The research presented in this thesis focuses on the molecular design of an oxidation-sensitive nanocarrier and its enzyme conjugate with a view of their application in the field of biomaterials. I have polarised our attention on a specific class of polymers, the polysulfides, for their environmental responsiveness (towards oxidising substances, a condition often associated with inflammatory reactions), interesting physico-chemical properties, ease of the preparation and multiple possibilities for further modifications and bioconjugations, which are perfectly suitable for the development as systems for drug delivery applications. In this work we firstly have focused on the synthesis of amphiphilic poly(propylene sulfide)-poly(ethylene glycol) (PPS-PEG) block copolymers by employing vinyl sulfone as the functional group to link the blocks and modify the end of the PEG. This study was followed by an investigation of the macromolecular interchange and payload exchange of the formed polymeric micelles to understand the 'co-formulation' events, employing fluorophores (dansyl groups) and quenchers (dabsyl groups) either as terminal groups in macroamphiphiles or as encapsulated hydrophobic payloads. In another part of the work, I have developed a micellar system with which simultaneously to two of the most important ROS: superoxide and hydrogen peroxide, for inflammation-responsive drug release. The system is composed of superoxide dismutase (SOD) conjugated to oxidation-sensitive amphiphilic polysulfide/PEG block copolymers; the conjugate combines the SOD reactivity towards superoxide with that of hydrophobic thioethers towards hydrogen peroxide. Specifically, here we have demonstrated how this hybrid system can efficiently convert superoxide into hydrogen peroxide, which is then 'mopped-up' by the polysulfides. This mode of operation is functionally analogous to the SOD/catalase combination, with the advantage of being based on a single and more stable system.

The goal of this project was to develop a non-toxic amphiphilic diblock copolymer nanoparticulate drug delivery system that will solubilize paclitaxel (PTX) and retain the drug in plasma. Methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (MePEG-b-PCL) diblock copolymers loaded with PTX were characterized and their physicochemical properties were correlated with their performance as nanoparticulate drug delivery systems. A series of MePEG-b-PCL was synthesized with PCL blocks ranging from 2-104 repeat units and MePEG blocks of 17, 44 or 114 repeat units. All copolymers were water soluble and formed micelles except MePEG₁₁₄-b-PCL₁₀₄, which was water insoluble and formed nanospheres. Investigation of the effects of block length on the physicochemical properties of the nanoparticles was used to select appropriate copolymers for development as PTX nanoparticles. The critical micelle concentration, pyrene partition coefficient and diameter of nanoparticles were found to be dependent on the PCL block length. Copolymers based on a MePEG molecular weight of 750 g/mol were found to have temperature dependent phase behavior. Relationships between the concentration of micellized drug and the compatibility between the drug and core-forming block, as determined by the Flory-Huggins interaction parameter, and PCL block length were developed. Increases in the compatibility between PCL and the drug, as well as longer PCL block lengths resulted in increased drug solubilization. The physicochemical properties and drug delivery performance characteristics of MePEG₁₁₄-b-PCL₁₉ micelles and MePEG₁₁₄-b-PCL₁₀₄ nanospheres were compared. Nanospheres were larger, had a more viscous core, solubilized more PTX and released it slower, compared to micelles. No difference was seen in the hemocompatibility of the nanoparticles as assessed by plasma coagulation time and erythrocyte hemolysis. Micellar PTX had an in vitro plasma distribution similar to free drug. The majority of micellar PTX associated with the lipoprotein deficient plasma fraction (LPDP). In contrast, nanospheres were capable of retaining more of the encapsulated drug with significantly less PTX partitioning into the LPDP fraction. In conclusion, although both micelles and nanospheres were capable of solubilizing PTX and were hemocompatible, PTX nanospheres may offer the advantage of prolonged blood circulation, based on the in vitro plasma distribution data, which showed that nanospheres retained PTX more effectively. / Pharmaceutical Sciences, Faculty of / Graduate

Highly crosslinked epoxy resin systems are essential in aerospace applications due to the high operating temperatures. Although highly crosslinked epoxy resins have the required glass transition temperature (Tg) for the application, they are inherently brittle and matrix toughness is improved by incorporation of a second phase. Previous studies have focused mostly on toughening of lightly crosslinked epoxy systems, whereas this study investigates toughening of a highly crosslinked epoxy resin system using thermoplastic toughners poly(ether sulfone) (PES) and a poly(methyl methacrylate)-b- poly(butyl acrylate)-b-poly(methyl methacrylate) (MAM) block copolymer (BCP).

