Synthesis, characterisation and cytotoxicity evaluation of novel polymeric carriers for polymer therapeutics: From free radical polymerisation to atom transfer radical polymerisation

Polymer therapeutics include water-soluble polymers designed as carriers for drugs, proteins or DNA. Over the last two decades, they have found increasing clinical use against cancer and other diseases. A growing number is in clinical trials or on the market. However, the polymers used so far have limitations including heterogeneity in structure, molecular weight, polydispersity, drug carrying capacity, lack of control of architecture and biodegradability of polymer backbone. Therefore, the aim of this study was to synthesise and characterise a library of linear/star homo/copolymers with potential for further development as second-generation polymer therapeutics. Atom Transfer Radical Polymerisation (ATRP) and (chain transfer agent - CTA) Free Radical Polymerisation (FRP) techniques were used to synthesise water-soluble amine-based acrylamide and methacrylate homo/copolymers. Nuclear magnetic resonance, gel permeation chromatography, infrared and titration were used for characterisation. In vitro cytotoxicity studies of the polymers towards a murine melanoma cell line were performed using a cell viability evaluating colorimetric assay. Molecular weights (from 3,000 to 550,000 g.mol --1) were successfully adjusted by varying either the initiator or CTA to monomer ratios. Semitelechelic homo/copolymers with either carboxylic acid or hydroxyl termini were obtained using mercapto-based CTA. Either stable or degradable star-shaped poly(dimethylaminoethyl methacrylate) were obtained by copper-mediated ATRP using previously synthesised multifunctional initiators (4, 5 or 8 initiating moieties). A linear increase of predictable molecular weight with monomer conversion and narrow polydispersity (1.3) were observed. Amongst other molecular parameters systematically tested, the amount of cationic residues had the most striking effect on the cell viability. To conclude, conditions were optimised for the synthesis of a library of water- soluble amine-based homo/copolymers with different molecular weight, composition, charge density and architecture using several polymerisation techniques. Preliminary evaluation of polymer cytotoxicity associated to molecular parameters is vital for intelligently designing future, novel, and biocompatible polymeric carriers

Synthesis, characterisation and cytotoxicity evaluation of novel polymeric carriers for polymer therapeutics : from free radical polymerisation to atom transfer radical polymerisation

Polymer therapeutics include water-soluble polymers designed as carriers for drugs, proteins or DNA. Over the last two decades, they have found increasing clinical use against cancer and other diseases. A growing number is in clinical trials or on the market. However, the polymers used so far have limitations including heterogeneity in structure, molecular weight, polydispersity, drug carrying capacity, lack of control of architecture and biodegradability of polymer backbone. Therefore, the aim of this study was to synthesise and characterise a library of linear/star homo/copolymers with potential for further development as second-generation polymer therapeutics. Atom Transfer Radical Polymerisation (ATRP) and (chain transfer agent - CTA) Free Radical Polymerisation (FRP) techniques were used to synthesise water-soluble amine-based acrylamide and methacrylate homo/copolymers. Nuclear magnetic resonance, gel permeation chromatography, infrared and titration were used for characterisation. In vitro cytotoxicity studies of the polymers towards a murine melanoma cell line were performed using a cell viability evaluating colorimetric assay. Molecular weights (from 3,000 to 550,000 g.mol --1) were successfully adjusted by varying either the initiator or CTA to monomer ratios. Semitelechelic homo/copolymers with either carboxylic acid or hydroxyl termini were obtained using mercapto-based CTA. Either stable or degradable star-shaped poly(dimethylaminoethyl methacrylate) were obtained by copper-mediated ATRP using previously synthesised multifunctional initiators (4, 5 or 8 initiating moieties). A linear increase of predictable molecular weight with monomer conversion and narrow polydispersity (1.3) were observed. Amongst other molecular parameters systematically tested, the amount of cationic residues had the most striking effect on the cell viability. To conclude, conditions were optimised for the synthesis of a library of water- soluble amine-based homo/copolymers with different molecular weight, composition, charge density and architecture using several polymerisation techniques. Preliminary evaluation of polymer cytotoxicity associated to molecular parameters is vital for intelligently designing future, novel, and biocompatible polymeric carriers.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Phénotypage et génotypage des syndromes lipodystrophiques de l'adulte (évaluation de la mesure de l'interleukine 7)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially