This talk will focus on recent developments in RAFT Polymerization which include new RAFT agents ... more This talk will focus on recent developments in RAFT Polymerization which include new RAFT agents and their application, new methods of transforming RAFT synthesized polymers, and recent studies in understanding the kinetics and mechanism of the RAFT process.
Protein-based vaccines offer a number of important advantages over organism-based vaccines but ge... more Protein-based vaccines offer a number of important advantages over organism-based vaccines but generally elicit poor CD8+ T cell responses. We have previously demonstrated that pH-responsive, endosomolytic polymers can enhance protein antigen delivery to major histocompatibility complex class I (MHC-I) antigen presentation pathways thereby augmenting CD8+ T cell responses following immunization. Here, we describe a new family of nanocarriers for protein antigen delivery assembled using architecturally distinct pH-responsive polymers. Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize linear, hyperbranched, and core-crosslinked copolymers of 2-(N,N-diethylamino)ethyl methacrylate (DEAEMA) and butyl methacrylate (BMA) that were subsequently chain extended with a hydrophilic N,N-dimethylacrylamide (DMA) segment copolymerized with thiol-reactive pyridyl disulfide (PDS) groups. In aqueous solution, polymer chains assembled into 25 nm micellar nanoparticles and enabled efficient and reducible conjugation of a thiolated protein antigen, ovalbumin. Polymers demonstrated pH-dependent membrane-destabilizing activity in an erythrocyte lysis assay, with the hyperbranched and cross-linked polymer architectures exhibiting significantly higher hemolysis at pH ≤ 7.0 than the linear diblock. Antigen delivery with the hyperbranched and cross-linked polymer architecture enhanced in vitro MHC-I antigen presentation relative to free antigen, whereas the linear construct did not have a discernible effect. The hyperbranched system elicited a four- to fivefold increase in MHC-I presentation relative to the cross-linked architecture, demonstrating the superior capacity of the hyperbranched architecture in enhancing MHC-I presentation. This work demonstrates that the architecture of pH-responsive, endosomolytic polymers can have dramatic effects on intracellular antigen delivery, and offers a promising strategy for enhancing CD8+ T cell responses to protein-based vaccines.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The novel profluorescent nitroxide, 1,1,3,3tetramethyldibenzo[e,g]isoindolin-2-yloxyl (TMDBIO) wa... more The novel profluorescent nitroxide, 1,1,3,3tetramethyldibenzo[e,g]isoindolin-2-yloxyl (TMDBIO) was investigated as a probe for the formation of polymer alkyl radicals during the thermo-oxidative degradation of unstabilised polypropylene. TMDBIO possesses a very low fluorescence quantum yield due to quenching by the nitroxide group, however when the free radical moiety is removed by reaction with alkyl radicals (to give an alkoxyamine), strong fluorescence is observed. Using spectrofluorimetry, the reaction of the nitroxide with polymer alkyl radicals during oxidation has been monitored. Significantly, the trapping of polymer alkyl radicals during the "induction period" at 120 o C is observed, when it is not possible to detect changes in the polymer using either chemiluminescence or infrared spectroscopy. This highlights the sensitivity of this method and represents the direct observation of free radical generation in polypropylene in the "induction period". TMDBIO also successfully stabilises polypropylene under thermo-oxidative conditions, which is consistent with its action as a radical trap. At elevated temperatures (150 o C), at the end of the "induction period" when the polymer is extensively degraded, the fluorescence decreases, due to secondary oxidation of the TMDBIO.
The bulk polymerizations of styrene and methyl methacrylate in the presence of model polymerdithi... more The bulk polymerizations of styrene and methyl methacrylate in the presence of model polymerdithiocarbonate adducts as mediators and benzoyl peroxide (BPO) as a conventional initiator were kinetically studied. The polymerization rate, hence the concentration of polymer radical P · , was proportional to [BPO] 1/2 . The pseudo-first-order activation rate constants k act were determined by the GPC peak-resolution method. The results showed that k act is directly proportional to [P · ], indicating that reversible addition-fragmentation chain transfer (RAFT) is the only important mechanism of activation. The magnitude of the exchange rate constant k ex (= k act /[P · ]) was strongly dependent on both the structures of the dithiocarbonate group and the polymer. The k ex values for the three RAFT systems examined in this work were all very large, explaining why these systems can provide low-polydispersity polymers from an early stage of polymerization.