The aim of this research is to fabricate an electrically conducting, smooth, continuous and sensitive nanofiber using tri-block copolymer PS-b-PDMS-b-PS and SWCNTs by electrospinning. The electronic nanofibers may be utilized for effective biosensing applications. The SWCNTs have been of great interest to researchers because of their exceptional electrical, mechanical, and thermal properties. The nanoscale diameter, high aspect ratio, and low density make them an ideal reinforcing candidate for novel nanocomposite material. Electrically conducting fibers are prepared by electrospinning a solution of PS, PS-b- PDMS-b-PS and functionalized SWCNTs using solvent DMF. The fibers formed have an average diameter and height of 5 and 4 μm respectively. These fibers are characterized by SEM, AFM, and optical microscopy. The electrical characterization of a single fiber shows an almost linear graph of current vs. voltage using the Kelvin Sensing method. This linear graph exemplifies the conducting nature of the fiber. Future work includes preparing nanofibers decorated with functional groups and binding with specific type of enzyme or protein to study their I-V behavior. This approach or method can be utilized for bio-sensing activities, especially for the detection of various antibodies and protein molecules.

Nature is an excellent design that inspires scientists to develop smart systems. In the realm of separation technology, biological membranes have been an ideal model for synthetic membranes due to their ultrahigh permeability, sharp selectivity, and stimuliresponse. In this research, fabrications of bioinspired membranes from block copolymers were studied. Membranes with isoporous morphology were mainly prepared using selfassembly and non-solvent induced phase separation (SNIPS). An effective method that can dramatically shorten the path for designing new isoporous membranes from block copolymers via SNIPS was first proposed by predetermining a trend line computed from the solvent properties, interactions and copolymer block sizes of previously-obtained successful systems. Application of the method to new copolymer systems and fundamental studies on the block copolymer self-assembly were performed. Furthermore, the manufacture of bioinspired membranes was explored using (1) poly(styrene-b-4-hydroxystyrene-b-styrene) (PS-b-PHS-b-PS), (2) poly(styrene-bbutadiene- b-styrene) (PS-b-PB-b-PS) and (3) poly(styrene-b-γ-benzyl-L-glutamate) (PSb- PBLG) copolymers via SNIPS. The structure formation was investigated using smallangle X-ray scattering (SAXS) and time-resolved grazing-Incidence SAXS. The PS-b- PHS-b-PS membranes showed preferential transport for proteins, presumably due to the hydrogen bond interactions within the channels, electrostatic attraction, and suitable pore dimension. Well-defined nanochannels with pore sizes of around 4 nm based on PS-b- PB-b-PS copolymers could serve as an excellent platform to fabricate bioinspired channels due to the modifiable butadiene blocks. Photolytic addition of thioglycolic acid was demonstrated without sacrificing the self-assembled morphology, which led to a five-fold increase in water permeance compared to that of the unmodified. Membranes with a unique feather-like structure and a lamellar morphology for dialysis and nanofiltration applications were obtained from PS-b-PBLG copolymers, which exhibited a hierarchical self-assembled morphology with confined α-helical polypeptide domains. Our results suggest that bioinspired nanochannels can be designed via block copolymer self-assembly using classical methods of membrane preparation. Investigation of the membrane formation mechanism leads us to a better understanding of the design strategies for the development of self-assembled nanochannels from block copolymers. In further outlook, our research could give a contribution to the discovery of future generation materials for water purification and desalination, as well as biological separation.

