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2022
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Polyelectrolytes dissolve in aqueous solution by releasing the counterions. However, the liquid-liquid phase separation occurs when two oppositely charged polyelectrolyte solutions are mixed, and this is called complex coacervation. Because of electrostatic interaction, the complex coacervate, which is polyelectrolyte condensed phase, has been used as salt and pH responsive vehicles for charged molecules, such as DNA, RNA, and metal ions. To expand the use of complex coacervate for drug delivery in vivo, it is important to control the particle size.
The self-assembly is representative method to form the nanoparticles. The AB block copolyelectrolyte, which has neutral A block and oppositely charged B block, can be self-assembled by the electrostatic attraction, resulting in the formation of complex coacervate core micelles, C3Ms. Because of identical properties of core of C3Ms with complex coacervate, the C3Ms has been studied in wide application fields, including biomedical and food industry. Understanding of the C3Ms enhances the applicability in diverse area. For C3Ms as a drug delivery vehicle, the structure and kinetics are important factors. The structure, including overall and core dimension, are related to the loading capacity, and cell penetration. In addition, the static and dynamic properties are required for reproducibility, controlled drug releases, and stability of C3Ms. To investigate the structure and properties of C3Ms, the well-defined C3Ms are introduced.
In this study, the poly(ethylene oxide-b-allyl glycidyl ether) (EOAGE) is prepared by living anionic ring opening polymerization, and functionalized by charged moieties (i.e., ammonium (A), guanidinium (G), carboxylate (C), and sulfonate group (S)) using thiol-ene click reaction. The C3Ms are simply formed by mixing of two oppositely charged block copolyelectrolytes solutions, and denoted as A+S (x), A+C (x), G+S (x), and G+C (x), respectively, where x is degree of polymerization of core block. The structure of C3Ms as a function of core block length and ionic strength is characterized by dynamic light scattering (DLS) and small angle x-ray/neutron scattering (SAX/NS) measurements. The swollen core with a significant amount of water and relaxed corona block are observed, indicating that it is crew-cut type micelles. Furthermore, the salt-dependent core radii of C3Ms shows good agree with the theoretical approaches derived from scaling law of interfacial tension, and structure. These results suggest that the structure of C3Ms can be controlled by free energy balance, and low interfacial tension is main reason for C3Ms structure. The equilibrium kinetics of C3Ms are investigated by time-resolved small angle neutron scattering (TR-SANS) measurement. The scattering length density difference between hydrogen and deuterium is used as contrast variation technique. Based on the mixing of normal C3Ms and deuterium labeled C3Ms, the chain exchange rates are observed with increasing salt concentration. The relaxation rate of polyelectrolyte chain in core is affected by salt concentration, resulting in the salt-dependent mobility. The master relaxation curve from time-salt superposition is captured by proposed model equation, including the contribution of electrostatic energy, interfacial energy for chain expulsion, and block polydispersity. We believe that our work enhances the fundamental understanding of the C3Ms, resulting in the precise control and effective design principles.
The self-assembly is representative method to form the nanoparticles. The AB block copolyelectrolyte, which has neutral A block and oppositely charged B block, can be self-assembled by the electrostatic attraction, resulting in the formation of complex coacervate core micelles, C3Ms. Because of identical properties of core of C3Ms with complex coacervate, the C3Ms has been studied in wide application fields, including biomedical and food industry. Understanding of the C3Ms enhances the applicability in diverse area. For C3Ms as a drug delivery vehicle, the structure and kinetics are important factors. The structure, including overall and core dimension, are related to the loading capacity, and cell penetration. In addition, the static and dynamic properties are required for reproducibility, controlled drug releases, and stability of C3Ms. To investigate the structure and properties of C3Ms, the well-defined C3Ms are introduced.
In this study, the poly(ethylene oxide-b-allyl glycidyl ether) (EOAGE) is prepared by living anionic ring opening polymerization, and functionalized by charged moieties (i.e., ammonium (A), guanidinium (G), carboxylate (C), and sulfonate group (S)) using thiol-ene click reaction. The C3Ms are simply formed by mixing of two oppositely charged block copolyelectrolytes solutions, and denoted as A+S (x), A+C (x), G+S (x), and G+C (x), respectively, where x is degree of polymerization of core block. The structure of C3Ms as a function of core block length and ionic strength is characterized by dynamic light scattering (DLS) and small angle x-ray/neutron scattering (SAX/NS) measurements. The swollen core with a significant amount of water and relaxed corona block are observed, indicating that it is crew-cut type micelles. Furthermore, the salt-dependent core radii of C3Ms shows good agree with the theoretical approaches derived from scaling law of interfacial tension, and structure. These results suggest that the structure of C3Ms can be controlled by free energy balance, and low interfacial tension is main reason for C3Ms structure. The equilibrium kinetics of C3Ms are investigated by time-resolved small angle neutron scattering (TR-SANS) measurement. The scattering length density difference between hydrogen and deuterium is used as contrast variation technique. Based on the mixing of normal C3Ms and deuterium labeled C3Ms, the chain exchange rates are observed with increasing salt concentration. The relaxation rate of polyelectrolyte chain in core is affected by salt concentration, resulting in the salt-dependent mobility. The master relaxation curve from time-salt superposition is captured by proposed model equation, including the contribution of electrostatic energy, interfacial energy for chain expulsion, and block polydispersity. We believe that our work enhances the fundamental understanding of the C3Ms, resulting in the precise control and effective design principles.
