Master of Science in Biomedical Engineering, Cleveland State University, 2025, Washkewicz College of Engineering

Electrospinning is a method of fabricating polymeric nanofibers and nanoparticles by utilizing the force created by an electric field. In this study, thermoplastic polyurethane (TPU) and poly(lactic-co-glycolic acid) (PLGA) were used to create nanofibers and nanoparticles, respectively. This study aimed to use these polymers to create a network of nanofibers with nanoparticles incorporated in situ, which, to the best of our knowledge, has not been attempted before. Furthermore, this concept was utilized to encapsulate two different kinds of drugs: sodium nitroprusside (SNP) and vascular endothelial growth factor (VEGF). SNP is a vasodilator and was encapsulated within the TPU nanofibers, while VEGF was loaded into the PLGA nanoparticles. The effect of various electospinning parameters on nanoparticle formation was explored. Once the formulations were developed and electrospun, the morphology and size of the nanofibers and nanoparticles were evaluated using scanning electron microscope (SEM) imaging and ImageJ software analysis. In the nanofiber-nanoparticle composite samples, the diameter of the TPU nanofibers was 632.68 ± 291.49 nm (n=25) without encapsulated drug and 443.78 ± 171.50 nm (n=25) with the incorporation of SNP (p < 0.001). Compared to the composite sample, the TPU nanofibers were approximately 100 nm smaller in diameter for both loaded and non-loaded formulations. The PLGA nanoparticles had a large variability in diameter and therefore a definite trend in diameter was not evident. Fourier transform infrared spectroscopy confirmed the presence of SNP but could not definitively show the presence iv of VEGF. Drug encapsulation within these composite scaffolds was measured to determine the encapsulation efficiency. Future studies will explore the drug release profile from these electrospun nanofibers and electrosprayed nanoparticles.

PhD, University of Cincinnati, 2025, Pharmacy: Pharmaceutical Sciences

Neovascularization contributes to various posterior segment eye diseases such as age-related macular degeneration and diabetic retinopathy. RNA nanoparticles, derived from the packaging RNA three-way junction motif (pRNA-3WJ) of bacteriophage phi29 DNA packaging motor, were demonstrated thermodynamically and chemically stable and promising to serve as a nanodelivery system. RNA nanoparticles were demonstrated previously to enter the corneal and retinal cells after subconjunctival injection for ocular delivery. In the present study, antiangiogenic aptamers (anti-vascular endothelial growth factor (VEGF) and anti-angiopoietin-2 (Ang2) aptamers) were conjugated to RNA nanoparticles. The objectives were to investigate the clearance and distribution of these angiogenesis-inhibiting RNA nanoparticles after subconjunctival injection in vivo and their antiangiogenic effects for inhibiting ocular neovascularization in vitro. The results in the whole-body fluorescence imaging study showed that the clearance of RNA nanoparticles was size-dependent with no significant differences between RNA nanoparticles with and without the aptamers except for pRNA-3WJ. The distribution study of RNA nanoparticles by confocal microscopy of the dissected eye tissues in vivo indicated cell internalization of the larger RNA nanoparticles in the retina and retinal pigment epithelium after subconjunctival injection, and the larger nanoparticles with aptamers showed higher levels of cell internalization than those without. In the two-dimensional WST-1 cell proliferation assay in vitro, RNA nanoparticles with multiple aptamers had higher antiangiogenic effects. Both WST-1 proliferation assay and spheroid sprouting assay showed that the RNA nanoparticles with the aptamers had desirable antiangiogenic effects and conjugating multiple numbers or types of therapeutic aptamers on the RNA nanoparticles could enhance these effects. In addition, a correlation between the 3D spheroid sprouting and 2D WST-1 pr (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2025, Pharmaceutical Sciences