The primary aim of this work is to explore the potential applications of isoporous block copolymer membranes. Block copolymers (BCPs) have demonstrated their versatility in the formation of isoporous membranes. However, application spectrum of these isoporous membranes can be further broadened by exploring the technical aspects, such as desired surface chemistry, well-defined pore size, appropriate pore density, stimuli responsive behavior, and by imparting desired functionalities through chemical modifications. We believe, by exploring these possibilities, isoporous membranes hold tremendous potential as high performance next generation separation membranes. Motivated by these attractive prospects we systematically investigated novel routes for modification of isoporous membranes and their implications on properties and performance of the membranes for various applications. In this work, polystyrene-block-poly(4-vinyl pyridine) (PS-b-P4VP) has been selected to fabricate isoporous membranes using non-solvent induced phase separation (NIPS). We selected PS-b-P4VP since its well-defined isoporous morphology is studied in detail and it is extensively characterized. In order to further widen the application bandwidth of BCP membranes, it is desirable to integrate different functionalities in the BCP architecture through a straightforward approach like post-membrane-modification or fabrication of composite membranes to impart anticipated functionalities. The most critical challenge in this approach is to retain the well-defined nanoporous morphology of BCP membranes. We focused on exploring new routes for chemical functionalization of isoporous PS-b-P4VP membranes via various in-situ and post-membrane fabrication approaches. To date, most of the work reported in the literature on PS-b-P4VP presented different routes to fabricate isoporous membranes and their conventional performance in liquid separations. Few efforts have been dedicated to alter the chemistry of PS-b-P4VP membranes by tuning the reactivity of the chemically active P4VP block or the surface chemistry to enhance the membrane performance for desired applications. During the Ph.D. study, we primarily focused on: (i) post modification approach, (ii) surface modification and (iii) in-situ membrane modification approach for fabrication of the mixed-matrix nanoporous membranes without altering the isoporous morphology of the membrane. The membranes fabricated using the mentioned above routes were tested for different applications like stimuli-responsive separations, self-cleaning membranes, protein separations and high-performance humidity sensors.

Isoporous membranes are attractive for the regulation and detection of transport at the molecular level. A well-defined asymmetric membranes from diblock copolymers with an ordered nanoporous membrane morphologies were fabricated by the combination of block copolymer self-assembly and non-solvent-induced phase separation (NIPS) technique. This is a straightforward and fast one step procedure to develop integrally anisotropic (“asymmetric”) membranes having isoporous top selective layer. Membranes prepared via this method exhibit an anisotropic cross section with a thin separation layer supported from underneath a macroporous support. These membrane poses cylindrical pore structure with ordered nanopores across the entire membrane surfaces with pore size in the range from 20 to 40 nm. Tuning the pore morphology of the block copolymer membranes before and after fabrication are of great interest. In this thesis, we first investigated the pore morphology tuning of asymmetric block copolymer membrane by complexing with small organic molecules. We found that the occurrence of hydrogen-bond formation between PS-b-P4VP block copolymer and –OH/ –COOH functionalized organic molecules significantly tunes the pore morphology of asymmetric nanoporous membranes. In addition, we studied the complexation behavior of ionic liquids with PS-b-P4VP block copolymer in solutions and investigated their effect on final membrane morphology during the non-solvent induced phase separation process. We found that non-protic ionic liquids facilitate the formation of hexagonal nanoporous block copolymer structure, while protic ionic liquids led to a lamella-structured membrane. Secondly, we demonstrated the catalytic activity of the gold nanoparticle-enhanced hollow fiber membranes by the reduction of nitrophenol. Also, we systematically investigated the pore morphology of isoporous PS-b-P4VP using 3D imaging technique. Thirdly, we developed well-distributed silver nanoparticles on the surface and pore walls of PS-b-P4VP block copolymer membranes and then investigated the biocidal activity of the silver nanoparticles grown membranes. Finally, a novel photoresponsive nanostructured triblock copolymer membranes were developed by phase inversion technique. In addition, the photoresponsive behavior on irradiation with light and their membrane flux and retention properties were studied.

