Pharmaceutics and Drug Design Commons^™

Avaren-Fc's Effects On Lymphoma Cells., Jacob Hahn

Electronic Theses and Dissertations

This thesis investigates the therapeutic potential of Avaren-Fc (AvFc), a novel lectin fusion protein that integrates the Fc region of human IgG1 with the engineered lectin Avaren, specifically targeting lymphoma. The study delineates the in vitro binding capabilities of Avaren-Fc with a human B-cell lymphoma cell line, a canine B-cell lymphoma cell line, healthy canine peripheral blood mononuclear cells (PBMCs), and healthy human PBMCs. AvFc was shown to exhibit significant binding to human lymphoma cells. Furthermore, the direct cytotoxicity of Avaren-Fc against canine lymphoma cells, canine lymphoma cells and healthy canine PBMCs was assessed. It was found that there is …

Safety Evaluation Of Epicertin, An Oral Biotherapeutic Candidate For Treating Ulcerative Colitis: A 28-Day Repeated Dose Toxicity Study., Jimmy Fernando Cifuentes Jimenez

Electronic Theses and Dissertations

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic, relapsing inflammation of the colon and rectum with limited treatment options. Among them, immunosuppressive agents have a high rate of adverse side effects and do not cure the disease. EPICERTIN (EPT), a recombinant variant of the cholera toxin B subunit (CTB) with a C-terminal hexapeptide extension consisting of a KDEL endoplasmic reticulum (ER) retention motif, is a promising oral biotherapeutic candidate for the treatment of UC. EPT has demonstrated mucosal healing activity in mouse models of colitis and human colonic explants. EPT's mechanism of action involves binding to GM1 …

Cbl Regulation Of C-Met Signaling In Corneal Epithelial Cells., Kate Elise Tarvestad Laise

Electronic Theses and Dissertations

The cornea is the most anterior portion of the eye and permits light passage through to retina, allowing formation of a clear image as long as it remains healthy. If the cornea sustains damage, it creates and entrance for foreign body invasion, infection, and ultimately blindness in the immunocompromised eye. Healing the corneal tissue is critical for vision restoration and pain alleviation, as it is the most densely innervated tissue in the body. Growth factors and their cognate receptors are currently under investigation as tools to restore proper corneal physiology. We hypothesize that manipulating the hepatocyte growth factor (HGF) /c-Met …

Advancing Continuous Manufacturing: The Role Of Process Analytical Technology In Process Development, Samuel R. Henson

Electronic Theses and Dissertations

The pharmaceutical industry is actively pursuing technologies which improve manufacturing processes with the goal of producing high-quality pharmaceutical products for patients, manifesting in an industry-wide investment in continuous manufacturing (CM). Process analytical technology (PAT) has been recognized for its successful monitoring of critical quality attributes during routine production and is often cited alongside CM due to its ability to make timely, in-line measurements of intermediate materials. Various PAT tools are valuable in process development, particularly as continuous wet granulation processes are developed for use within pharmaceutical manufacturing. This work applied PAT and chemometric modeling during CM process development to enhance …

Efficient Development Of Density-Insensitive Near-Infrared Methods For In-Line Drug Content Monitoring In Continuous Powder Streams, Natasha L. Velez-Silva

Electronic Theses and Dissertations

A well-defined action plan to respond effectively to sudden changes in product demand is critical for preventing drug shortages within the pharmaceutical industry. An effective way to increase the output of a continuous manufacturing (CM) process is through flow rate adjustments. However, robust analytical methods must be in place to ensure consistent analytical performance across varying flow rates. Existing approaches for mitigating the physical effects of flow rate on Near-Infrared (NIR) measurements are often burdensome. Thus, efficient robust modeling strategies that reduce the current calibration burden and ensure model insensitivity to the physical variations in CM systems are needed. In …

Injectable Formulations For Localized Delivery Of Immunomodulators, Ketki Velankar