Applications of Lipid Nanoparticles (LNPs) for mRNA delivery has drastically increased in interest after the success and approval of the two LNPs/mRNA vaccines for the SARS-CoV-2 virus. mRNA is a unique class of biologics drugs because it can be manufactured entirely in chemically defined cell free systems and confer intricate biological activities. However, administration of mRNA alone is not effective since it is prone to degradation and requires a delivery vehicle. Although many delivery vectors including both viral and nonviral vectors are currently undergoing evaluations, LNPs are currently most clinically advanced. The objective of this dissertation is to explore how LNPs can be strategized to improve the functional delivery of mRNA by investigating each lipid component individually. Chapter 1 reviews current methodologies for evaluating LNPs delivery efficiency and the role of each individual lipid components in the overall LNPs functionality and delivery fate. Chapter 2 examines how the ionizable lipid can be designed with an active small molecule for added functionality of the LNPs in addition to mRNA delivery. Specifically, the lysophosphatidic acid receptor 1 antagonist was synthesized into the ionizable lipid (LA-LNPs), which formed stable LNPs that delivered A20 mRNA in primary mouse lung fibroblasts. In stimulated fibroblasts mimicking activated fibrotic state, administration of LA-LNPs mitigate cellular migration and proliferation to reduce markers of fibrosis. Chapter 3 explores the replacement of the PEG lipid with an alternative polysarcosine (pSar) lipid in current FDA approved LNPs formulations. Both in vitro and in vivo analysis demonstrated that pSar formulated LNPs can retain or even enhance mRNA delivery efficiency when compared to PEG lipid formulated LNPs. Further immunogenicity evaluations showed comparable immunogenic profiles between PEG and pSar formulated LNPs which highlight the potential of formulating functional LNPs without any P (open full item for complete abstract)

Doctor of Nursing Practice , Case Western Reserve University, 2025, School of Nursing

Background: Hysterectomy, the second most common procedure for women, requires effective perioperative pain management. Enhanced Recovery After Surgery (ERAS) pathways emphasize multimodal analgesia, including esmolol, a short acting beta-1 antagonist, and dexmedetomidine, an alpha-2 agonist. However, it remains unclear whether one is superior in minimizing postoperative opioid consumption, mitigating postoperative pain, and expediting patient recovery, particularly in adult females undergoing a robotic-assisted laparoscopic hysterectomy. Purpose: This quality improvement project examined the use of intraoperative esmolol and dexmedetomidine infusions and their impact on postoperative outcomes in adult females undergoing robotic-assisted laparoscopic hysterectomies, with a focus specifically on opioid consumption, length of stay, and pain scores in the post-anesthesia care unit (PACU). Methods: A retrospective chart review of 395 adult females that underwent a robotic-assisted laparoscopic hysterectomy at a tertiary care facility in Northeast Ohio analyzed PACU opioid consumption, PACU length of stay, and PACU pain scores using descriptive statistics, Levene's test for equality of variances, and One-way ANOVA. Results: There was no statistical difference observed between the esmolol and dexmedetomidine groups in terms of PACU opioid consumption, PACU length of stay, and PACU pain scores. Discussion: Findings suggest clinical equivalence of esmolol and dexmedetomidine as multimodal analgesic options, aligning with existing literature that highlights their opioid-sparing and pain-modulating benefits. This may offer provider insight and flexibility on anesthetic plan based on patient needs. Variability in outcomes may reflect patient factors, surgical techniques, and synergistic effects of other ERAS modalities. Further research with larger samples and prospective designs is needed to clarify their roles in optimizing recovery.

Doctor of Philosophy, Case Western Reserve University, 2025, Physiology and Biophysics

The 5-HT3R is a pentameric ligand-gated ion channel (pLGIC) which is responsible for fast ionotropic signaling across the membrane in response to binding of the neurotransmitter serotonin (5-HT). Expression of the 5-HT3R is found throughout various organ systems and neuronal tissues, including prominent expression within the vagal afferents innervating the GI tract from the dorsal vagal complex of the brain stem, forming a gut-brain interface which contributes to peristalsis and the emetic reflex. Abnormal signaling through the 5-HT3R within the vagal gut-brain interface is implicated in pathologies such as irritable bowel syndrome (IBS) and chemotherapy-induced nausea and vomiting (CINV), which is treated clinically by setrons, a family of 5-HT3R-specific antagonists. High-resolution protein structures of the 5-HT3R in complex with 5-HT and setrons have been determined previously, providing molecular insights into drug-receptor interactions. However, structural studies have yet to provide a comprehensive, structure-based mechanism for orthosteric and allosteric modulation of the 5-HT3R. Additionally, most structural studies have investigated recombinant homopentamers of the 5-HT3A subunit, despite the expression of up to four additional subunits (5-HT3B-E) in physiological tissues. Here, I examine the structural basis for 5-HT3AR agonism, partial-agonism, antagonism, and allosteric modulation by high-resolution cryogenic electron microscopy (cryo-EM) structure determination. Cryo-EM imaging of the 5-HT3AR in complex with the partial agonists SMP100 and ALB148471 reveal that partial agonists might ultimately achieve their functional outcome by shifting conformational equilibrium to an intermediate extent to that of agonists and antagonists, and that ligand efficacy is correlated with ligand binding mode and twisting within the extracellular domain. Additionally, preliminary cryo-EM data of the 5-HT3AR in complex with the allosteric modulators Δ9-tetrahydrocannab (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Pharmaceutical Sciences

Immune checkpoint inhibitors (ICIs), and immunotherapy as a whole, have been the at the forefront of cancer research for the past two decades. They have revolutionized the oncology field, and their efficacy has helped cure cancer patients, not just treat them. However, for reasons unknown, only 25-45% of patients respond to treatment. Mechanisms of ICI resistance are poorly understood and there are few biomarkers available to identify patients that will respond. Two factors associated with ICI resistance are cancer cachexia-associated increases in exogenous mAb clearance (CL) and the sex-dependent differences in nuclear hormone signaling. In this dissertation, I describe novel immune-intrinsic cancer-induced fluctuations in expression of the neonatal Fc receptor (FcRn). I also determined that in mice absent FcRn:ICI binding, cachexia-associated increased ICI CL disappears, suggesting the role of this receptor in cachexia-induced elevated ICI CL. In a separate tumor model of ICI resistance, female mice were treated with anti-PD1 in combination with two structurally distinct estrogen receptor beta (ERβ) agonists – OSU-ERβ-12 and LY500307. Tumor growth was limited in the combination treatment groups, and in a dose-dependent fashion in the OSU-ERβ-12-treated mice. Splenic immunophenotyping suggests the synergistic effects of the ERβ agonists and anti-PD1 in modulating tumor growth were due to immune activation, rather than direct action on the tumor. Together, these studies advance our knowledge of immune checkpoint inhibitor resistance mechanisms and how to overcome them.

Doctor of Philosophy, The Ohio State University, 2024, Comparative Biomedical Sciences

Over the past 2 decades, the adaptor protein transducin beta-like 1 (TBL1X) has been shown to be upregulated in solid tumors and hematologic malignancies and its overexpression associated with poor clinical outcomes. Moreover, TBL1X dysregulation has been implicated as a key component of oncogenic prosurvival signaling, cancer progression, and metastasis. In addition to its role in regulating major transcriptional programs (e.g. the SMRT/NCOR/BCL6 co-repressor complex, Wnt/β catenin, and NF-κB signaling), the Alinari laboratory has shown that, in diffuse large B-cell lymphoma (DLBCL), TBL1X stabilizes key oncogenic proteins, such as PLK1 and c-MYC, through interaction with a SKP1-CUL1-F-box protein supercomplex. Previously, we showed that targeting TBL1X genetically and pharmacologically with tegavivint (Iterion), a first-in-class small molecule, results in significant DLBCL cell death in vitro and in vivo. Despite this promising evidence of therapeutic potential, cure is not appreciated. As DLBCL is characterized by poor prognosis in the relapsed and refractory (R/R) setting, novel therapeutic options are urgently needed. Given the central role of TBL1X in modulating multiple oncogenic pathways in cancer, we hypothesized that treatment with tegavivint triggers pro-survival signaling, and that combined targeting of compensatory pathways with tegavivint will maximize the therapeutic potential of this agent in DLBCL. Thus, the first section of this dissertation is aimed at identification and mechanistic characterization of synthetic lethal partners that cooperate with tegavivint in DLBCL. Next, given that mantle cell lymphoma (MCL) is an area expertise for our laboratory and the function of TBL1X in MCL was entirely unexplored, we aimed to extend our knowledge of TBL1X as an oncoprotein and therapeutic target into this aggressive and incurable B-cell lymphoma. MCL patients who progress on targeted therapies, such as ibrutinib, have a short survival, and there is thus (open full item for complete abstract)

