Master of Science (MS), Bowling Green State University, 2021, Biological Sciences

Using bacteria in cancer therapies is an emerging area of research. Certain bacteria can target tumors, and therapy can involve either the direct (colonize, invade, and deplete metabolic nutrients) or indirect action (deliver a therapeutic payload or "uncloak" the tumor to the immune system) of the bacteria. However, many of the best-suited bacterial species are pathogenic and require extensive genetic engineering to reduce or eliminate their pathogenicity before they can be used therapeutically. The facultative anoxygenic photoautotroph Rhodobacter sphaeroides is non-pathogenic, and has been shown to target tumors. We have been investigating its use as a vector for delivering 5-aminolevulinic acid (ALA) to tumors, where it functions as a prodrug in photodynamic therapies. ALA is a precursor in the formation of heme, and elevated concentrations delivered to tumor cells leads to overproduction of all products in the heme biosynthetic pathway, including precursor tetrapyrroles. In the presence of oxygen and therapeutic wavelengths of light, these molecules generate reactive oxygen species that destroy the tumor cells. R. sphaeroides naturally produces copious amounts of ALA for heme and bacteriochlorophyll synthesis needed to support photosynthetic growth. Prior studies have already shown that it is possible to engineer these bacteria to produce and excrete ALA in amounts that are suitable for photodynamic therapy (Zeilstra-Ryalls, 2013, unpublished results). A survey of wild type strains to identify which one grows best phototrophically under simulated intratumoral conditions was performed. By disrupting the genes in the optimal strain that code for ALA synthase enzymes a mutant was created that relies upon exogenous ALA for growth. Its minimal ALA requirement, as well as its ability to tolerate the presence of high concentrations of ALA under phototrophic conditions was then assessed. The latter was necessary in order to determine wheth (open full item for complete abstract)

Committee: Jill Zeilstra-Ryalls Ph.D (Advisor); Raymond Larsen Ph.D (Committee Member); Vipaporn Phuntumart Ph.D (Committee Member) Subjects: Biology; Biomedical Research; Microbiology; Molecular Biology; Oncology

Master of Science (M.S.), University of Dayton, 2025, Chemistry

Photodynamic therapy (PDT) is an exciting and emerging field of cancer treatment that acts in a much more selective manner via targeted cellular localization and localized irradiation to activate a photosensitizing drug in order to generate reactive oxygen species (ROS) that ultimately lead to cell death. Evidence has suggested that the endoplasmic reticulum (ER), one of the largest and most important cellular organelles, could be an important target in PDT. Interested in that idea, and to the ends of creating new photosensitizers (PS) that might accomplish this goal, a new far-red light activated iodo-substituted boron dipyrromethene (BODIPY) fluorescent dye capable of subcellular localization within the ER, producing high quantum yields of ROS is herein reported. As such, the following research has found that the generation of reactive oxygen species within the ER, caused by this BODIPY (BDP-1I) evokes oxidative stress, which in turn causes immunogenic cell death. The synthesis, characterization, spectroscopic properties, and cellular studies are thoroughly presented. The ability of this BODIPY dye, and its congener (BDP-1), to act as a PDT agent in breast cancer cells suggests promising organelle-targeted therapeutics that could help push the field of PDT to new heights.

Committee: Shawn Swavey (Advisor) Subjects: Chemistry

Doctor of Philosophy, Case Western Reserve University, 2025, Biomedical Engineering

Due to recent advancements in the field of cancer imaging and diagnostic techniques, most solid human cancers are diagnosed at earlier stages while the cancer is still localized to a primary tumor site. For this reason, surgery remains the cornerstone of curative treatment with the primary objective of surgical intervention being the complete removal of the tumor, aiming to eliminate cancerous tissues. Ideally, this goal is achieved in a single surgical procedure, ensuring no residual malignant tissue remains. However, achieving complete resection can be challenging, particularly in traditional surgeries where surgeons primarily rely on gross visual inspection and tactile feedback to identify and remove the tumor. This increases the risk of leaving behind microscopic cancer cells that are not visible or palpable during the procedure. As a result, there is a significant risk of Positive Surgical Margins (PSMs), where cancer cells are present at the edge of the resected tissue. PSMs are a critical concern because they often result in tumor recurrence and necessitate additional treatments including adjuvant therapies, such as radiation therapy, chemotherapy and so on. These therapies, while essential for reducing the risk of recurrence, substantially increase the overall cost and complexity of treatment and add to the physical and emotional burden on patients, prolonging the recovery process and potentially impacting their quality of life. The challenge of achieving complete tumor resection underscores the need for improved surgical technologies and adjunct treatments that can enhance the live visualization of tumor removal and simultaneously treat the remaining tissues to reduce tumor recurrence and improve overall survival. To address these challenges, this research aims to enhance treatment strategies for prostate cancer (PCa) through innovative theranostic approaches utilizing Prostate-Specific Membrane Antigen (PSMA) as a key biomarker. PSMA is notably overex (open full item for complete abstract)