Electronic Theses and Dissertations

Dysregulation of immune homeostasis is fundamental to the development of autoimmune disorders. Fibroblastic reticular cells (FRCs) within lymph nodes play crucial roles in forming a microenvironment conducive to immune cell interactions and regulating autoreactive T cells driving autoimmune diseases. Studies have shown the potential of FRCs as a form of personalized cell therapy to correct dysregulated immune responses. Successful translational efforts, however, require the cells to be formulated as injectable suspensions while retaining their native architecture, which is essential for their regulatory functions. The main challenge resides in retaining the native reticular organization of FRCs lost in conventional monolayer cultures …

Uptake Of Extracellular Vesicles Into Brain Endothelial Cells And Development Of Motor Neuron-Derived Extracellular Vesicles For Amyotrophic Lateral Sclerosis, Jhanvi Rajan Jhaveri

Electronic Theses and Dissertations

Extracellular vehicles (EVs) are an emerging class of drug carriers and are primarily reported to be internalized into recipient cells via a combination of endocytic routes such as clathrin-mediated, caveolae-mediated and macropinocytosis pathways. In part one of this thesis, (1) we investigated potential effects of homotypic vs. heterotypic interactions by studying the cellular uptake of homologous EVs (EV donor cells and recipient cells of the same type) vs. heterologous EVs (EV donor cells and recipient cells of different types) and (2) determined the route of EV internalization into low pinocytic/hard-to-deliver cell models such as brain endothelial cells ( …

Delivery Of Mitochondria-Containing Engineered Extracellular Vesicles To The Blood-Brain Barrier For Ischemic Stroke Therapy, Kandarp Dave

Electronic Theses and Dissertations

Ischemic stroke is the second leading cause of death worldwide, and the lack of effective treatment options is an unmet clinical need for stroke survivors. Ischemic stroke-induced oxygen-glucose deprivation (OGD) in the affected brain tissue leads to mitochondrial dysfunction and adenosine triphosphate (ATP) depletion in the brain endothelial cells (BECs) lining the blood-brain barrier (BBB). ATP deprivation in the BECs dysregulates actin cytoskeleton dynamics, resulting in BBB breakdown. Restoration of blood flow (i.e., reperfusion) upon the first-line stroke treatment further leads to BBB breakdown and widens the paracellular spaces between BECs. …

Investigation Of Avaren-Fc's Therapeutic Potential Against Ovarian Cancer., Katarina Lee Mayer

Electronic Theses and Dissertations

This thesis describes the investigation of Avaren-Fc (AvFc), a novel lectin-based therapeutic fusion protein consisting of the recombinant Avaren lectin and the Fc region of human IgG1, against ovarian cancer. AvFc possesses selectivity toward tumor associated N-linked high-mannose-type glycans. The present study demonstrates AvFc’s in vitro activity against OVCA cell lines via antibody-dependent cell-mediated cytotoxicity and its ability to extend the survival of mice challenged with murine ID8 OVCA cells after repeated systemic administration. Furthermore, AvFc treatment in this model was found to increase the presence of peritoneal leukocytes, suggesting a shift toward an improved antitumor immune response. Another key …

Electrochemical Modulation Of Surface Plasmon Wave To Investigate Dna-Based Sensing Platforms And Detection Of Sars-Cov2., Anil Sharma

Electronic Theses and Dissertations

This study offers a thorough comparative analysis of optical and electrical signaling strategies for assessing the electrochemical properties of different redox-labeled DNA-based biosensing platforms. In addition, it illustrates the development of an optical interrogation technique with electrochemical modulation of surface plasmon waves (ECM-SPW) as a route for analyzing and implementing DNA-based hybridization sensors. For those quantitative analyses, we chose a model sensing platform composed of a methylene blue (MB)-modified single-stranded DNA (ssDNA) signaling probe and an unlabeled capture ssDNA probe that complements the signaling probe. Two types of signaling probes were employed in this work: one with MB attached to …

Preclinical Stability Assessment Of Epicertin, A Biotherapeutic Candidate For Ulcerative Colitis Mucosal Healing., Wendy Michelle Kittle