Doctor of Philosophy, University of Akron, 2024, Polymer Science

Polymer-based coacervates can be prepared from a large variety of compositions. This provides versatility to coacervates as a material platform, but can also make them difficult to characterize, especially when other molecules or biologics are used in the same solution. The Joy lab has previously developed a platform to make thermoresponsive coacervating polyesters in a modular fashion. This allows us to make incremental changes to the coacervate structure and thus better observe how the structure affects the properties in various applications. In this work, we look at coacervates for hemostatic materials for non-compressible torso hemorrhage, and as sustained release drug delivery vehicles for colchicine release. Through a variety of experimental methods, our goal is to link structural changes in the coacervating polyester to the performance of the coacervate. The performance of our hemostatic coacervate was evaluated using clotting time tests, hemolysis tests, and rheology to determine how our materials interact with blood components. The trend in this data was further confirmed with in vivo mouse model studies which showed that the coacervates can perform well as hemostatic materials, and that the in vitro studies can effectively screen materials. We have also shown that amines in our coacervates are not effective and contrary to expectations and literature may increase bleeding times. To better predict coacervate properties on drug release, we employ NMR techniques such as STD and DOSY to better understand the strength of interactions between the coacervate and drug. The final drug release study confirms our NMR findings, and while the NMR techniques are not easily quantifiable, they do show an excellent relative predictability which can also be used to screen materials for an application. Ultimately, the tools employed for understanding coacervate performance enhance our understanding of their behavior in applications such as hemostasis and sustained (open full item for complete abstract)

PhD, University of Cincinnati, 2024, Pharmacy: Pharmaceutical Sciences

Remdesivir and molnupiravir are two COVID-19 drugs approved by FDA. Both remdesivir and molnupiravir, are ester prodrugs and require hydrolysis to exert antiviral activity. Carboxylesterases constitute a class of hydrolases with high catalytic efficiency. Humans express two major carboxylesterases (CES1 and CES2) that differ in substrate specificity. Based on the structural of remdesivir and molnupiravir, it is hypothesized that remdesivir is a CES1 substrate, while molnupiravir is preferably hydrolyzed by CES2. As many as 20+ individual human liver samples were tested and the hydrolysis of remdesivir and molnupiravir was significantly correlated with the level of CES1 and CES2, respectively. Microsomes from liver and lung hydrolyzed remdesivir in a manner consistent with CES1 expression levels. Importantly, recombinant CES1 but not CES2 hydrolyzed remdesivir; recombinant CES2 but not CES1 hydrolyzed molnupiravir, collectively establishing that remdesivir is a CES1 substrate and molnupiravir is a CES2 substrate. On the other hand, the structure of remdesivir suggests its potential as a CES2 inhibitor. Purified CES2 was used to confirm the inhibition of CES2 by remdesivir across various CES2 substrates. To gain more inhibition insight, another two CES2 inhibitors were also included and tested for potential irreversible or covalent inhibition. Rapid dilution assay and filtration assay conclusively demonstrated that remdesivir and sofosbuvir are irreversible inhibitors, while orlistat is a reversible inhibitor. Site-directed mutagenesis and remdesivir binding assay showed certain residues such as G148, G149, A150, G154 and S228, were critical for remdesivir binding but completely loss the enzymatic activity, suggesting remdesivir and sofosbuvir are covalent CES2 inhibitors. Based on the above two conclusions, which state that molnupiravir requires CES2 for hydrolysis and that remdesivir is an irreversible and covalent inhibitor, it is hypothesized that there is a (open full item for complete abstract)

PhD, University of Cincinnati, 2024, Pharmacy: Pharmaceutical Sciences

There is increasing recognition of the pivotal role of the microbiome in addressing numerous questions about human health and disease. Exploring the role of the microbiome in the gastrointestinal tract and skin – the two largest reservoirs of the human microbiota – can provide valuable insights into the pathology and treatment of various diseases. Our first specific aim was to investigate the translocation of gut bacteria to the heart in a murine model of myocardial infarction (MI). In a novel discovery, we demonstrated that gut bacteria, which permeate into the systemic circulation after myocardial infarction, can colonize and proliferate within the heart, thus uncovering the existence of the heart microbiome. This observation was further validated through various techniques by using E. coli Nissle 1917 (EcN) as a tracer bacterium. Our second aim was directed towards developing a gut microbiome-based therapeutic construct to treat post-MI intestinal hyperpermeability. We engineered EcN to express F. prausnitzii-derived microbial anti-inflammatory molecule (MAM) and investigated its safety, efficacy, and mechanism of action in the MI model. Treatment with our recombinant construct, EcN-MAM, resulted in increased survival, enhanced cardiac function, and decreased cardiac fibrosis compared to the placebo group. As an exploratory aim, we also investigated the potential use of microbiome-based constructs for dermatological applications. We engineered EcN to express shinorine, a natural sunscreen, and evaluated its efficacy in an ex vivo human and porcine skin models of ultraviolet radiation (UVR)-induced DNA damage and a reconstructed human epidermis model of UVR-induced reactive oxygen species (ROS) damage. We found that our developed construct, EcN-SH, was effective in protecting against both UVR-induced DNA damage and ROS damage.