Research of new sustainable and low cost materials, such as cellulose, is of high interest. Modifications of the cellulose can be performed in order to create a “smart” material which responds to external stimuli, such as variations in pH and temperature, by changing its properties. This “smart” behavior is observed in some polymers, however, for certain applications they exhibit poor mechanical properties. These polymers can be bound by physical adsorption to cellulose, both in macro and nano scale, creating an improved “smart” composite material. In this project, thermoresponsive block-copolymers with different lengths of poly (diethylene glycol) methacrylate (PDEGMA) and poly N-(2-dimethylamino ethyl) methacrylate (PDMAEMA) in only one length, PDMAEMA-b-PDEGMA, were synthesized employing atom transfer radical polymerization (ATRP). 1H-NMR, SEC and DLS were used to characterize the block-copolymers. UV-Vis spectroscopy was employed to confirm the thermo-responsive behavior of the charged and uncharged block-copolymers, being lower for the higher molecular weight ones due to the higher polymer-polymer interactions. In a second step, PDMAEMA was charged positively by quaternization of its amine group with ICH3. Polyelectrolyte titration was used to determine the total number of charges in the quaternized block-copolymers. In addition, TEMPO-oxidized nanofibrillated cellulose (NFC) was produced by procedures found in literature. Finally, adsorption of the cationic block-copolymers onto the anionic NFC in tris base at pH 8.3 was performed and purified by consecutive filtrations, creating a novel smart composite material with different PDEGMA lengths in the block-copolymer. FT-IR confirmed that the block-copolymers were successfully adsorbed to the NFC. TGA results showed a higher thermal stability for the composite than for the TEMPO-NFC and quaternized block-copolymers. The block-copolymer modified NFC exhibited thermoresponsive behavior with LCST’s ranging from 30 to 44 °C, from higher to lower molecular weights, respectively.  Adsorption of polyelectrolytes in modified cellulose could be a promising way to create smart improved materials in further research.

This thesis focuses on the surface patterning by using nanoporous block copolymer (BCP) stamps. Polystyrene‐block‐poly(2‐vinylpyridine) (PS‐b‐P2VP) was used as model BCP. Nanoporous BCP stamps were fabricated by replication of lithographically patterned silicon molds. Nanopores inside of BCP stamps were generated by swelling‐induced pore formation. A method for scanner-based capillary stamping (SCS) with spongy nanoporous BCP stamps was developed. First, in the course of stamps design using replication molding of PS-b-P2VP against surface-modified macroporous silicon molds, PS-b-P2VP fiber rings remaining on the macroporous silicon molds were obtained that allow immobilization of water drops on the hydrophobically modified surfaces of the macroporous silicon molds. Water drops immobilized by these rings can be prevented from dewetting within the PS‐b‐P2VP fiber rings. Second, after spongy nanoporous PS-b-P2VP stamps had been obtained, preliminary experiments with non-inked PS-b-P2VP stamps revealed that parts of the stamps’ contact elements can be lithographically transferred onto counterpart surfaces. As a result, arrays of nanostructured submicron PS‐b‐P2VP dots with heights of ∼100 nm onto silicon wafers and glass slides were produced. Lastly, the SCS technique was developed, which overcomes the limitation of time-consuming re-inking procedures associated with classical soft lithography including microcontact printing (µCP) and polymer pen lithography (PPL) with solid stamps, as well as the limitations regarding throughput of scanning probe‐based serial writing approaches such as nanoscale dispensing (NADIS) and other micropipetting techniques. In addition, sizes of stamped droplets can be controlled by adjusting surface wettability and dwell time.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18518号 / 工博第3910号 / 新制||工||1600(附属図書館) / 31404 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 澤本 光男, 教授 伊藤 紳三郎, 教授 中條 善樹 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM