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Hydrogen sulfide (H2S) is an endogenously produced signaling gas involved in numerous cellular functions. At the appropriate concentration, exogenous administration of this gasotransmitter regulates vasodilation, promotes angiogenesis of endothelial cells, and generally exhibits beneficial effects as an anti-inflammatory and antioperoxidative agent. H2S is also capable of acting as a gaseous chemotherapeutic agent. Therefore, the therapeutic potential of exogenous delivery of H2S is vast. The delivery of H2S is complicated by its gaseous nature. Under physiologically relevant conditions, H2S is rapidly depleted from solution by oxidation and/or degassing. Therefore, direct exogenous delivery is difficult. To date, most studies have employed Na2S as a convenient H2S source. However, the rapid surge in H2S concentration upon Na2S dissolution followed by its rapid decline poorly mimics the sustained production of low concentrations of H2S that occurs in biological systems. We synthesized a library of S-aroylthiooximes (SATOs)—H2S-releasing compounds that more aptly mimic in vivo H2S concentrations. SATOs are synthesized via reaction of a S-aroylthiohydroxylamine and an aldehyde or ketone. SATOs release H2S in response to a thiol functionality. H2S release from SATOs could be controlled, with H2S release half-lives on the order of minutes to hours. SATO chemistry was utilized to prepare H2S-releasing polymers. Copolymers prepared using RAFT polymerization could be functionalized with SATOs with conversions > 99%, and these polymers released H2S on a similar timescale to our small molecule donors, confirming the viability of SATO formation as a post-polymerization modification strategy. SATO-functionalized polymer amphiphiles were prepared that self-assembled into micelles or vesicles based on their composition. H2S was released from these polymer assemblies more slowly than from the small molecules and statistical polymers. These H2S-releasing micelles were employed in in vitro cytotoxicity studies. H2S released from the micelles was found to be selectively toxic to human colon cancer cells compared with healthy fibroblasts. These polymeric micelle donors outperformed existing H2S donors in terms of their toxicity towards cancer cells. The observed enhanced toxicity was suspected to arise from the slow and sustained release of H2S from the micelles. / Ph. D. / Hydrogen sulfide (H2S) is biologically relevant gas involved in numerous cellular functions. At the appropriate concentration, administration of this gasotransmitter exhibits potentially beneficial effects in multiple biological systems. H2S is also capable of acting as a gaseous chemotherapeutic agent. Therefore, the therapeutic potential of H2S is vast. The delivery of H2S is complicated by its gaseous nature. Under physiologically relevant conditions, H2S is rapidly depleted from solution by oxidation and/or degassing. Therefore, direct external delivery is difficult. To date, most studies have employed used sulfide salds as a convenient H2S source. However, these poorly mimic the production of low concentrations of H2S that occurs in biological systems. We synthesized a library of S-aroylthiooximes (SATOs)—H2S-releasing molecules that more aptly mimic H2S concentrations in the body. SATOs can be triggered to release H2S by biologically relevant compounds. H2S release from SATOs could be controlled over minutes to hours. SATO chemistry was utilized to prepare H2S-releasing polymers. Copolymers were prepared using and functionalized with SATOs, and these polymers released H2S on a similar timescale to our small molecule donors. SATO-functionalized nanoparticles were also prepared. H2S was released from these nanoparticles assemblies more slowly than from the small molecules and polymers. H2S released from the micelles was found to be selectively toxic to human colon cancer cells compared with healthy cells. These nanoparticle donors outperformed existing H2S donors in terms of their toxicity towards cancer cells. The observed enhanced toxicity was suspected to arise from the slow and sustained release of H2S from the nanoparticles.

Cancer remains a leading cause of death in the United States. The most common treatment options include chemotherapy, but poor solubility, adverse side effects and differential drug sensitivity hamper clinical applications. Current chemotherapy generally aims to deliver drugs at the limit of toxicity, assuming that higher dosage increases efficacy, with little attention paid to potential benefits of tunable release. Growing evidence suggests that releasing drugs at a constant rate will be as effective as a single bolus dose. To test this hypothesis, it is critical to develop drug delivery systems that fine-tune drug release and elucidate the impact of tunable drug release rates on chemotherapeutic efficacy. Block copolymer micelles, spherical nanoassemblies with a core-shell structure, are widely used in recent research. Micelles for this study were engineered to release a model drug (doxorubicin: DOX) at differential rates under acidic conditions, corresponding to tumor tissue (pH < 7). Three specific aims were pursued: to develop drug carriers capable of tuning drug release rates; to determine activity of developed carriers in vitro; and to elucidate effects of tunable drug release rates in vivo. Block copolymers with covalently linked DOX were synthesized and self-associated, forming micelles. Drug binding linkers (glycine, aminobenzoate, or hydrazide) were used to tune release of DOX. Micelles were characterized to determine physicochemical properties such as particle size, drug entrapment yields, and drug release parameters. Characterization revealed that drug release profiles were modulated by interchanging drug binding linkers. Micelles were evaluated in vitro to elucidate the effect of tunable drug release. Micelles delivered drugs at a slower, prolonged rate compared to free DOX. Cytotoxicity and cellular internalization analysis revealed that by slowing release rates, micelles kill cells more efficiently. Biodistribution studies showed that micelles decrease DOX accumulation in peripheral tissue while increasing the maximum tolerated dose. Antitumor activity studies verified that micelles with slower release rates better suppressed tumor growth. This further confirms that release rates play a key role in chemotherapeutic efficacy. Therefore, this thesis provides better insights into the effects of tunable drug release in tumors, leading the way for improved chemotherapy treatments in the future.