Committee: James Basilion (Advisor); Jeffrey Capadona (Committee Chair); Efstathios Karathanasis (Committee Member); John Letterio (Committee Member); Xinning Wang (Committee Member) Subjects: Biomedical Engineering; Oncology; Therapy

Master of Science (M.S.), University of Dayton, 2024, Chemistry

Two BODIPY dyes with varying substituents have been synthesized and characterized. Coordination of [Ru(bpy)2Cl]+ complexes to different N-atoms, depending on the structure of the dye, resulting in a series of BODPIY-Ru(II) complexes, RuBDP-1 and Ru2BDP-2. The spectroscopic and electrochemical properties of the BODIPY dyes and their Ru(II) analogs have been characterized. The electronic spectra of these compounds reveal the intense absorption typical of the (π-π*) transition localized on the BODIPY core. Additional metal-centered charge transfer transitions associated with the [Ru(bpy)2Cl]+ moieties are observed at higher energy compared to the BODIPY transitions. RuBDP-1 exhibits significant singlet oxygen generation determined using a singlet oxygen trap in acetonitrile solutions. Ru2BDP-2 demonstrates the ability to generate singlet oxygen within the PDT window; however, it is limited in its quantum yield of singlet oxygen which translates to its limited ability to photocleave cpDNA.

Committee: Shawn Swavey (Advisor); Justin Biffinger (Committee Member); Vladimir Benin (Committee Member) Subjects: Biochemistry; Chemistry

PhD, University of Cincinnati, 2023, Arts and Sciences: Chemistry

Iron is a critical resource in the environment. Marine bacteria have adapted to iron stress by producing siderophores, molecules with functional groups that have a high affinity for Fe(III). Other trivalent metals (M(III)), such as the Group IIIA metals, may also bind to siderophores. As redox-inactive metals, Al(III), Ga(III), and In(III) can compete for Fe(III) binding sites and disrupt cellular metabolism. The rising acidity of Earth's oceans is expected to increase the solubility and availability of Group IIIA ions, so their interactions with biological and biologically-inspired organic ligands are increasingly relevant. This dissertation explores the structure, spectroscopy, and stability of Group IIIA complexes with siderophore-inspired ligands bearing α-hydroxy acids (X-Sal-AHA), and investigates the photochemical reactivity of a nano-encapsulated Fe(III) complex with X-Sal-AHA. Al(III) and In(III) complexes with siderophore-inspired chelates bearing α-hydroxy acids, [X-Sal-AHA], have been prepared. Crystals of trinuclear and binuclear complexes of Al(III) with the [3,5-diCl-Sal-AHA] ligand have been characterized by X-ray crystallography, and their structures compared to previously published Ga(III), Fe(III), and U(VI) complexes with the same ligand. The structure of the trinuclear Al(III) complex is analogous to those found for Fe(III) and Ga(III). The carbonate-bridged binuclear Al(III) complex has a different pattern of chelation than either the trivalent metal complexes or the dimeric U(VI) complex. Mass spectroscopy results suggest that In(III) also forms a trinuclear complex, despite its similarity in size to U(VI). The Al(III), Ga(III), In(III), and Fe(III) complexes have been characterized by UV-Visible absorption spectroscopy, spectropolarimetry, and fluorescence emission spectroscopy, and these methods have been used to examine the stability of the Group IIIA complexes to water and to metal substitution by Fe(III). The [MIII3(3,5-diCl-Sal-AH (open full item for complete abstract)

Committee: Michael Baldwin Ph.D. (Committee Chair); David Smithrud Ph.D. (Committee Member); Allan Pinhas Ph.D. (Committee Member) Subjects: Chemistry