Electronic Theses and Dissertations

EPICERTIN is a biotherapeutic candidate for mucosal healing in ulcerative colitis (UC), a major type of inflammatory bowel disease (IBD). Despite the critical role of mucosal healing in achieving successful remission of UC, there are currently no targeted mucosal healing agents available. EPICERTIN has previously demonstrated epithelial repair and mucosal healing activity in colon epithelial cells, murine colitis models, and tissue explants from IBD patients, highlighting its therapeutic potential to meet this unmet need for UC patients. The development of appropriate chemistry, manufacturing, and controls (CMC) data will facilitate our ultimate goal to bring EPICERTIN to the clinic for a …

Delivery Of Gemcitabine, Stearoyl Gemcitabine And Paclitaxel Through Plga Nanoparticles And Its Effect On The Desmoplasia Of Pancreatic Cancer Spheroids, Rishabh Bahl

Electronic Theses and Dissertations

Pancreatic cancer is one of the deadliest cancers to treat. The primary cause for the drug resistance is the dense extracellular matrix (ECM) that surrounds the tumor and restricts blood supply. Gemcitabine (GEM) and paclitaxel (PTX) are drugs that are clinically used in the treatment of pancreatic cancer. GEM, however, is rapidly metabolized by cytidine deaminase (CDA) and eliminated from the body, and paclitaxel is a substrate for P- glycoprotein (P-gp) efflux receptors. Drug delivery using nanoparticles has been reported to help improve drug half-lives and bypass efflux receptors. This thesis aims to encapsulate PTX in PLGA nanoparticles (PTX-NP) and …

Breast Tissue As A Local Drug Reservoir For Anticancer Therapy In Breast Cancer, Saniia Shchinar

Electronic Theses and Dissertations

Breast cancer, particularly the estrogen receptor-positive (ER+) subtype, remains a formidable challenge in oncology. Traditional oral therapies for ER-positive breast cancer, such as selective estrogen receptor modulators (SERMs) like Tamoxifen (TAM) and Toremifene (TOR), often encounter issues related to limited bioavailability, metabolic complications, and significant systemic side effects. These side effects include the risk of blood clots, hot flashes, vaginal dryness, menstrual cycle disruptions, and uterus cancer, which can hinder long-term adherence to preventive therapy. The exploration of local drug delivery into breast tissue presents a promising alternative to tackle these challenges. In this study, we explored the feasibility of …

The Implications Of The Halogen Atom On The Physical Stability Of Amorphous Solid Dispersions, Mustafa Bookwala

Electronic Theses and Dissertations

Amorphous solid dispersions (ASD), although a promising formulation strategy for poorly water-soluble drugs, are susceptible to rapid, spontaneous recrystallization owing to their metastable nature. Non-covalent interactions (NCI) between the drug and polymer are known to help prevent ASD physical destabilization. Conventionally, hydrogen-bonding (H-bonding) is considered important for ASD formation and persistence. However, carbon-bound halogen atoms, which are frequently present on drug molecules and can form specific halogen-bonds (X-bond) with the polymer, remain relatively unexplored with respect to their ability to stabilize ASDs. It was, therefore, hypothesized that the presence of a peripheral Br on bromopropamide, and Cl on chlorpropamide will …

Systematic Product And Process Design Of Versatile Perfluorocarbon Nanoemulsions For Elimination Of Hypoxia And Reactive Oxygen Species, Eric Lambert

Electronic Theses and Dissertations

According to a 2022 report, organs destined for transplantation are discarded 15% of the time for various reasons (Israni et al. 2022). This highlights a critical need in transplant practices. Transplant donor tissues are in need of essential nutrients, including molecular oxygen, to maintain integrity during preservation. A current trend in preservation is to perfuse the ex vivo tissue graft with nutrient-rich aqueous perfusate on a closed circuit. This practice, known as machine perfusion (MP) is limited by the absence of an oxygen-carrying component in the perfusate. Additionally, injuries to the recipient are sustained on reperfusion of the transplanted …