Free radical polymerization with reversible addition±fragmentation chain transfer (RAFT polymeriz... more Free radical polymerization with reversible addition±fragmentation chain transfer (RAFT polymerization) is discussed with a view to answering the following questions: (a) How living is RAFT polymerization? (b) What controls the activity of thiocarbonylthio compounds in RAFT polymerization? (c) How do rates of polymerization differ from those of conventional radical polymerization? (d) Can RAFT agents be used in emulsion polymerization? Retardation, observed when high concentrations of certain RAFT agents are used and in the early stages of emulsion polymerization, and how to overcome it by appropriate choice of reaction conditions, are considered in detail. Examples of the use of thiocarbonylthio RAFT agents in emulsion and miniemulsion polymerization are provided.
Living radical polymerization with reversible addition-fragmentation chain transfer (RAFT polymer... more Living radical polymerization with reversible addition-fragmentation chain transfer (RAFT polymerization) can be achieved with the use of dithiocarbamate derivatives that have the nonbonded electron pair of the nitrogen included as part of an aromatic system. These compounds have been shown to be highly effective in RAFT polymerization of styrene and (meth)acrylate esters to produce polymers of predetermined molecular weight and narrow polydispersity (usually <1.2). By contrast, simple N,Ndialkyl dithiocarbamates (those compounds previously described as "photoiniferters") are ineffective as RAFT agents. The reasons for the different behavior are discussed.
This paper describes a versatile and effective method for the control of free radical polymerizat... more This paper describes a versatile and effective method for the control of free radical polymerization and its use in the preparation of narrow polydispersity polymers of various architectures. Living character is conferred to conventional free radical polymerization by the addition of a thiocarbonylthio compound of general structure S=C(Z)SR, for example, S=C(Ph)SC(CH3)2Ph. The mechanism involves Reversible Addition-Fragmentation chain Transfer and, for convenience of referral, we have designated it the RAFT polymerization. The process is compatible with a very wide range of monomers including functional monomers such as acrylic acid, hydroxyethyl methacrylate, and dimethy laminoethyl methacrylate. Examples of narrow polydispersity (51.2) homopolymers, copolymers, gradient copolymers, end-functional polymers, star polymers, A-B diblock and A-B-A triblock copolymers are presented.
The reactions of tert-alkyl peroxypivalates 1 (R ) methyl, ethyl, and n-propyl) with styrene in t... more The reactions of tert-alkyl peroxypivalates 1 (R ) methyl, ethyl, and n-propyl) with styrene in the presence of the free-radical scavenger (1,1,3,3-tetramethyl-2,3-dihydro-1H-isoindol-2-yl)oxyl (2) have been studied at 60°C. tert-Butyl and tert-alkoxyl radicals (tert-butoxyl, tert-pentyloxyl, and terthexyloxyl radicals) were generated from the thermolysis of 1, and the derivative alkyl radicals (methyl, ethyl, n-propyl, and 4-hydroxy-4-methylpentyl radicals) were formed by subsequent unimolecular reactions ( -scission and 1,5-H shift) of the corresponding tert-alkoxyl radicals. The extent of the unimolecular reactions of the tert-alkoxyl radicals (versus addition to styrene) and the relative reactivity of alkyl radicals toward addition to styrene were obtained from the competitive addition/trapping reactions. The absolute rate constants for the addition of tert-butyl, ethyl, methyl, and n-propyl radicals to styrene at 60°C were estimated to be (7.4, 4.7, 5, and 5.4) × 10 5 M -1 s -1 , respectively.