PhD, University of Cincinnati, 2024, Pharmacy: Pharmaceutical Sciences

AAntibiotic resistance poses a significant global health crisis, threatening the efficacy of treatments for bacterial infections. The rapid emergence of resistant strains has outpaced new antibiotic development, exacerbated by reduced research investment. This situation highlights the urgent need for innovative strategies to combat resistant bacteria. Supramolecular chemistry offers a promising approach, particularly using macrocycles such as cyclodextrins, calixarenes, cucurbiturils, and pillararenes. These macrocycles are characterized by their unique structures and host-guest complexation capabilities, making them ideal candidates for enhancing antibiotic properties. By incorporating antibacterial agents, these macrocycles can directly interact with bacterial membranes, disrupt biofilms, and inhibit bacterial growth. Their modular nature allows for the inclusion of multiple functional groups, enabling the design of complex structures with synergistic antibacterial effects, particularly against multidrug-resistant bacteria. In this project, we synthesized and characterized polyphenolic macrocycles that encapsulate antibiotics to combat bacterial resistance. The inclusion complexation process was analyzed using NMR and FTIR techniques. Binding constants from 1H-NMR titration revealed that levofloxacin forms more stable complexes with resorcinarene than with ß-cyclodextrin, aligning with MD simulations. Geometric characteristics of the inclusion complexes assessed through 2D NMR analysis confirmed that different moieties of various FQs fit into a single host cavity, improving activity against Gram-negative bacteria. These findings suggest that encapsulation in polyphenolic macrocycles is a promising strategy for utilizing FQs against antibiotic-resistant bacteria. The spatial characteristics of the inclusion complexes, unveiled through 1D and 2D NMR experiments, indicated the involvement of the piperazine moiety of the FQs in the inclusion process. In vitro ex (open full item for complete abstract)

PhD, University of Cincinnati, 2024, Pharmacy: Pharmaceutical Sciences

The percutaneous absorption of drug molecules is a primary concern in transdermal and topical drug development. The mechanisms of absorption have been heavily studied. However, some impactful factors are still unclear. We postulate that lipid solubility; particle size and particle distribution are the primary determinates of redissolution of solvent-deposited solids on the skin. Lipid solubility can be estimated from melting point and lipophilicity. Consequently, the topical drug and cosmetic ingredients in which we are interested will be divided into hard solids and soft solids based on these properties. This study probes the mechanisms by which volatile solvents (water, ethanol) and a nonionic surfactant (Triton X-100) influence the skin permeation of dissolved solutes following deposition of small doses onto unoccluded human skin. Nine compounds (niacinamide, caffeine, p-phenylenediamine, eugenol, testosterone, benzoic acid, cinnamyl alcohol, thioglycolic acid and geraniol) were tested for the crystallization effect and four solutes (niacinamide, caffeine, testosterone and geraniol) were further studied for the spreading effect at doses close to that estimated to saturate the upper layers of the stratum corneum. Methods included tensiometry, visualization of spreading on skin, polarized light microscopy and in vitro permeation testing using radiolabeled solutes. Ethanol, aqueous ethanol and dilute aqueous Triton solutions all yielded surface tensions below 36 mN/m, allowing them to spread easily on the skin, unlike water (72.4 mN/m) which did not spread. Deposition onto skin of niacinamide or caffeine from pure water and ethanol led to crystalline deposits on the skin surface, whereas the same amounts applied from aqueous ethanol and 2% Triton did not. Skin permeation of these compounds was inversely correlated to the extent of crystallization. A separate study with caffeine showed the absence of a dose-related skin permeability increase with Triton. Permeation o (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Pharmaceutical Sciences