No description available.

In the early 2000s, hydrogen sulfide (H₂S) was added to the family of molecules known as gasotransmitters, a class of endogenously produced and freely diffusing biological signaling molecules. Since this discovery, biologists and chemists have sought to understand the physiological roles of H₂S and to elucidate the potential benefits of exogenous H₂S delivery. As a result, many synthetic small molecule donor compounds have been created to deliver H₂S in response to various biologically relevant stimuli. Furthermore, macromolecular and supramolecular H₂S donor systems have been created to protect donors in the biological milieu, extend release kinetics, or control H₂S release conditions. Thus, H₂S-donating nanostructures with precisely tuned release rates provide invaluable tools for further investigating the biological roles and therapeutic potential of H₂S. This work describes two polymer micelle systems for the controlled delivery of H₂S. The first system is based on H2S-releasing polymer amphiphiles with varying degrees of a plasticizing comonomer incorporated into the core-forming block. The glass transition temperature of the core-forming block varied predictably with incorporation of the plasticizing comonomer. Accordingly, the half-life of H₂S release decreased from 4.2 h to 0.18 h with increasing core-forming block mobility. The second system is based on H₂S releasing polymer amphiphiles with varying degrees of crosslinking in the core-forming block. The crosslinked system was designed to achieve control over H₂S release rate with minimal dilution of donor in the core-forming block. The half-life of H₂S release increased from 117 min to 210 min with increasing crosslink density in the core-forming block, further demonstrating that H₂S release rates can be precisely controlled by tuning micelle core mobility. Beyond control over H₂S release rate, further study of the biological roles of H₂S requires donor systems with precisely triggered release. To this end, this dissertation also discusses efforts to investigate fundamental micelle–unimer relationships. This section includes an evaluation of the impact of core-forming block mobility on micelle–unimer coexistence utilizing a model polymer amphiphile system. Unimer populations correlated with glass transition temperatures of the core-forming block, suggesting the need to consider micelle core mobility when discussing polymer chain phase behavior of amphiphilic block copolymers. Finally, this work discloses new methods for the radical polymerization of poly(olefin sulfones) with control over molecular weight. POSs are a unique class of polymers with great potential for stimuli-responsive depolymerization to generate sulfur dioxide (SO₂), a signaling gas related to H₂S. / Doctor of Philosophy / Hydrogen sulfide (H2S) is commonly known for its pungent odor and toxicity. Despite this negative stigma, H2S has been revealed as a vital signaling molecule in both plants and animals. This discovery has prompted the coordination of biologists and chemists in an effort to better understand the roles of H2S in the body. Driven by this motive, great interest has centered around the development of finely tuned molecules designed to generate H2S in the body, termed H2S donors. A variety of synthetic H2S donors have been reported with various conditions enabling release. Building on this work, the development of polymeric H2S donors with tunable release rates will enable investigation into the complex behavior of H2S in the body. The first half of this dissertation focuses on the design and synthesis of two polymeric H2S donor systems for the controlled release of H2S. These systems take advantage of sequestering the H2S donating species inside a polymeric nanostructure in water called a micelle. Because H2S release requires a triggering molecule to enter the polymeric nanostructure, release rate can be tuned by modifying the mobility of the structure. The first system discussed demonstrates this concept by increasing the flexibility of the micelle core. As expected, H2S release rates increased with increasing flexibility. The second system discussed advances this idea by limiting mobility within the micelle core, rather than increasing flexibility. Accordingly, H2S release rates decreased with decreasing mobility within the micelle core. The latter half of this dissertation broadly explores the development of polymeric signaling gas delivery vehicles with triggered release conditions. We first investigate the impact of polymer chain flexibility on the formation of micelles in water. Polymer chain flexibility significantly impacted the balance between micelles and unassembled polymer chains in solution, suggesting the need to consider this characteristic when designing donor systems for precise release conditions. Lastly, we discuss the development of controlled polymerization techniques for poly(olefin sulfones). We envision that poly(olefin sulfones) will be a useful class of polymers in the design of donor systems relying on triggered depolymerization for release of the signaling gas sulfur dioxide.

