PCL with a cyano end-group; (2) conversion of the CN end-group into NH2 end-group by hydrogenation to obtain NH2-PEO-PCL; (3) ROP of gamma-benzyl-L-glutamate-N-carboxyanhydrides (Bz-L-GluNCA) with NH2-PEO-PCL as macroinitiator to obtain the target triblock copolymer. The structures from CN-PEO precursor to the triblock copolymers were confirmed by FT-IR and H-1 NMR spectroscopy, and their molecular weights were measured by gel permeation chromatography. The monomer of Bz-L-GluNCA can react almost quantitatively with the amino end-groups of NH2-PEO-PCL macroinitiator by ROP.

Studies of the cationic polymerisation of vinylic and energetic cyclic ether monomers

The cationic polymerisation of various monomers, including cyclic ethers bearing energetic nitrate ester (-ON02) groups, substituted styrenes and isobutylene has been investigated. The main reaction studied has been the ring-opening polymerisation of 3- (nitratomethyl)-3-methyl oxetane (NIMMO) using the alcohol/BF3.0Et2 binary initiator system. A series of di-, tri- and tetrafunctional telechelic polymers has been synthesised. In order to optimise the system, achieve controlled molecular weight polymers and understand the mechanism of polymerisation the effects of certain parameters on the molecular weight distribution, as determined by Size Exclusion Chromatography, have been examined. This shows the molecular weight achieved depends on a combination of factors including -OH concentration, addition rate of monomer and, most importantly, temperature. A lower temperature and OH concentration tends to produce higher molecular weight, whereas, slower addition rates of monomer, either have no significant effect or produce a lower molecular weight polymer. These factors were used to increase the formation of a cyclic oligomer, by a side reaction, and suggest, that the polymerisation of NIMMO is complicated with endbiting and back biting reactions, along with other transfer/termination processes. These observations appear to fit the model of an active-chain end mechanism. Another cyclic monomer, glycidyl nitrate (GLYN), has been polymerised by the activated monomer mechanism. Various other monomers have been used to end-cap the polymer chains to produce hydroxy ends which are expected to form more stable urethane links, than the glycidyl nitrate ends, when cured with isocyanates. A novel monomer, butadiene oxide dinitrate (BODN), has been prepared and its homopolymerisation and copolymerisation with GL YN studied. In concurrent work the carbocationic polymerisations of isobutylene or substituted styrenes have been studied. Materials with narrow molecular weight distributions have been prepared using the diphenyl phosphate/BCl3 initiator. These systems and monomers are expected to be used in the synthesis of thermoplastic elastomers.

Hydrogels for dermal applications

This thesis is concerned with the development of hydrogels that adhere to skin and can be used for topical or trans dermal release of active compounds for therapeutic or cosmetic use. The suitability of a range of monomers and initiator systems for the production of skin adhesive hydro gels by photopolymerisation was explored and an approximate order of monomer reactivity in aqueous solution was determined. Most notably, the increased reactivity of N-vinyl pyrrolidone within an aqueous system, as compared to its low rate of polymerisation in organic solvents, was observed. The efficacy of a series of photoinitiator systems for the preparation of sheet hydrogels was investigated. Supplementary redox and thermal initiators were also examined. The most successful initiator system was found to be Irgacure 184, which is commonly used in commercial moving web production systems that employ photopolymerisation. The influence of ionic and non-ionic monomers, crosslinking systems, water and glycerol on the adhesive and dynamic mechanical behaviour of partially hydrated hydrogel systems was examined. The aim was to manipulate hydrogel behaviour to modify topical and transdermal delivery capability and investigated the possibility of using monomer combinations that would influence the release characteristics of gels by modifying their hydrophobic and ionic nature. The copolymerisation of neutral monomers (N-vinyl pyrrolidone, N,N-dimethyl acrylamide and N-acryloyl morpholine) with ionic monomers (2-acrylamido-2-methylpropane sulphonic acid; sodium salt, and the potassium salt of 3-sulphopropyl acrylate) formed the basis of the study. Release from fully and partially hydrated hydrogels was studied, using model compounds and a non-steroidal anti-inflammatory drug, Ibuprofen. Release followed a common 3-stage kinetic profile that includes an initial burst phase, a secondary phase of approximate first order release and a final stage of infinitesimally slow release such that the compound is effectively retained within the hydrogel. Use of partition coefficients, the pKa of the active and a knowledge of charge-based and polar interactions of polymer and drug were complementary in interpreting experimental results. In summary, drug ionisation, hydrogel composition and external release medium characteristics interact to influence release behaviour. The information generated provides the basis for the optimal design of hydrogels for specific dermal release applications and some understanding of the limitations of these systems for controlled release applications.