Doctor of Philosophy, The Ohio State University, 2022, Chemistry

Photochemotherapeutics can be created by accessing the excited states of Ru(II) polypyridyl complexes. Some excited state properties of these systems allow for processes such as photoinduced ligand exchange, in which a photolabile ligand is replaced with a solvent molecule upon excitation with light, or energy transfer, where the excited state can sensitize the generation of a reactive oxygen species (ROS), including singlet oxygen. The work herein applies these two features in photochemotherapy (PCT) and photodynamic therapy (PDT) as techniques to achieve cell death. These methods are new alternatives to traditional chemotherapeutics, such as cisplatin, which have several adverse side effects due to poor selectivity for cancer cells. A series of five ruthenium polypyridyl complexes of the type Ru(bpy)2P(PhR)3(CH3CN)]2+ (bpy = 2,2'-bipyridine) with triphenylphosphine derivatives, P(PhR)3 (R = OCH3, Me, H, F, CF3) were synthesized and characterized to further understand the effect of changes of electronic structure on the photodissociation of acetonitrile. Characterization methods include 1H and 31P NMR, ESI-MS, cyclic voltammetry, luminescence, and single-crystal X-ray diffraction. Photolysis of this series exhibits a clean transition from reagent to photoproduct for all five complexes. [Ru(bpy)2P(PhOMe)3(CH3CN)]2+ proved to be the most efficient at photosubstitution with a measured quantum yield, Ф400 of 0.076. In contrast, the photoinduced CH3CN dissociation measured for [Ru(bpy)2P(PhCF3)3(CH3CN)]2+ was the least efficient in the series, with Ф400 = 0.026. Quantum yields were compared with Hammett parameters, phosphine pKa values, 31P-NMR signals, and HOMO-LUMO gaps. These results show that more effective PCT Ru(II) complexes can be synthesized through the incorporation of electron donating substituents. Complexes [Ru(tpy)(qdppz)](PF6)2 (4.1; qdppz = 8-quinyldipyridophenazine, tpy = 2,2′:6′,2′′-terpyridine) and [Ru(qdppz)2](PF6)2 4.2 were characterized here (open full item for complete abstract)

Committee: Claudia Turro (Advisor); Kisha Radliff (Committee Member); Casey Wade (Committee Member); Hannah Shafaat (Committee Member) Subjects: Chemistry; Inorganic Chemistry

Doctor of Philosophy, The Ohio State University, 2022, Chemistry

Cancer is the second leading cause of death in the United States, killing an average of ~1,640 Americans per day in 2018. Rates of cancer deaths in the country have been steadily declining since the millennium due to widespread research efforts for more effective treatments, cures, new vaccines, targeted public health programs, and improved cancer screening, however, the disease is predicted to kill ~1,670 people per day in the United States in 2022. The anticancer drug cisplatin is used in approximately half of all chemotherapies and has played an important role in improving the survival of prostate cancer patients, increasing 5-year survival rates from ~50% in the 1960s to >95% in 2016. However, cisplatin has low specificity, making it toxic to healthy cells as well as cancerous cells, inflicting serious side effects on patients and demonstrating the need for selective cancer treatments. Light-based cancer treatments offer spatiotemporal selectivity absent in traditional cancer treatments by only activating drugs in an irradiated area. Importantly, this localized treatment prevents systemic toxicity. Photodynamic therapy (PDT) agents produce reactive oxygen species (ROS) upon irradiation which induce oxidative stress in cells that can lead to cell death. When these ROS are produced in a cancerous tumor, cell death prevents the spread of the cancer. This method is clinically approved and is realized with the drug Photofrin, an organic PDT agent used in the treatment of esophageal cancer. Ruthenium(II) complexes are excellent candidates for PDT agents as they possess long-lived excited states capable of producing ROS, absorb light throughout the visible region, and possess highly tunable ligand structures. The Ru(II) polypyridyl PDT agent TLD-1433 successfully completed Phase I trials in humans for the treatment of bladder cancer, has recently entered Phase II trials, and looks to be promising for future Ru(II) PDT drugs. Ruthenium complexes are also capable of (open full item for complete abstract)

Committee: Claudia Turro (Advisor); Hannah Shafaat (Committee Member); Christine Thomas (Committee Member); Cristoph Lepper (Committee Member) Subjects: Chemistry; Inorganic Chemistry

PhD, University of Cincinnati, 2022, Arts and Sciences: Chemistry

Nanoparticles are defined as particulate materials with sizes ranging between 1-1000 nm. Because of the development of nanotechnology-based science, many significant milestones have been achieved for sensors and therapeutics in recent years. When it comes to sensors, not only has nanotechnology enhanced the selectivity and sensitivity in the detection of various analytes, but it has also enabled the development of simpler, faster, and portable devices. The development of nanoparticles for therapeutics is not far behind. Nanomaterial-based therapeutics have enhanced drug targeting, delivery, and specificity, which has led to significant improvements in the efficacy of treatments while keeping toxicity at low levels. Despite all the significant achievements obtained already by the incorporation of nanotechnology into sensors and therapeutics, these fields could benefit further from employing the next generation of nanoparticles. The focus of the research described here was on the synthesis, characterization, and better understanding of new nanoparticle-based sensors and therapeutics. More specifically, in Chapter 2, the use of a paramagnetic nanoparticle to detect oligonucleotides through nuclear relaxation was explored. The proof-of-concept presented in Chapter 2 widened the application of nuclear relaxation to different biotargets, such as enzymes and cells. Moreover, due to its simplicity, sensitivity, robustness, and portability, if further developed, the sensing scheme described in Chapter 2 has the potential to improve point-of-care diagnostics. Chapter 3 comprises the design, synthesis, and characterization of a singlet oxygen sensor based on the Singlet Oxygen Sensor Green (SOSG) working principle. In the presence of the target molecule, the fluorescence properties of the designed probe were changed, indicating its sensing capability. Despite the preliminary nature of the results presented in Chapter 3, they already provide a better un (open full item for complete abstract)