Immune checkpoint inhibitors (ICIs) are monoclonal antibody drugs intended to bind inhibitory receptors on immune cells and block downstream regulatory immune signaling, stimulating anti-tumor immunity. ICIs are revolutionizing modern cancer management, becoming first line therapy for the treatment of malignancies like Non-Small Cell Lung Cancer (NSCLC), Renal Cell Carcinoma RCC), and more[1]. While a promising treatment option, durable responses to ICIs are variable, with current estimates stating that only 20-40% of patients respond to treatment depending upon cancer type, staging, and other variables [2]. A strong prognostic indicator of response to ICI therapy is rate of drug clearance. Retrospective analyses have identified that patients with a high rate of ICI clearance have reduced overall survival versus patients with slower rate of ICI clearance, independent of dose and subsequent drug exposure. The disconnect between circulating ICI levels and therapeutic response indicate that elevated rate of ICI CL serves as a biomarker for, but not a cause of, refractory response to ICI therapy[3, 4]. Knowledge of the underlying mechanisms linking ICI CL and efficacy will increase our ability to predict durable responses to ICI therapy in patients. Many reports citing the relationship between ICI CL and efficacy highlight that a many of the patients displaying elevated ICI CL also display disease severity markers that parallel the description of cancer associated cachexia[3-5]. Cancer cachexia is a multifactorial syndrome characterized by irreversible losses of skeletal muscle mass with or without losses in adipose tissue. Cancer cachexia is a unique state of dysmetabolism characterized by chronic inflammation and an overall disruption in energy expenditure homeostasis. Patients with cancer cachexia generally do not respond well to cancer therapy, and specifically, cachectic patients show a general resistance to ICI therapy[6-10]. The work reported here builds o (open full item for complete abstract)

DNP, Kent State University, 2024, College of Nursing

The management of dementia is a difficult task in all healthcare settings. Behavioral and psychological symptoms of dementia (BPSD) affect 90% of individuals with dementia. One-third of older individuals living with dementia are regularly prescribed antipsychotic medications to handle dementia-related behaviors. For six decades the FDA has been aware that antipsychotics were being used in nursing homes to sedate residents for BPSD, without dementia being an approved diagnosis. The serious side effects and increased risk of death have led to changes in nursing home policy and regulation. The Centers for Medicare and Medicaid (CMS) teamed up with Federal and State agencies and proposed dementia care planning that involves assessing BPSD and utilizing non-pharmacologic interventions. The primary objective of this project is to determine if educating staff in non-pharmacological management of BPSD will reduce antipsychotic medication use. Method This evidence-based quality improvement (QI) project is based on Lewin's Change Theory of unfreezing, moving, and refreezing. Using the PDSA method to move the process forward, a team was established, and a plan of action was developed to reduce the administration of antipsychotics by educating staff in non-pharmacological interventions. Sixteen nursing staff (n-16) were trained over four days in nonpharmacologic dementia care management. A pre-and-post-assessment questionnaire was conducted. Twenty-two resident participant's medications were reviewed by the Psychiatric Mental Health Nurse Practitioner (PMHNP), and gradual drug reductions (GDRs) were ordered. GDRs are a CMS compliance requirement for nursing homes conducted as standard practice based on the pharmacist recommendations and an important recommendation by CMS in antipsychotic reduction are conducted and documented by the consulting PMHNP. Nursing responses to patients with GDRs who presented with behaviors and antipsychotic dose reduction (open full item for complete abstract)

Doctor of Philosophy, Case Western Reserve University, 2024, Pharmacology

Globally, an estimated 420 million people today suffer from debilitating vision loss caused by age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), or glaucoma; a large majority of these cases (up to 90%) have only minimally effective or no treatment options available. These chronic, progressive retinal diseases arise from a complex interplay of genetic and environmental factors that disrupt, and eventually compromise, cellular and tissue stability. Such disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, effective treatments to preserve eyesight have remained elusive for the millions of patients suffering from these debilitating disorders, especially in the vast majority of cases that are in early stages of disease progression, wherein lies the greatest opportunity to slow or halt vision loss. In the coming decades, population aging will exacerbate the increase in global prevalence of vision impairment and blindness, thus underscoring a critical, unmet need for innovative, new ophthalmic medications. In pre-clinical studies, we demonstrated the efficacy of prototypical ‘stress resilience-enhancing drugs' (SREDs) that preserved both retinal morphology and function across a variety of genetic and environmental animal models of AMD, DR, RP, and glaucoma. These small-molecule therapies can be subdivided according to primary mechanism of action, resulting in two distinct subclasses of SREDs: 1) epigenetic modulators that include inhibitors of select histone deacetylases (HDACi) or methyltransferases (SUVi); and 2) selective inhibitors of cyclic nucleotide phosphodiesterases (PDEi). With pharmacological inhibition of histone deacetylase 11 (HDAC11) or suppressor of variegation 3-9 homolog 2 (SUV39H2), key histone-modifying enzymes involved in promoting reduced chromatin accessibility, stress-induced retinal (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Pharmaceutical Sciences