Hgf-Mediated C-Met Signaling In Human Corneal Epithelial Cells., Kate Tarvestad

Electronic Theses and Dissertations

Vision is often regarded as the primary sense of humans. The cornea is the main refractive tissue that permits light through to the retina, allowing a clear image. When the cornea sustains damage, it opens a pathway for infection and blindness through fibrotic processes. Healing the corneal tissue is critical for vision restoration and pain alleviation. Growth factors and their cognate receptors are currently under investigation as tools to restore proper corneal physiology. We hypothesize that manipulating the hepatocyte growth factor (HGF)/ c-Met signaling pathway is one route to promote quality corneal healing. This thesis investigates the signaling, trafficking, and …

Quality By Design Based Optimization Of Anti-Inflammatory Nanoemulgels For Local Treatment Of Burn Wounds, Leah Dickey

Electronic Theses and Dissertations

Burns are some of the most traumatizing and damaging skin injuries, with the potential of causing extensive internal damage that increases the risk of chronic wound development. Oral and topical analgesics in combination with antibiotics can provide temporary relief and improve wound healing progress for both mild and severe burns. However, recurrent systemic exposure to pain relievers and antibiotics has been associated with adverse side effects including nausea, drowsiness, abdominal pain, etc., and increased risk of new infections or even ulcers. Local and targeted drug delivery systems, such as nanomedicine, have gained attention as potentially more effective alternatives to improve …

Development Of Anti-Inflammatory Theranostic Nanocolloids Using Quality By Design Approaches, Michele Herneisey

Electronic Theses and Dissertations

Nanocolloids are attractive delivery vehicles for drugs with poor aqueous solubility. Despite this, relatively few nanocolloid products exist on the market. Currently, there is a lack of standardization in the pre-clinical, academic setting regarding nanocolloid development and quality control testing. Adaptation of quality by design (QbD) methods used in the pharmaceutical industry to nanocolloid development is a desirable approach that can improve nanocolloid product and process understanding, resulting in an increased number of marketable products.

The central hypothesis of this work is that QbD approaches can be utilized to optimize theranostic (therapeutic and diagnostic) nanocolloid stability, drug loading, and imaging …

Development Of A Combined Feedforward-Feedback Quality Control System For Extended-Release Granules Using A Quality By Design Approach, Yuxiang Zhao

Electronic Theses and Dissertations

Objectives

For a fluid bed film coating process to consistently deliver quality products, its control system needs to be robust against the variability of input materials and environmental disturbances. Presently, limited studies have been reported to understand the effects and interactions of the material attributes, environmental variables, and process parameters on the product in vitro drug dissolution. A control system can be developed with a proper understanding of the coating process, by adjusting the process parameters in feedback and feedforward manners to compensate for the undesired effect caused by disturbances, and ensure consistent product quality.

Methods

The control system was …

Histone Deacetylases In Alcohol Associated Liver Disease., Srineil Bodduluri

Electronic Theses and Dissertations

Alcohol abuse is endemic worldwide and there is no FDA approved treatment for Alcohol-Associated Liver Disease (ALD). Many scholars have posited that targeting Histone Deacetylases (HDAC) may be therapeutic in ALD intervention. In this study, the changes in hepatic gene expression and immune phenotyping of mice undergoing chronic plus binge alcohol exposure was examined. The characterization of relative mRNA levels for all 18 HDAC were performed. Results showed decreased expression of the genes HDAC 1,7,9,10,11 and Sirtuin enzymes (SIRT) 3,4,5,7. Other pathways related to lipid metabolism as well as systemic inflammation and hepatic injury also exhibited significant changes. These altered …

The Role Of Src In Nsclc Cell And Lung Fibroblast Migration On 3d Cell-Derived Matrix., Austin M Krueger

Electronic Theses and Dissertations

Lung cancer is responsible for the most cancer deaths between males and females, with a 6% five-year survival rate. Cancer metastasis is one of the leading causes of lung cancer lethality. Our lab has developed a method to culture cells on cell-derived matrix (CDM) and study cell-ECM interactions. This study utilized multiple cell migration methods to investigate the migration of NSCLC cells and IMR90 lung fibroblasts, both together and independently, on 2D plastic and 3D CDM. Our results showed that inhibiting Src, a significant influencer of cell migration and member of integrin activation, blocked cancer cell migration on 2D and …