Committee: David Smithrud Ph.D. (Committee Member); Allan Pinhas Ph.D. (Committee Member); Michael Baldwin Ph.D. (Committee Member) Subjects: Chemistry

Doctor of Philosophy, University of Akron, 2021, Chemistry

Photodynamic therapy (PDT) has attracted significant attention as an alternative approach to traditional cancer therapies such as radiotherapy, chemotherapy, and surgery. PDT involves irradiating a drug (the photosensitizer) with a photon of light to generate singlet oxygen (1O2) that then proceeds to kill cancer cells. Porphyrin-based photosensitizers have been widely used in PDT. Porphyrins have a significant absorption in the visible region (400-700 nm), little dark toxicity, and long-lived triplet states that can lead to high singlet oxygen production. Porphyrins are known to accumulate in tumor cells in high concentrations, but aggregation, resulting from π-π stacking, often leads to a reduction in fluorescence and 1O2 quantum yields. Porphyrins are also highly hydrophobic, leading to low bioavailability and making intravenous administration difficult. Ground state curcumin analogs have been shown to have significant anti-cancer activity against various cancer lines, although these molecules have a low bioavailability due to poor absorption and fast metabolism. Four novel porphyrin-curcumin analog conjugates (1-4) have been synthesized (Figure 1) for use as photosensitizers in the photodynamic treatment of pancreatic ductal adenocarcinoma (PDAC) and lung cancer. Porphyrin-curcumin analog conjugates have several advantages over the individual components: (1) improvement of stability, bioavailability, and tumor site accumulation of curcumin analogs, (2) the presence of two flexibly connected chromophores that will prevent aggregation of the porphyrin component, improving both fluorescence and 1O2 quantum yields, (3) the presence of two chromophores that may maximize triplet-triplet energy transfer with 3O2 and improve 1O2 generation efficiency. Capecitabine (Xeloda) and Gemcitabine (Gemzar) are standard chemotherapeutic agents for pancreatic cancer patients. However, Capecitabine and Gemcitabine are highly water-soluble drugs; so, they are rapidly removed from t (open full item for complete abstract)

Committee: David Modarelli (Advisor); Claire Tessier (Committee Member); Leah Shriver (Committee Member); Jordan Renna (Committee Member); Chrys Wesdemiotis (Committee Member) Subjects: Organic Chemistry

Master of Science (MS), Wright State University, 2020, Pharmacology and Toxicology

Photodynamic therapy (PDT) involves the use of light at an appropriate wavelength acting on a photosensitizing chemical to cause cell death via generation of reactive oxygen species. PDT has been useful in the management of skin conditions (like acne, psoriasis) and cancers like superficial skin, esophageal and non-small cell lung cancers. In addition to these therapeutic effects, previous murine studies from our group have demonstrated that topical PDT induces immunosuppression in vivo. Thus, topical PDT of skin can generate systemic effects through unknown mechanisms. Our group showed that PDT induces an immunosuppressive effect which occurs partly via Platelet-Activating Factor Receptor (PAFR) signaling. Of importance, PAFR signaling can generate Microvesicle particles (MVP). MVPs are small extracellular membrane-enclosed particles believed to mediate cell-to-cell communication via the transport of bioactive signaling substances. The present studies tested if PDT could generate MVP release. Our studies used in vitro, ex vivo (human skin explants) and in vivo (murine) models. PDT increased MVP release across the different cell lines tested in vitro as well as treatment of human skin explants ex vivo. Murine studies also revealed a significant increase in MVP levels in skin and blood following PDT treatment. We also found a limited role for PAFR in this PDT-generated MVP release. These studies reveal a consistent production of MVPs following PDT and thus, provide insights into a possible novel mechanism whereby PDT exerts systemic effects via the generation of MVPs.