Cancers and leishmaniasis are distinct diseases, but the effects of each on people and communities are similarly devastating. Cancers cause over 10 million deaths worldwide each year, and are so widespread that nearly every person has lost a loved one to them, myself included. Leishmaniasis primarily affects tropical countries and in many places where access to medical care is limited, and the visceral form of the disease requires medical treatment to increase chances of survival above 5%. Both cancers and visceral leishmaniasis are diseases that the human immune system alone often cannot overcome, so the continued research into treatments is crucial to develop new and better tools to fight against these diseases. This dissertation details drug discovery efforts for two different projects, one against each disease; chapter 1 introduces readers to each disease state, chapter 2 describes the synthesis and biological evaluation of anticancer compounds, and chapter 3 describes the synthesis and biological evaluation of antileishmanial compounds. Following the serendipitous discovery of an antileukemia hit compound with an arylimidamide-azole scaffold, a series of analogs was synthesized to evaluate modifications to the scaffold. A robust structure-activity relationship (SAR) was developed through the synthesis of these compounds, and analysis of this relationship pointed to specific chemical modifications to the scaffold which improved their anticancer potency. Combining these favorable modifications led to compounds with >4-fold improved potency compared to the parent compound. Among the most potent compounds in this iv series was 2.9k, which displayed an IC50 value of 100 nM against the acute myeloid leukemia (AML) cell line OCI-AML3. Promising compounds in this series were then further evaluated for broad anticancer activity, pharmacokinetic properties, and mechanism of action as described in chapter 2. The antileishmanial compounds described in this dissertation (open full item for complete abstract)

PhD, University of Cincinnati, 2024, Pharmacy: Pharmaceutical Sciences

The global drug delivery market value for topical and transdermal products is estimated to be $114.2 billion. Time, effort, and investments are placed towards the advancement of innovative approaches to deliver drugs. An important aspect to consider in the success of skin drug delivery is the dose of the applied drug for skin delivery. In this research, we aimed to examine factors affecting dose delivery under a) topically applied finite dose conditions and b) semi-occluded transdermal patch system. The study of the relationship between the amount of drug applied to the skin and fraction of drug absorbed can improve our understanding of finite-dose percutaneous. It has been previously shown that an increase in the dose applied to the skin leads to a decrease in the fraction of drug permeated the skin (dose-dependent effect). The first objective of this research was to examine the dose-dependent effect using permeants of varying physiochemical properties. The dose-dependent effect was studied using human epidermal membrane under finite dose conditions in Franz diffusion cell with model permeants at a range of doses. The dose-dependent effect was evident with model permeants caffeine, corticosterone, dexamethasone, and estradiol, consistent with the relationship of decreasing fraction of dose permeated the skin at increasing the applied dose. However, no significant dose-dependent effect was observed for the polar model permeants urea, mannitol, tetraethyl ammonium, and ethylene glycol, suggesting different transport mechanisms for these permeants. It was also found that, at relatively high doses, estradiol, dexamethasone, and corticosterone could increase the permeation of polar and lipophilic permeants, which could counter the dose-dependent effect under the conditions studied. The second objective was to study the effect of transdermal adhesive coat weight (patch thickness) on the rate of drug delivery. Drug-in-adhesive patches of 1.6% w/w estradiol and 1.5% w/w te (open full item for complete abstract)

