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Observing and studying how life forms behave, i.e., their movement, adaptability, and so on, have enabled human beings to develop new technologies or optimize existing ones. One of the more noticeable phenomena in Nature is morphogenesis. Morphogenetic processes exist in different stages of biological development, from cellular division to tissue and organ formation. It is easy to observe shape development during mophogenesis due to emerging imaging techniques. However, it is hard to understand this process due to its complex organization, and the morphogenetic responses can be induced by a variety of chemicals or mechanical stresses and are subject to the stochastic fluctuation of the environment, making it even more difficult to acquire a fundamental understanding. It is natural to think of mimicking the complex biological process using simplified synthetic approaches. Endowing synthetic protocells with the ability to control their shape and motion autonomously would enable them to perform more like a biological system, but with less complexity. Creating synthetic morphogenesis would potentially further our understanding in biological morphogenetic processes. Moreover, we can borrow some of the morphogenetic functions in engineered materials to achieve a variety of applications, including artificial tissues, self-healing materials, controlled drug delivery, manipulation of soft robots, among others. In this dissertation, we used a synthetic cellular system controlled by a reaction regulated network that imitates the genetic control as a minimal model to understand the potential mechanisms of morphogenesis. Different simulation methods were used depending on the length scales of interest in each problem. We studied the following aspects of the minimal model system: (a) catalytic reaction induced local morphological control of amphiphilic diblock copolymer vesicles; (b) non-equilibrium control over the self-assembled structures of amphiphilic surfactants; and (c) diffusiophoretic/self-diffusiophoretic motion of colloidal particles in response to the concentration gradient field. The results obtained in this thesis work will provide a valuable road-map to guide future experiments.

No description available.

Amphiphilic block copolymers based on poly(ethylene glycol) (PEG) and poly(vinylidene fluoride) (PVDF) were synthesized by RAFT polymerization. The commercial poly(ethylene glycol) methyl ether (Me-PEG-OH, 20 Kg/mol) and difunctional polyethylene glycol (OH-PEG-OH, 20 Kg/mol) were used to synthesize diblock copolymers (Me-PEG-b-PVDF), and triblock copolymers (PVDF-b-PEG-b-PVDF) respectively. For the synthesis, the esterification reaction followed by the SN2 reaction was employed to make macro CTA (Me-PEG-XA, XA-PEG-XA, XA refers to the xanthate group). The macro CTAs were used further for VDF polymerization in dimethyl carbonate (DMC) inside the autoclave. Different molecular weights of the PVDF block (whether in the diblocks or the tribolcks) were obtained based on changes in the reaction time. The resulting block copolymers were molecularly characterized by FT-IR, 1H,19F-NMR, and SEC. The thermal properties were studied by DSC and TGA. Furthermore, the crystalline phase characterization was investigated by XRD and FT-IR. Being the obtained block copolymers are amphiphilic, their self-assembly was achieved by nanoprecipitation in DMF/water, and they were analyzed by DLS and TEM.