Committee: Jeffrey B. Travers M.D., Ph.D. (Advisor); Ravi P. Sahu Ph.D. (Committee Member); Ji C. Bihl M.D., Ph.D. (Committee Member) Subjects: Biomedical Research; Medicine; Pharmacology

Doctor of Philosophy, The Ohio State University, 2019, Chemistry

With over one million new cases predicted for the year 2020 and an average five-year survival rate of only 66%, cancer remains one of the most challenging medical issues of our lifetime. Currently anticancer drugs such as cisplatin, while effective, offer limited selectivity for cancerous cells over healthy cells and cause severe systemic side effects. Photoactivated drugs offer significant advantages over traditional therapies, as they allow for precise spatial and temporal control over the delivery of a biologically active species from a prodrug using light. Developing such photoactivated drugs, however, requires a detailed understanding of their photophysical and photochemical properties after the absorption of a photon. Polypyridyl Ru(II) complexes are particularly suited for use as photoactivated drugs, as they exhibit intense absorptions in the visible spectrum and reactivity from several different excited states. This work examines the photochemistry of a series of Ru(II) complexes capable of killing cells through both the generation of reactive oxygen species as well as photoinduced drug dissociation. In addition, the photophysical and photochemical properties of nitrile-containing Ru(II) complexes are also studied in detail. The results presented herein reveal efficient photoinduced dissociation of nitrile ligands from mixed triplet metal-to-ligand charge transfer (3MLCT/ligand) excited states, instead of from the triplet ligand field (3LF) states traditionally thought to be responsible for ligand dissociation in Ru(II) complexes. Moreover, the complexes in this work that exhibit the greatest quantum yields of ligand dissociation also contain the most red-shifted absorption spectra (important for therapeutic use), demonstrating that efficient ligand dissociation can occur using red light with judicious choice of ancillary ligands, instead of requiring the introduction of a large degree of steric distortion.

Committee: Claudia Turro (Advisor); Hannah Shafaat (Committee Member); Terry Gustafson (Committee Member) Subjects: Chemistry; Inorganic Chemistry; Physical Chemistry

Master of Science (M.S.), University of Dayton, 2019, Chemistry

Cancer remains a significant obstacle in modern healthcare, and efforts are needed to discover and advance new treatment methods and compounds. Accordingly, two novel dipyrrin compounds, consisting of a heteroleptic monometallic ruthenium(II) complex and a heteroleptic trimetallic ruthenium(II) complex, were synthesized and characterized for use as photosensitizers in photodynamic therapy of cancer. In the monometallic complex, a π to π* transition is observed originating from the bipyridyl groups along with overlapping MLCT from Ru(dπ) to bpy(π*) and ligand centered transition occurring at a range between 520 nm and 600 nm. The trimetallic complex contains an expected π to π* dipyrrin transition at 294 nm and Ru(dπ) to bpy(π*) MLCT transitions at 355 nm and 502 nm. An intense transition occurring at 578 nm from overlapping dipyrrin π to π* and Ru(dπ) to dipyrrin(π*) is also observed. These transitions were predominantly analyzed through electrochemical and spectroelectrochemical experiments. Performance of the complexes was initially tested through irradiation in the 600 to 850 nm photodynamic therapy window while in the presence of plasmid DNA, with both complexes showing the ability to cause photo-damage to the DNA backbone. However, in the absence of oxygen, the trimetallic Ru(II) complex also generated photo-induced DNA damage, which is suggestive of a photo-oxidative Type I process. Cytotoxicity of the complexes up to 50 µM concentration towards A549 lung cancer cells was negligible in the absence of light. The trimetallic complex demonstrated significantly greater photo-cytotoxicity compared to the monometallic analog upon irradiation of the cells with a 420 nm low power light source. A dose dependent response curve results in an IC50 value of 92 µM for complex B.

Committee: Shawn Swavey (Committee Chair); Mark Masthay (Advisor); Angela Mammana (Advisor) Subjects: Biochemistry; Chemistry

Master of Science (M.S.), University of Dayton, 2019, Chemistry

The projects described in this thesis were focused on studying two aspects of singlet oxygen. The first is the ability of singlet oxygen to be generated by photosensitizers for use in photodynamic therapy and the second is the ability of singlet oxygen to be quenched with β-carotene. Photodynamic therapy (PDT) is a medical technique which utilizes a photosensitizing drug, light of a certain wavelength and molecular oxygen to generate singlet oxygen, a toxic oxidizing species. When present, singlet oxygen will rapidly react with surrounding biomolecules, causing cellular damage that ultimately leads to cell death. To the ends of creating a photosensitizer for PDT, a new pi-extended dipyrrin containing isoquinolpyrrole has been synthesized by solvent free reactions with trifluoroacetic acid (TFA) as a catalyst. The borondipyrrin (Bodipy) of the isoquinolpyrrole was synthesized by standard procedures followed by synthesis of the bis-ruthenium(II) Bodipy analog. The spectroscopic properties of this complex show the typical intra-ligand charge transfer transitions (ILCT) along with the Ru(π) to ligand(π*) metal to ligand charge transfer (MLCT) transitions. An intense transition at 608 nm with molar absorptivity greater than 100,000 M-1 cm-1 associated with the ππ* transition of the Bodipy core is observed. In acetonitrile solutions the bis-Ru(II)-Bodipy complex generates significant singlet oxygen when irradiated with low energy light. In aqueous solutions the complex is capable of photo-nicking plasmid DNA when irradiated within the photodynamic therapy (PDT) window of 600 to 850 nm. β-carotene (βC) is an orange pigment present in the photosynthetic reaction center (PRC) of green plants, where it plays a vital role in photosynthesis: It quenches singlet oxygen before it damages chlorophyll and other components of the PRCs. During photosynthesis, βC temporarily converts from its native orange–450 state to a pink–515 state via the so–called 515nm Effect. Because of (open full item for complete abstract)