PhD, University of Cincinnati, 2024, Pharmacy: Pharmaceutical Sciences

Among chemical UV filters approved by the US FDA, avobenzone (AVO) is the most efficient and commonly used UVA filter in broad-spectrum sun care products. However, one pitfall of AVO is a lack of photostability leading to a decrease in its UV protection capacity. Its photostability primarily depends on the solvent system (solvents, emollients, and UV filters) and excipients in its vicinity (i.e., other UV filter molecules, and triplet or single quenchers). Moreover, when AVO and octinoxate (OCT), a UVB filter, are used in combination, it appears that the photo-instability of AVO can cause the photolysis of OCT. It has been reported that forming inclusion complexes with ß-cyclodextrins (ß-CD) enhanced the photoactive performance of AVO and OCT by improving their photostability and reducing skin permeation. However, most studies have investigated the complexes in solvents unintended for cosmetic formulations. Most importantly, the mechanism of host-guest complexation and photo-stabilization by ß-CD has not yet been revealed. Therefore, this dissertation aims to investigate the effect of macrocyclic compounds (ß-CD vs Cucurbit[7]uril (CB[7]) on the photostability of AVO and OCT in aqueous environment, which is motivated by three research questions. What are the differences in the complexation of AVO and OCT with ß-CD and CB[7]? How do forming complexes with ß-CD and with CB[7] affect the photostability, skin permeation, and efficacy of AVO and OCT? Finally, what is the impact of ethanol as a cosolvent on the complexation and photostability of AVO and OCT? To examine these questions, we prepared complexes of AVO-ß-CD, AVO-CB[7], OCT-ßCD, and OCT-CB[7] and characterized the complexes both in solution phase and solid state using several analytical techniques. We also conducted photostability studies for all complexes, skin permeation tests for AVO complexes, and evaluated the efficacy for all complexes. The findings from the research show that ß-CD and CB[7] have s (open full item for complete abstract)

PhD, University of Cincinnati, 2024, Pharmacy: Pharmaceutical Sciences

Traumatic Brain Injury (TBI) is a primary cause of disability and death within the United States of America. In the clinic, TBI presents as extraordinarily heterogenous pathologies given that brain injuries may be induced by a plethora of diverse and deleterious environmental interactions including but not limited to penetrating head injuries, acceleration-deceleration inertial forces acting upon the parenchyma of the brain, and exposure to blast waves. In civilian populations, it is thought that the reporting of TBIs, particularly mild TBIs (mTBI) or concussions, is significantly lower than the true prevalence in the population at large. Although the pathologies associated with each TBI are often distinct between cases and vary between individuals, sustaining a TBI significantly and unilaterally increases the risk for developing chronic emotional, social, and psychological complications regardless of injury modality which represents a critical factor in determining quality of life for those afflicted. The prevalence of psychosocial abnormalities includes an increased risk for developing major depressive disorder (MDD), anxiety disorders like generalized anxiety disorder (GAD) and panic disorders, as well as post-traumatic stress disorder (PTSD) is greatly increased in individuals who have sustained neurotrauma. Decades of research have linked the monoamine neurotransmitter serotonin (5HT) and the central serotonin system to the development and maintenance of mood, memory, and perception and have localized the nexus of serotonergic signaling to a midbrain structure called the raphe nucleus (RN). While the United States Food and Drug Administration (FDA) -approved pharmacotherapies for the treatment of disorders like anxiety and depression, selective serotonin reuptake inhibitors (SSRIs), are moderately efficacious in attenuating non-injury elicited psychopathologies, the application of these drugs in the context of TBI does not significantly improve patient outcomes (open full item for complete abstract)

PhD, University of Cincinnati, 2024, Pharmacy: Pharmaceutical Sciences

Commercial sunscreen products have been developed to protect human skin from ultraviolet radiation (UVR) with the use of chemical ingredients known as ultraviolet filters (UVFs). Sunscreens are important in protecting human health by preventing skin cancer. However, there have been several scientific publications investigating the potential impact of UVFs on environmental health in recent years. In response to the growing concern, the National Academies of Sciences, Engineering, and Medicine (NASEM) published a review consensus report on this topic and one knowledge gap identified is the need to further research environmental emissions of UVFs. This doctoral research set out to investigate two variables important to environmental emissions estimates of sunscreen UVFs: the amount applied to the skin (i.e., application thickness) and the amount released from the skin (i.e., release percentage). The hypothesis that was tested is the assumption of 100% sunscreen and UVF release from the skin is not representative of real-world conditions and leads to over-estimates of direct environmental emissions of UVFs from sunscreens. Three different studies were designed and executed to test this hypothesis. A large-scale web-based survey was developed and fielded to participants with the aim to measure sunscreen application aided by a visual reference and determine a more representative overall value for the United States (US) population. In the end, three online surveys and one home usage study were conducted. Results of this research support the inference that consumers are not applying the US Food and Drug Administration recommended application of 2.0 mg/cm2 and individual sunscreen application is highly variable. Next, two sunscreen rinse-off and release experiments were conducted. An in vivo rinse-off experiment using human volunteers aimed to determine a baseline UVF release percentage. The data from these experiments determined the average UVF release percentage wa (open full item for complete abstract)