Eur. Polym. J. VoL 25, No. 7/8, pp. 671-676, 1989 0014-3057/89 $3.00 + 0.00 Printed in Great Brit... more Eur. Polym. J. VoL 25, No. 7/8, pp. 671-676, 1989 0014-3057/89 $3.00 + 0.00 Printed in Great Britain. All rights reserved Copyright 1989 Maxwell Pergamon Macmillan pie THE MECHANISM OF INITIATION IN THE FREE RADICAL POLYMERIZATION OF N-VINYLCARBAZOLE ...
Cumyloxy (1-methyl-1-phenylethoxy) radicals have been generated by thermolysis (60") of dicumyl h... more Cumyloxy (1-methyl-1-phenylethoxy) radicals have been generated by thermolysis (60") of dicumyl hyponitrite in methyl methacrylate and styrene. The carbon-centred radicals formed by interaction of cumyloxyl with the respective monomers were trapped as stable adducts of 1,1,3,3-tetramethylisoindolin-2-yloxyl. Extensive hydrogen atom abstraction and methyl radical generation as well as double-bond addition were observed in methyl methacrylate. Styrene underwent only double-bond addition by both cumyloxy and methyl radicals. Some possible implications of these results for polymer structure are discussed. A kinetic study of the decomposition of dicumyl hyponitrite in cyclohexane at various temperatures gave for the rate constant. Rate constants for the addition of cumyloxyl to methyl methacrylate (k % 2 x lo4 dm3 mol-I s-') and styrene (k % 2 x lo5 dm3 mol-' s-') at 60" have been estimated.
... Julia Krstina, Graeme Moad,* Ezio Rizzardo, and Catherine L. Winzor CSIRO, Division of Chemic... more ... Julia Krstina, Graeme Moad,* Ezio Rizzardo, and Catherine L. Winzor CSIRO, Division of Chemicals and Polymers, Private Bag 10, Rosebank MDC, Clayton, Victoria 3169, Australia Charles T. Berge and Michael ... (16) Darmon, MJ; Berge ... (17) Cacioli, P.; Hawthorne, D. G.; Laslett ...
This talk will focus on recent developments in RAFT Polymerization which include new RAFT agents ... more This talk will focus on recent developments in RAFT Polymerization which include new RAFT agents and their application, new methods of transforming RAFT synthesized polymers, and recent studies in understanding the kinetics and mechanism of the RAFT process.
Protein-based vaccines offer a number of important advantages over organism-based vaccines but ge... more Protein-based vaccines offer a number of important advantages over organism-based vaccines but generally elicit poor CD8+ T cell responses. We have previously demonstrated that pH-responsive, endosomolytic polymers can enhance protein antigen delivery to major histocompatibility complex class I (MHC-I) antigen presentation pathways thereby augmenting CD8+ T cell responses following immunization. Here, we describe a new family of nanocarriers for protein antigen delivery assembled using architecturally distinct pH-responsive polymers. Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize linear, hyperbranched, and core-crosslinked copolymers of 2-(N,N-diethylamino)ethyl methacrylate (DEAEMA) and butyl methacrylate (BMA) that were subsequently chain extended with a hydrophilic N,N-dimethylacrylamide (DMA) segment copolymerized with thiol-reactive pyridyl disulfide (PDS) groups. In aqueous solution, polymer chains assembled into 25 nm micellar nanoparticles and enabled efficient and reducible conjugation of a thiolated protein antigen, ovalbumin. Polymers demonstrated pH-dependent membrane-destabilizing activity in an erythrocyte lysis assay, with the hyperbranched and cross-linked polymer architectures exhibiting significantly higher hemolysis at pH ≤ 7.0 than the linear diblock. Antigen delivery with the hyperbranched and cross-linked polymer architecture enhanced in vitro MHC-I antigen presentation relative to free antigen, whereas the linear construct did not have a discernible effect. The hyperbranched system elicited a four- to fivefold increase in MHC-I presentation relative to the cross-linked architecture, demonstrating the superior capacity of the hyperbranched architecture in enhancing MHC-I presentation. This work demonstrates that the architecture of pH-responsive, endosomolytic polymers can have dramatic effects on intracellular antigen delivery, and offers a promising strategy for enhancing CD8+ T cell responses to protein-based vaccines.