Committee: Shawn Swavey PhD (Committee Co-Chair); Mark Masthay PhD (Committee Co-Chair); Jeremy Erb PhD (Committee Member) Subjects: Chemistry; Inorganic Chemistry; Physical Chemistry

Doctor of Philosophy, The Ohio State University, 2018, Chemistry

Photoinduced ligand exchange is a phenomenon that has been observed in Ru(II) polypyridyl complexes, where upon excitation with visible light, a bond between the metal and ligand is broken, the ligand is released, and the resulting open coordination site on the metal is filled by a solvent molecule. The work herein describes the application of photoinduced ligand exchange in compounds designed to possess dual activity against cancer and other diseases in the form of a combination of photochemotherapy (PCT) and photodynamic therapy (PDT). The poor selectivity of conventional chemotherapy drugs, such as cisplatin, lead to several negative side effects. PCT and PDT agents offer an alternative to traditional chemotherapy with increased selectivity, since the compound is only active in tissue that is exposed to light. In addition, photoinduced ligand exchange can to applied to photoactivation of fluorescent dyes, such that when the dye ligand is tethered to the Ru metal center its emission quneched. Upon irradaition with visible light, the dye ligand is released or "uncaged", turning on its emission. Most of the photoactivatable dyes reported to date feature organic caging groups that require high energy UV light to release the caged molecule and activate its fluorescence. This is not ideal for biologial applications since high energy UV light can cause damage to living systems. Therefore, Ru(II)–dye complexes, were synthesized and characterized. Before photolysis, the Ru(II)-dye complexes were weakly emissive due to quenching by the Ru(II) center.

Committee: Claudia Turro (Advisor) Subjects: Chemistry

Doctor of Philosophy, The Ohio State University, 2017, Chemistry

Cancer is a disease that affects the lives of millions of people across the word. Current FDA approved treatments are not targeted enough to only treat the cancer without producing systematic toxicity and severe side effects, clearly showing that drugs that are more selective for cancer are needed. Photodynamic therapy (PDT) and photochemotherapy (PCT) were developed as a means to better target cancer only. Both PDT and PCT utilize a laser light source to activate a sensitizer at the location of the cancer, this allows for spatiotemporal control. Between the two therapies, three mechanisms of action can be attained: singlet oxygen production, ligand exchange for the ability to bind to biomolecules, or redox chemistry with DNA or biomolecules. Other ways to target cancer are also being explored through selective DNA mismatch detection. The work herein will focus on developing Rh2(II,II) complexes as potential PCT agents as well as targeted mismatch DNA detectors. Cis-H,H-[Rh2(OCCH3NH)2(LL)(CH3CN)4]2+ (LL = dppz, 1 and dppn, 2) were synthesized and characterized. Irradiation of complexes 1 and 2 followed by 1H NMR showed that the photoproducts Cis-H,H-[Rh2(OCCH3NH)2(CH3CNeq)(D2Oeq)(DD)]2+ (DD = dppz, 5a and dppn, 6a) were produced as 1 equivalence of CH3CN was exchanged for a D2O molecule. Complex 2 was found to have a 0.0033(1) photo-aquation quantum yield when measured with 450 nm irradiation. This was found to be an order of magnitude smaller compared to complex 1, which was measured to be of 0.040(3) with 450 nm irradiation. The lower photo-aquation quantum yield of 2 arises from the fact that it has other pathways to deactivate because it can also produce 1O2. Quantification of 1O2 production for 2 was determined to be 0.22(7), which is still better than the FDA approved Photofrin®. Thermal denaturation and relative viscosity studies with complex 2 show a p-stacking interaction with double-stranded DNA consist with intercalation, but titrations done with the (open full item for complete abstract)