Cationic ring opening polymerisation (CROP) of oxetane and its derivatives using oxonium derived initiators

Several cationic initiator systems were developed and used to polymerise oxetane with two oxonium ion initiator systems being investigated in depth. The first initiator system was generated by the elimination of a chloride group from a chloro methyl ethyl ether. Adding a carbonyl co-catalyst to a carbocationic centre generated the second initiator system. It was found that the anion used to stabilise the initiator was critical to the initial rate of polymerisation of oxetane with hexafluoroantimonate resulting in the fastest polymerisations. Both initiator systems could be used at varying monomer to initiator concentrations to control the molecular number average, Mn, of the resultant polymer. Both initiator systems showed living characteristics and were used to polymerise further monomers and generate higher molecular weight material and block copolymers. Oxetane and 3,3-dimethyl oxetane can both be polymerised using either oxonium ion initiator system in a variety of DCM or DCM/1,4-dioxane solvent mixtures. The level of 1,4-dioxane does have an impact on the initial rate of polymerisation with higher levels resulting in lower initial rates of polymerisation but do tend to result in higher polydispersities. The level of oligomer formation is also reduced as the level of 1,4-dioxane is increased. 3,3-bis-bromomethyl oxetane was also polymerised but a large amount of hyperbranching was seen at the bromide site resulting in a difficult to solvate polymer system. Multifunctional initiator systems were also generated using the halide elimination reactions with some success being achieved with 1,3,5-tris-bromomethyl-2,4,6-tris-methyl-benzene derived initiator system. This offered some control over the molecular number average of the resultant polymer system.

Human la protein interaction with GCAC near the initiator AUG enhances hepatitis C virus RNA replication by promoting linkage between 5 ` and 3 ` untranslated regions

Human La protein has been implicated in facilitating the internal initiation of translation as well as replication of hepatitis C virus (HCV) RNA. Previously, we demonstrated that La interacts with the HCV internal ribosome entry site (IRES) around the GCAC motif near the initiator AUG within stem-loop IV by its RNA recognition motif (RRM) (residues 112 to 184) and influences HCV translation. In this study, we have deciphered the role of this interaction in HCV replication in a hepatocellular carcinoma cell culture system. We incorporated mutation of the GCAC motif in an HCV monocistronic subgenomic replicon and a pJFH1 construct which altered the binding of La and checked HCV RNA replication by reverse transcriptase PCR (RT-PCR). The mutation drastically affected HCV replication. Furthermore, to address whether the decrease in replication is a consequence of translation inhibition or not, we incorporated the same mutation into a bicistronic replicon and observed a substantial decrease in HCV RNA levels. Interestingly, La overexpression rescued this inhibition of replication. More importantly, we observed that the mutation reduced the association between La and NS5B. The effect of the GCAC mutation on the translation-to-replication switch, which is regulated by the interplay between NS3 and La, was further investigated. Additionally, our analyses of point mutations in the GCAC motif revealed distinct roles of each nucleotide in HCV replication and translation. Finally, we showed that a specific interaction of the GCAC motif with human La protein is crucial for linking 5' and 3' ends of the HCV genome. Taken together, our results demonstrate the mechanism of regulation of HCV replication by interaction of the cis-acting element GCAC within the HCV IRES with human La protein.

Payone : incentive for epidemic protocol-based anonymity system

Anonymity systems maintain the anonymity of communicating nodes by camouflaging them, either with peer nodes generating dummy traffic or with peer nodes participating in the actual communication process. The probability of any adversary breaking down the anonymity of the communicating nodes is inversely proportional to the number of peer nodes participating in the network. Hence to maintain the anonymity of the communicating nodes, a large number of peer nodes are needed. Lack of peer availability weakens the anonymity of any large scale anonymity system. This work proposes PayOne, an incentive based scheme for promoting peer availability. PayOne aims to increase the peer availability by encouraging nodes to participate in the anonymity system by awarding them with incentives and thereby promoting the anonymity strength. Existing incentive schemes are designed for single path based approaches. There is no incentive scheme for multipath based or epidemic based anonymity systems. This work has been specifically designed for epidemic protocols and has been implemented over MuON, one of the latest entries to the area of multicasting based anonymity systems. MuON is a peer-to-peer based anonymity system which uses epidemic protocol for data dissemination. Existing incentive schemes involve paying every intermediate node that is involved in the communication between the initiator and the receiver. These schemes are not appropriate for epidemic based anonymity systems due to the incurred overhead. PayOne differs from the existing schemes because it involves paying a single intermediate node that participates in the network. The intermediate node can be any random node that participates in the communication and does not necessarily need to lie in the communication path between the initiator and the receiver. The light-weight characteristics of PayOne make it viable for large-scale epidemic based anonymity systems.