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The novel profluorescent nitroxide, 1,1,3,3tetramethyldibenzo[e,g]isoindolin-2-yloxyl (TMDBIO) wa... more The novel profluorescent nitroxide, 1,1,3,3tetramethyldibenzo[e,g]isoindolin-2-yloxyl (TMDBIO) was investigated as a probe for the formation of polymer alkyl radicals during the thermo-oxidative degradation of unstabilised polypropylene. TMDBIO possesses a very low fluorescence quantum yield due to quenching by the nitroxide group, however when the free radical moiety is removed by reaction with alkyl radicals (to give an alkoxyamine), strong fluorescence is observed. Using spectrofluorimetry, the reaction of the nitroxide with polymer alkyl radicals during oxidation has been monitored. Significantly, the trapping of polymer alkyl radicals during the "induction period" at 120 o C is observed, when it is not possible to detect changes in the polymer using either chemiluminescence or infrared spectroscopy. This highlights the sensitivity of this method and represents the direct observation of free radical generation in polypropylene in the "induction period". TMDBIO also successfully stabilises polypropylene under thermo-oxidative conditions, which is consistent with its action as a radical trap. At elevated temperatures (150 o C), at the end of the "induction period" when the polymer is extensively degraded, the fluorescence decreases, due to secondary oxidation of the TMDBIO.
The bulk polymerizations of styrene and methyl methacrylate in the presence of model polymerdithi... more The bulk polymerizations of styrene and methyl methacrylate in the presence of model polymerdithiocarbonate adducts as mediators and benzoyl peroxide (BPO) as a conventional initiator were kinetically studied. The polymerization rate, hence the concentration of polymer radical P · , was proportional to [BPO] 1/2 . The pseudo-first-order activation rate constants k act were determined by the GPC peak-resolution method. The results showed that k act is directly proportional to [P · ], indicating that reversible addition-fragmentation chain transfer (RAFT) is the only important mechanism of activation. The magnitude of the exchange rate constant k ex (= k act /[P · ]) was strongly dependent on both the structures of the dithiocarbonate group and the polymer. The k ex values for the three RAFT systems examined in this work were all very large, explaining why these systems can provide low-polydispersity polymers from an early stage of polymerization.
Free radical polymerization with reversible addition±fragmentation chain transfer (RAFT polymeriz... more Free radical polymerization with reversible addition±fragmentation chain transfer (RAFT polymerization) is discussed with a view to answering the following questions: (a) How living is RAFT polymerization? (b) What controls the activity of thiocarbonylthio compounds in RAFT polymerization? (c) How do rates of polymerization differ from those of conventional radical polymerization? (d) Can RAFT agents be used in emulsion polymerization? Retardation, observed when high concentrations of certain RAFT agents are used and in the early stages of emulsion polymerization, and how to overcome it by appropriate choice of reaction conditions, are considered in detail. Examples of the use of thiocarbonylthio RAFT agents in emulsion and miniemulsion polymerization are provided.
Living radical polymerization with reversible addition-fragmentation chain transfer (RAFT polymer... more Living radical polymerization with reversible addition-fragmentation chain transfer (RAFT polymerization) can be achieved with the use of dithiocarbamate derivatives that have the nonbonded electron pair of the nitrogen included as part of an aromatic system. These compounds have been shown to be highly effective in RAFT polymerization of styrene and (meth)acrylate esters to produce polymers of predetermined molecular weight and narrow polydispersity (usually <1.2). By contrast, simple N,Ndialkyl dithiocarbamates (those compounds previously described as "photoiniferters") are ineffective as RAFT agents. The reasons for the different behavior are discussed.