Committee: Claudia Turro (Advisor) Subjects: Chemistry

PhD, University of Cincinnati, 2017, Arts and Sciences: Chemistry

In this dissertation, I first developed and optimize an upconversion nanoparticles-based DNA detection scheme on different target DNA sequences, and then I explored the syntheses and characterizations of a nanomaterial-photosensitizer platform used for photodynamic therapy of cancer cells and bacteria in vitro. In the first project, a novel ligase-assisted signal-amplifiable DNA detection scheme is demonstrated based on luminescent resonance energy transfer between upconversion nanoparticles and the intercalating dye, SYBR Green I. Target DNA serves as a template for two DNA probes, one of them covalently attached to upconversion nanoparticles, to be joined into a long, hairpin-forming DNA by ligase. The number of the resulting DNA strand, which brings SYBR Green I close to the upconversion nanoparticles, is amplified through thermal cycling. The method was proven to display high sensitivity and specificity for DNA detection. Factors affecting the detection specificity and sensitivity, including ligation temperature, the amount of ligase, and the number of thermal cycles, have been investigated to optimize the performance of the detection method. Based on our result, the detection scheme can easily differentiate the BRAF V600E mutation from the wild-type sequence with a mutant-to-wild-type ratio of 1:1000. A detection limit of 1 fmole BRAF V600E mutation is achieved. While for the target sequence of EGFR T790M, the differentiate ratio is 1:100. The results show that 0.01 pmole of EGFR T790M mutant can be readily detected. In the second project, I report a hybrid singlet oxygen production system, where strong resonance coupling between silver nanoparticles and photosensitizing molecules results in exceptionally high singlet oxygen production under both visible light and near-infrared light excitation, even for the photosensitizing molecules without near-infrared absorption. Also, our results indicate that the hybrid photosensitizers display low cytotoxicity wi (open full item for complete abstract)

Committee: Peng Zhang Ph.D. (Committee Chair); William Heineman Ph.D. (Committee Member); Pearl Tsang Ph.D. (Committee Member) Subjects: Nanotechnology

Doctor of Philosophy, Case Western Reserve University, 2017, Chemistry

Sulfur-substituted purine and pyrimidine nucleobases—also known as thiobases—are among the world's leading prescriptions for chemotherapy and immunosuppression. Long-term treatment with some of the purine derivatives of these drugs has recently been correlated with the photo-induced formation of carcinomas. Establishing an in-depth understanding of the photochemical properties of these thiobase drugs may provide a route to overcoming these carcinogenic side effects, or, alternatively, may provide a basis for developing highly-effective compounds for targeted photochemotherapy. In this thesis work, a broad investigation is undertaken, surveying the excited-state dynamics and photochemical reactions of nearly every sulfur-substituted analog of the canonical DNA and RNA nucleobases. The thiobase derivatives are investigated using time-resolved absorption and emission spectroscopies in the femtosecond (10-15 s) to microsecond (10-6 s) time window. Coupling these experiments with quantum chemical calculations, we have developed a molecular-level understanding of how sulfur-substitution so drastically perturbs the photochemical properties of the nucleobases. The structure-property relationships established by this work demonstrate the impact of site-specific sulfur substitution on the population and reaction dynamics of the excited triplet state. Some of the most photoreactive derivatives identified are applied to human epidermoid carcinoma cells and shown to effectively decrease their proliferation upon exposure to a low dose of light. The results presented in this body of work demonstrate the utility of fundamental photochemical investigations for driving the development of next-generation photochemotherapeutics, while simultaneously elucidating overarching principles for the impact of sulfur substitution (thionation) on the photochemical properties of organic chromophores.

Committee: Carlos Crespo-Hernández (Advisor); Mary Barkley (Committee Chair); Clemens Burda (Committee Member); Geneviève Sauvé (Committee Member); Nancy Oleinick (Committee Member) Subjects: Analytical Chemistry; Biochemistry; Chemistry; Experiments; Molecules; Pharmaceuticals; Physical Chemistry; Quantum Physics

Doctor of Philosophy, Case Western Reserve University, 2016, Biomedical Engineering

Each year, one million new cases of cancer are diagnosed in the United States and each case is unique, making it hard disease to prevent and treat. In the past few decades, nanoparticles have emerged as a promising platform for the development of cancer therapies. Unlike small molecule drugs, nanoparticles can be both passively and actively targeted towards tumor sites (both primary and metastatic sites). Additionally, they are able to carry large cargos for delivery of monotherapy or combination therapy, while also decreasing systemic side effects often associated with small molecule cancer therapies. Nanoparticles in the clinic, as well as in clinical and pre-clinical trials have been predominantly spherical in shape. However, recent data suggest that high aspect ratio nanoparticles may have advantages for cancer treatment, including decreased uptake by phagocytic cells, improved margination, and enhanced tumor homing and penetration. Despite this, synthesis of these materials remains challenging using chemical approaches. Therefore, I turned to towards the study of plant virus-based nanoparticles, and my dissertation focused on the study and development of high aspect ratio viral nanoparticles. Specifically, I focused on the plant viruses tobacco mosaic virus (TMV) and potato virus X (PVX). My initial studies evaluated TMV as a model high aspect ratio nanoparticle and determined that it had improved diffusion into a 3D spheroid compared to a spherical virus. Additionally, I determined that it could be stably loaded with via non-covalent interactions with a cationic photosensitizer for photodynamic therapy. In the central body of my thesis I developed the filamentous virus PVX for cancer therapy. Stealth coated PVX filaments exhibited substantially extended circulation time, while also decreasing recognition by PVX-specific antibodies, an important step towards translation of this platform. Addition of targeting ligands on the surface of the PVX filament led to se (open full item for complete abstract)