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Today, drugs are an integral part of healthy human life, with new drug entities being introduced every year in clinic. The advancement of drug development brings complexity and variation, in terms of both physical and chemical properties. Some of these physicochemical characteristics are many times suboptimal, eventually requiring robust delivery systems that can precisely deliver the drugs to the desired tissues. Although many materials have been studied for the generation of drug delivery systems, there is always a need for biomaterials with better properties that can translate into superior delivery systems. In this context, new drug delivery systems that are interface-engineered at materials level for better stability and delivery efficiency in vitro and in vivo are introduced in this dissertation. In the first part of the dissertation, novel oil/water interface-engineered amphiphilic block copolymer micelles that were previously introduced by our lab were assessed for their stability in the presence of various esterase enzymes present in serum and on blood vessel walls, normally encountered by drug delivery systems on route to the targeted tissues. I also assessed the vulnerability of the polymeric micelles in presence of enzymes typically present either inside the tumor cells or secreted in the tumor microenvironment. I revealed the selective stability of empty- and docetaxel-loaded polymeric micelles to enzymatic degradation en route/in tumors and I have correlated this selective stability with polymer structure and interfacial engineering mentioned above. The unique delivery capabilities of interfacial-engineered polymeric micelles were tested in vivo using a mouse model of triple negative breast cancer. We proved that our novel engineered triblock copolymer-based drug delivery systems are superior to similar delivery systems made out of standard diblock copolymer micelles and also to the clinically used Taxotere® formulation towards cancer cell killing and tumor treatment, without displaying any significant toxicity in experimental animals. The second part of the dissertation focuses on the development and assessment of a pyridinium-based pseudo-gemini surfactant that combined the high nucleic acid packaging capacity of pyridinium lipids with the high transfection efficiency of gemini surfactants while displaying a reduced associated cytotoxic effect. I have analyzed the temperature treatment on compaction of nucleic acids into lipoplexes and I have established a high temperature annealing method for this purpose. This novel formulation technique allowed a substantial reduction of the amount of amphiphiles required to compact a specific amount of nucleic acids. This in turn also reduced the cytotoxic effect associated with the use of pyridinium amphiphiles. The effect of inclusion of colipids to lipoplex compaction, the robustness and the transfection efficiency of the lipid/nucleic acid lipoplex systems were assessed in detail, and correlations between formulation composition and biological activity were established. I was also able to show for the first time that pyridinium pseudo-gemini surfactants were able to compact different types of nucleic acids, including pDNA, mRNA and siRNA at lower charge ratios than standard, state-of-the art formulations used for this purposes. I also showed that irrespective to the nucleic acid compacted within the lipoplexes, the novel amphiphiles can efficiently deliver the cargo into the targeted cells even in the presence of very high concentration of serum, a premise for future use of these amphiphiles and formulations in vivo. / Pharmaceutical Sciences

Cancer is currently the second most common cause of death in the world. Despite tremendous progress in the treatment of different forms of cancer, the five year survival rates for lung, colorectal, breast, prostate, pancreatic and ovarian cancers remain quite low. New therapies are urgently needed for the better management of these diseases. In this context, both therapeutic gene and drug delivery constitute promising approaches for cancer treatment and are addressed in this thesis. Focusing on gene delivery, we are proposing the use new pyridinium amphiphiles for obtaining gene delivery systems with improved stability and efficiency and low toxicity (Chapters 2 and 3). The main focus was on pyridinium gemini surfactants (GSs), which possess a soft charge, a high charge/mass ratio and a high molecular flexibility - all key parameters that recommend their use in synthetic gene delivery systems with in vitro and in vivo efficiency. In Chapter 2, we optimized a novel DNA delivery systems through interfacial engineering of pyridinium GS at the level of linker, hydrophobic chains and counterions. In Chapter 3, we tested the effects of blending pyridinium cationic GS into pyridinium cationic lipid bilayers and we have evaluated these blends towards plasmid DNA compaction and delivery process. We have also correlated the cationic bilayer composition with the dynamics of the DNA compaction process, and with transfection efficiency, cytotoxicity and internalization mechanism of resulted nucleic acid complexes. Toward improved drug delivery systems, we introduced new amphiphilic block copolymers synthesized from biocompatible and biodegradable segments. Although their capabilites for loading, transport and release of lipophilic substances stored in their hydrophobic cores are widely known, their stability in vivo is limited due to rapid degradation by esterases present in the body. In Chapter 4, we examined the possibility to increase the enzymatic stability of PEG-PCL macromolecular amphiphiles through interfacial engineering, in a process which separates the hydrophilic/hydrophobic interface from the degradable/non-degradable block interface. We evaluated the stability, toxicity, drug loading and release properties of these new polymers using docetaxel as a model chemotherapeutic drug. The results revealed how hydrophilic/ hydrophobic interface tuning can be used to adjust key properties of polymeric drug delivery systems of this type. / Pharmaceutical Sciences

<p> Block copolymers are a class of soft materials which can self-assemble into a variety of ordered structures. One method to induce new structures is the application of an external field such as an electric field. Previously, studies of the field-induced phase transitions are based on the assumption that the structural change follows certain symmetry pattern or simply using real-space numerical methods. The goal of the current project is to develop a simple analytic method to predict the structural change. Our approach is based on a linear response theory, in which the external field is taken as a perturbation and the lowest-order contribution to the solution is computed. We applied our method to the Landau-Brazovskii theory which is valid close to the order-disorder transition point of diblock copolymers. The result shows that there will be an additional term to the order parameter as a response to the external field. The structural change can be predicted by a new Fourier expansion of the order parameter. As an example, we examined the structural change of a body-centered cubic phase under an applied electric field.</p> / Thesis / Master of Science (MSc)