This paper describes a versatile and effective method for the control of free radical polymerizat... more This paper describes a versatile and effective method for the control of free radical polymerization and its use in the preparation of narrow polydispersity polymers of various architectures. Living character is conferred to conventional free radical polymerization by the addition of a thiocarbonylthio compound of general structure S=C(Z)SR, for example, S=C(Ph)SC(CH3)2Ph. The mechanism involves Reversible Addition-Fragmentation chain Transfer and, for convenience of referral, we have designated it the RAFT polymerization. The process is compatible with a very wide range of monomers including functional monomers such as acrylic acid, hydroxyethyl methacrylate, and dimethy laminoethyl methacrylate. Examples of narrow polydispersity (51.2) homopolymers, copolymers, gradient copolymers, end-functional polymers, star polymers, A-B diblock and A-B-A triblock copolymers are presented.
The reactions of tert-alkyl peroxypivalates 1 (R ) methyl, ethyl, and n-propyl) with styrene in t... more The reactions of tert-alkyl peroxypivalates 1 (R ) methyl, ethyl, and n-propyl) with styrene in the presence of the free-radical scavenger (1,1,3,3-tetramethyl-2,3-dihydro-1H-isoindol-2-yl)oxyl (2) have been studied at 60°C. tert-Butyl and tert-alkoxyl radicals (tert-butoxyl, tert-pentyloxyl, and terthexyloxyl radicals) were generated from the thermolysis of 1, and the derivative alkyl radicals (methyl, ethyl, n-propyl, and 4-hydroxy-4-methylpentyl radicals) were formed by subsequent unimolecular reactions ( -scission and 1,5-H shift) of the corresponding tert-alkoxyl radicals. The extent of the unimolecular reactions of the tert-alkoxyl radicals (versus addition to styrene) and the relative reactivity of alkyl radicals toward addition to styrene were obtained from the competitive addition/trapping reactions. The absolute rate constants for the addition of tert-butyl, ethyl, methyl, and n-propyl radicals to styrene at 60°C were estimated to be (7.4, 4.7, 5, and 5.4) × 10 5 M -1 s -1 , respectively.
Eur. Polym. J. VoL 25, No. 7/8, pp. 671-676, 1989 0014-3057/89 $3.00 + 0.00 Printed in Great Brit... more Eur. Polym. J. VoL 25, No. 7/8, pp. 671-676, 1989 0014-3057/89 $3.00 + 0.00 Printed in Great Britain. All rights reserved Copyright 1989 Maxwell Pergamon Macmillan pie THE MECHANISM OF INITIATION IN THE FREE RADICAL POLYMERIZATION OF N-VINYLCARBAZOLE ...
Cumyloxy (1-methyl-1-phenylethoxy) radicals have been generated by thermolysis (60") of dicumyl h... more Cumyloxy (1-methyl-1-phenylethoxy) radicals have been generated by thermolysis (60") of dicumyl hyponitrite in methyl methacrylate and styrene. The carbon-centred radicals formed by interaction of cumyloxyl with the respective monomers were trapped as stable adducts of 1,1,3,3-tetramethylisoindolin-2-yloxyl. Extensive hydrogen atom abstraction and methyl radical generation as well as double-bond addition were observed in methyl methacrylate. Styrene underwent only double-bond addition by both cumyloxy and methyl radicals. Some possible implications of these results for polymer structure are discussed. A kinetic study of the decomposition of dicumyl hyponitrite in cyclohexane at various temperatures gave for the rate constant. Rate constants for the addition of cumyloxyl to methyl methacrylate (k % 2 x lo4 dm3 mol-I s-') and styrene (k % 2 x lo5 dm3 mol-' s-') at 60" have been estimated.
... Julia Krstina, Graeme Moad,* Ezio Rizzardo, and Catherine L. Winzor CSIRO, Division of Chemic... more ... Julia Krstina, Graeme Moad,* Ezio Rizzardo, and Catherine L. Winzor CSIRO, Division of Chemicals and Polymers, Private Bag 10, Rosebank MDC, Clayton, Victoria 3169, Australia Charles T. Berge and Michael ... (16) Darmon, MJ; Berge ... (17) Cacioli, P.; Hawthorne, D. G.; Laslett ...
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