Committee: Nicole Steinmetz Ph.D. (Advisor); Horst von Recum Ph.D. (Committee Chair); Ruth Keri Ph.D. (Committee Member); David Schiraldi Ph.D. (Committee Member) Subjects: Biomedical Engineering; Nanotechnology

PhD, University of Cincinnati, 2016, Arts and Sciences: Chemistry

The objective of my research is to develop multifunctional nanoparticles for sensing and photodynamic therapy applications. Ethylenediaminetriacetic acid (EDTA)-functionalized silica nanoparticles were synthesized by microemulsion method. The EDTA groups on the nanoparticle surface have the role to chelate with metal ions to form paramagnetic nanoparticles in aqueous solution, which would reduce the relaxation rate of water protons. In this study, SiO2@TMS-EDTA@Fe3+ NPs and SiO2@TMS-EDTA@Gd3 NPs were used for detection of dopamine and phosphate ion, respectively. The results demonstrate that paramagnetic nanoparticles can be integrated into relaxation based detection schemes while avoiding the aggregation problem commonly associated with more widely used superparamagnetic nanoparticles. Lanthanide-based NaYF4:Yb3+,Tm3+ upconversion nanoparticles were synthesized in the presence of polyacrylicacid (PAA) via solvothermal method. This is an one step synthesis method to get uniform, reproducible and biocompatible NaYF4:Yb,Tm upconversion nanoparticles with –COOH surface functional groups. In this study, we designed a ligase-assisted signal-amplifiable DNA biosensor based on NaYF4:Yb3+,Tm3+ UCNPs with high sensitivity and specificity. Silver nanoparticles captured by mesoporous silica nanoparticles with photosensitizer (Ag@MS@HPIX) were synthesized using silver nitrate as the silver source, formaldehyde as the reducing agent, CTAB as the template/stabilizer, TEOS/TMS-EDTA as the silane source, sodium hydroxide as the catalyst, and HPIX as the loading photosensitizer. Ag@MS@HPIX NPs show strong enhanced singlet oxygen generation because of the strong resonance coupling between surface plasmon Ag nanoparticles and the photosensitizing molecules, consequently demonstrating highly efficient photodynamic inactivation (PDI) efficacy against both gram-positive and gram-negative bacteria. In this study, PDI efficacy of Ag@MS@HPIX NPs was tested against a multidrug- (open full item for complete abstract)

Committee: Peng Zhang Ph.D. (Committee Chair); William Heineman Ph.D. (Committee Member); Allan Pinhas Ph.D. (Committee Member); Thomas Ridgway Ph.D. (Committee Member) Subjects: Chemistry

Master of Science (M.S.), University of Dayton, 2016, Chemistry

Platinum(II) complexes of the type PtCl2L2, such as cisplatin---PtCl2 (NH3)2, have been widely studied and shown to have anti-tumor activity. On the other hand, ruthenium(II) complexes are known for their intense photophysical properties, biodiversity, and tumor targeting capabilities, which make them suitable as photosensitizers in photodynamic therapy. The efficacy of these complexes as anti-tumor agents is controlled by many variables such as cell permeability, availability of DNA repair processes, etc. A platinum(II)-DMSO complex and a ruthenium(II)-bypyridine complex have been incorporated into a thymidine based nucleoside through an N-3 pendant pyridyl nitrogen. Nucleosides are transported into the cell by particular trans-membrane proteins. This could increase the cellular uptake and reduce toxic side effects. Incubation of these two complexes with pUC18 circular plasmid DNA has been performed and followed by gel electrophoresis. The results show the formation of linearized forms of DNA. The structures of all intermediates and final compounds were confirmed by 1D-NMR (1H-NMR and 13C-NMR), 2D-NMR (H-C correlation, HMQC and HMBC), TOF-MS and 195Pt-NMR methodologies.

Committee: Kevin Church (Advisor); Shawn Swavey (Committee Member); Vladimir Benin (Committee Member) Subjects: Chemistry