목차
Chapter 1. Introduction 191.1 Complex Coacervate Core Micelles (C3Ms) 191.2 Dissertation Outline 201.3 References 23Chapter 2. Background 262.1 General characteristics of C3Ms 262.2 Structure of C3Ms 292.3 Chain dynamics of C3Ms 312.3.1 Formation kinetics in C3Ms 312.3.2 Equilibrium kinetics in C3Ms 322.4 References 35Chapter 3. Experimental section 403.1 Preparation of block copolyelectrolyte 403.2 Characterization of block copolyelectrolytes 433.2.1 Size exclusion chromatography (SEC) 433.2.2 Proton nuclear magnetic resonance (1H NMR) 443.3 Characterization of the C3Ms 463.3.1 Dynamic light scattering (DLS) 463.3.2 Small angle scattering (SAS) 473.3.3 Cryogenic transmission electron microscopy (Cryo-TEM) 51Chapter 4. Structure of complex coacervate core micelles 534.1 Introduction 534.2 Experimental section 554.2.1 Materials 554.2.2 Dynamic light scattering (DLS) 594.2.3 Cryogenic transmission electron microscopy (Cryo-TEM) 594.2.4 Small angle neutron scattering (SANS) 604.3 Model equation for C3Ms 644.4 Results and discussion 664.4.1 General consideration of C3Ms 664.4.2 DLS & Cryo-TEM 684.4.3 Small angle neutron scattering 724.5 Conclusion 794.6 References 81Chapter 5. Scaling relation of complex coacervate core micelles 915.1 Introduction 915.2 Experimental section 935.2.1 Materials 935.2.2 Synthesis of PEO-PAGE block copolymer 945.2.3 Ionic functionalization of PEO-PAGE 975.2.4 Small-angle neutron scattering (SANS) 975.2.5 SANS Fitting Model 985.3 Results and discussion 1015.3.1 Structure characterization of C3Ms 1015.3.2 Scaling theory of C3Ms 1115.4 Conclusion 1145.5 References 115Chapter 6. Salt-dependent structure of complex coacervate core micelles 1246.1 Introduction 1246.2 Experimental section 1266.2.1 Materials 1266.2.2 Synthesis of block copolyelectrolyte 1266.2.3 Preparation of complex coacervate core micelles (C3Ms) 1276.2.4 Dynamic light scattering (DLS) 1276.2.5 Small Angle X-ray Scattering (SAXS) 1296.2.6 Small Angle Neutron Scattering (SANS) 1296.2.7 Detailed fitting model 1306.3 Results and discussion 1316.3.1 Determination of critical salt concentration (CSC) 1316.3.2 Salt dependent structure of C3Ms 1336.3.3 Salt dependent properties of C3Ms 1366.3.4 Scaling relation between core radius and salt concentration 1386.3.5 Structure reversibility of C3Ms 1406.4 Conclusion 1426.5 References 143Chapter 7. Equilibrium kinetics of complex coacervate core micelles 1497.1 Introduction 1497.2 Experimental section 1517.2.1 Materials 1517.2.2 Polymer characterization 1537.2.3 Small angle neutron scattering 1567.2.4 SANS fitting model 1567.3 Results and discussion 1627.3.1 Preparation of C3Ms 1627.3.2 Time resolved SANS 1637.3.3 Relaxation behavior of C3Ms 1677.3.4 Salt dependent relaxation behavior of C3Ms 1737.3.5 Relaxation model fit for C3Ms 1767.3.6 Validation of relaxation model 1837.4 Conclusion 1847.5 References and Notes 186Chapter 8. Complex coacervate core micelles in drug delivery 1948.1 Introduction 1948.2 Experimental section 1968.2.1 Materials 1968.2.2 Synthesis and characterization of guanidinium-functionalized poly(ethylene oxide-b-allyl glycidyl ether) block copolyelectrolytes 1978.2.3 Fabrication and characterization of various siRNA-complexing polyplexes. 1988.2.4 Agarose gel electrophoresis assay 1988.2.5 Cell culture 1998.2.6 Cellular uptake analysis of various siRNA-complexing polyplexes 1998.2.7 In vitro cell viability test 1998.2.8 In vivo siRNA transfection 2008.3 Results and discussion 2018.3.1 Synthesis and characterization of G-PEO-PAGE block Copolyelectrolytes 2018.3.2 Characterization of siRNA/G-PEO-PAGE micelleplexes 2038.3.3 Efficient siRNA complexation by G-PEO-PAGE 2058.3.4 High colloidal stability of siRNA/G-PEO-PAGE micelleplexes 2058.3.5 Efficient cellular uptake of siRNA by G-PEO-PAGE 2078.3.6 Low cytotoxicity by siRNA/G-PEO-PAGE micelleplexes 2088.3.7 Efficient gene silencing by siRNA/G-PEO-PAGE micelleplexes 2098.4 Conclusion 2118.5 References 212Chapter 9. Conclusion and Outlook on future research 2179.1 Conclusion 2179.2 Outlook on future research 2199.2.1 Structure 2199.2.2 Kinetics 2209.3 References 221Abstract in Korean 223Acknowledgements 226
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