Polymers containing poly(1,3-cyclohexadiene) were synthesized using a novel pre-formed initiator comprised of an alkyllithium and a tertiary diamine. The use of a pre-formed intiator at moderate temperatures (25° C) enabled the synthesis of high molecular weight poly(1,3-cyclohexadiene) homopolymers (<Mn> = 50000) with narrow molecular weight distributions (<Mw>/<Mn> = 1.20). In contrast, the use of a conventional anionic initiation approach resulted in polymerizations that lacked significant degrees of livingness, which limited the polymer molecular weights to approximately 10000. Use of the preformed initiator resulted in a reduction in the degree of both chain termination and chain transfer. In addition, the livingness of the polymerization was shown to be a function of the monomer concentration and the polymerization temperature. The regiochemistry of the polymers were shown to be dependent on the tertiary amine used in the polymerization, which provided a route for the synthesis of polymers with a microstructure rich in either high 1,2-addition (70%) or high 1,4-addition (90%). A range of analytical methods were employed to determine the stereo and regiochemistry of poly(1,3-cyclohexadiene). These methods included 1H NMR, 13C NMR, and endgroup functionalization of the propagating center with chlorotrimethylsilane. The impact of regiochemistry on the thermal properties was examined using differential scanning calorimetry. In addition, the thermooxidative properties of these poly(1,3-cyclohexadiene) polymers were characterized in a series of oxidative studies and the onset of oxidative degradation occurred at 110° C. Perfectly alternating copolymers of poly(1,3-cyclohexadiene-alt-styrene) were synthesized, and the reactivity ratios for these copolymers (r1,3CHD = 0.022, rstyrene = 0.024) were determined using a conventional Mayo-Lewis approach. The effect of aromatization and hydrogenation on the thermal properties of these copolymers was determined using thermal gravimetric analysis and differential scanning calorimetry. The synthesis of poly(1,3-cyclohexadiene) DVB coupled star-shaped polymers was performed using a convergent arm-first approach in combination with a divinylbenzene coupling agent (PDI = 1.25). Well-defined poly(1,3-cyclohexadiene-block-isoprene)-star shaped polymers were synthesized and utilized for the development of novel high temperature thermoplastic elastomers, with excellent elastomeric properties (percent elongation = 745 %, tensile strength = 7.2 MPa). Atomic force microscopy in combination with differential scanning calorimetry verified the presence of microphase separation between the blocks. / Ph. D.

The synthesis of a variety of novel functionalized polymers using living polymerization techniques to achieve functional and stimuli responsive coatings on silica surfaces are described. Since microscopic features on a surface influence the overall wetting properties of the surface, a systematic investigation of the influence of polymer architecture on the microscopic characteristics of the modified surfaces was studied using silane-functionalized linear and novel star-branched polystyrene (PS). Star-branched modifiers provide functional and relatively well-defined model systems for probing surface properties compared to ill-defined highly branched systems and synthetically challenging dendrimers. Using these simple star-shaped macromolecules it was shown that the topographies of the polymer-modified surfaces were indeed influenced by the polymer architecture. A model explaining the observed surface features was proposed. A living polymerization strategy was also used to synthesize centrally functionalized amphiphilic triblock copolymers. The amphiphilic copolymers exhibited stimuli responsive changes in surface hydrophobicity. In spite of multiple solvent exposures, the copolymer films remained stable on the surface indicating that the observed changes in surface properties were due to selective solvent induced reversible rearrangement of the copolymer blocks. The chemical composition of the copolymers was tailored in order to tune the response time of the surface anchored polymer chains. Thus, the polymer coatings were used to reversibly change the surface polarities in an on-demand fashion and could find possible applications as smart adhesives, sensors and reusable membrane devices. In contrast to the afore-mentioned covalent modification approach, which often leads to permanent modification of surfaces, renewable surfaces exhibiting "universal" adhesion properties were also obtained through non-covalent modification. By employing hydrogen bonding interactions between DNA bases, surfaces functionalized with adenine groups were found to reversibly associate with thymine-functionalized polymers. This study describing the solvato-reversible polymer coating was the first demonstration on silica surfaces. A systematic investigation of the influence of surface concentration of the multiple hydrogen bonding groups and their structure on the extent of polymer recognition by the modified surfaces is also discussed. / Ph. D.