In this diploma thesis were studied solubilization properties of polysaccharides by using hydrophobic solutes (Sudan Orange G, Sudan Red G, (±)-alpha-Tocopherol, Pyrene, Perylene, Nile red), which were represented by alkyl derivates of hyaluronan. At first, a behaviour of individual hydrophobic solutes was investigated in variously polar solvents (Methanol, 1 Propanol, Chloroforme, Cyklohexane, n Heptane) and in the environment of varying ionic strength (water, 0.1 M and 0.4 M NaCl). Afterwards, solubilization properties of Sodium Dodecyl Sulfate model solubilizated the hydrophobic solutes into a core of micelles was examinate. We were interested in the solubilization capacity as the mol of solubilized molecules per mol micelles of surfactant corresponding with a state of micelles saturation. In the case of the solubilization of (±)-alpha-Tocopherol into the core of micelles, it was not possible to determine the solubilization capacity. So we changed the determination of universally solubilization power. The solubilization power is defined as mol of molecules solubilized per mol surfactant relative to the quantity solubilizate at the micelles saturation. Model system of Sodium Dodecyl Sulfate as a simple surfactant carrying a negative charge as the alkyl derivates of hyaluronan was selected bacause of its characteristics.The surfactant forms unimolar micelles and its critical micelle concentrations and aggregation numbers are tabelated for the investigated microenvironment. The main aim of the study was investigating of hydrophobic domains of alkyl derivates of hyaluronan as free places for incorporation hydropbobic solutes in the microenvironment of varying ionic strength. The critical aggregation concentrations were determined by the Pyrene 1:3 ratio method. For the research of micropolarity of alkyl derivates hyaluronan’s domains were selected two concentrations of derivates for the next research of solubilization experiments - the first concentration near the critical aggregation concentration and the second concentration above it. The effect of concentration of Pyrene on a core polarity of derivates was investigated. We discovered the influence of the concentration and the other we found a stationary area of the concentration. In the end we investigated the influence of preparation of solutions of derivates of hyaluronan on the core polarity by the concentration of pyrene which corresponds to the stationary area. The study of solubilization properties of alkyl derivates of hyaluronan is not a simple case as we assumed. When we measured spectra of the absorbance, higher concentration of derivates of hyaluronan belittle absorbance of solubilizates. At the experiment of solubilization with Sudan Red G we found out that Sudan Red G is not able to solubilizate into the hydrophobic core of micelles of hyaluronan’s derivates because of lipophilic or steric effects. We had to change Perylene as a new solubilizate. From the measured emission spectra we found saturation micelles. We can express the solubilization power of hyaluronan’s derivates for the concentration of Perylene. The main aim of the diploma thesis was to determine optimal way of the preparation of hyaluronan’s derivates solutions with required degree of solubilization.

Les nano-objets hybrides ou polymères connaissent un intérêt grandissant depuis plusieurs années mais peu sont étudiés sous irradiation. Dans ce travail, différents nano-objets ont été synthétisés et étudiés pour comprendre leur stabilité face à des rayonnements ionisants. Nous avons étudié l’effet de l’irradiation sur des copolymères à blocs amphiphiles pouvant s’organiser en micelles dans l’eau. Les objets varient par la nature de leur polymère hydrophobe et leur sensibilité aux rayonnements ionisants. Dans un cas, des polyméthacrylates ont été copolymérisés par ATRP à partir d’un PEG macro-amorceur. Dans un autre cas, pour accentuer l’effet de l’irradiation, un polysulfone aliphatique plus radiosensible, a été synthétisé via une polyaddition thiol-ène. Après nanoprécipitation, les objets ont été caractérisés avant et après irradiation par des techniques de diffusion et de chromatographie. En parallèle, on s’est intéressés également à des nanoparticules métalliques connues pour augmenter l’effet de l’irradiation. Des nanoparticules d’or greffées de polymères ont été synthétisées par voie « grafting to » après synthèse de macro-ligands par polymérisation radicalaire contrôlée. Après une caractérisation fine des objets, l’effet de l’irradiation a été étudié à la fois sur la taille des objets et la masse des polymères afin de déterminer la nature des phénomènes mis en jeu. / Hybrid and polymer nano-objects have known a growing interest these last years but few are studied under irradiation. In the present work, different nano-objects have been synthetized and studied to understand their stability towards ionizing rays. We have studied the effect of irradiation onto amphiphilic bloc copolymer that form micelles in water. Objects were varied by the nature of their hydrophobic bloc and their sensibility to ionizing rays. First, methacrylates were copolymerized by ATRP with a PEG macro-initiator. Secondly, to improve radiation effect, a more radiosensitive polymer, a polyolefinsulfone, was synthetized by a thiol-ene polyaddition. After nanoprecipitation, objects were caracterized before and after irradiation by scattering and chromatography techniques. In parallel we also studied metallic nanoparticles well known for improving irradiation effect. Polymer-grafted gold nanoparticles were synthetized via a “grafting to” technique, after the synthesis of macro-ligands by controlled radical polymerization. After a precise characterization of these objects, irradiation effect has been studied via changes in size and polymer mass. This will permit to determine the nature of induced phenomena.