Pharmacological Characterization Of Novel Serotonin Transporter Inhibitors Identified Through Computational Structure-Based Virtual Screening, Michael Wasko

Electronic Theses and Dissertations

Depression is a mental health disorder affecting greater than 350 million people worldwide with roughly 7% of the United States population diagnosed as of 2017. The selective serotonin reuptake inhibitors (SSRIs) have been the mainstay of pharmacotherapies for depression for the last 40 years. The SSRIs target the serotonin transporter (SERT), a monoamine transporter (MAT) responsible for terminating serotonergic neurotransmission. The SSRIs are not perfect therapeutics and suffer from delayed response times, inconsistent efficacy among patients, and often produce intolerable side effects. Therefore, a strong need exists to develop new antidepressants that are more efficacious and have fewer adverse effects. …

Gene Delivery To The Blood-Brain Barrier For Ischemic Stroke Therapy, Wanzhu Zhao

Electronic Theses and Dissertations

Stroke is a major cause of death in the United States. We aim to develop safe and efficient approaches for the treatment of stroke. Regenerative therapies have been identified as the major need for curing stroke [1]. We explored two different carriers (poly (ethylene glycol)_5k-poly (L-aspartate-diethylenetriamine)₄₈ (PEG-DET) / Pluronic P84 (P84) and exosomes (EXOs) / microvesicles (MVs)) to deliver brain-derived neurotrophic factor (BDNF) plasmid DNA (pDNA), a functional gene encoding a neurotrophin. In the first project, our data showed that DNA nanoparticles (NPs) with 0.03% P84 was a promising formulation to deliver Luciferase pDNA into immortalized human …

Pilot Study Exploring The Effect Of Targeted Cox-2 Inhibition In Macrophages Responding To Neuronal Injury; Promoting Enhanced Axonal Regeneration, Alyssa Brauckmann

Electronic Theses and Dissertations

Celecoxib nanoemulsion (CXB-NE) has been developed as a macrophage targeted analgesics by Dr. Janjic and her team at Duquesne University, (Janjic et al, 2018; Liu et al, 2020; Saleem et al, 2019b; Vasudeva et al, 2014). The CXB-NE nanoemulsion carrying a Nonsteroidal Anti-inflammatory (NSAID) inhibitor of COX-2 activity result in a reduction in PGE2 expression in macrophages. Using CXB-NE in rats that have peripheral nerve injury constricting the sciatic nerve relieves hypersensitivity, a pain-like behavior. The treatment also decreases inflammation associated with this chronic constriction injury (Janjic et al, 2018; Saleem et al, 2019b; Stevens et al, 2019). In this …

A Recombinant Cholera Toxin B Subunit Variant (Ctb-Kdel) Exhibits Unique Colon Mucosal Healing Effects That Have Therapeutic Implications For Inflammatory Bowel Disease., Joshua Mark Royal

Electronic Theses and Dissertations

This dissertation uncovers the mechanism and explores the utility of a recombinant cholera toxin B subunit (CTB) variant containing a KDEL endoplasmic reticulum (ER) retention motif (CTB-KDEL) as a drug candidate for the treatment of inflammatory bowel disease (IBD). CTB is a mucosal immunomodulatory protein that induces robust mucosal and systemic antibody responses. This well-known biological activity has been exploited in cholera prevention (as a component of Dukoral® vaccine) and vaccine development for decades. On the other hand, several studies have investigated CTB’s immunotherapeutic potential in the treatment of inflammatory diseases such as Crohn’s disease and asthma. Here, we reveal …

Design And Synthesis Of Pyrimidine Based Heterocycles As Potential Anti-Cancer Agents With Combination Chemotherapeutic Potential Or Targeted One Carbon Metabolism Inhibition And Anti-Opportunistic Agents, Arpit Doshi

Electronic Theses and Dissertations

This dissertation describes the design, synthesis and biological evaluation of monocyclic, bicyclic and tricyclic pyrimidine-based heterocycles as a) single agents with combination chemotherapy potential having dual antiangiogenic effects and cytotoxic effects or b) one-carbon metabolism inhibitors for targeted tumor therapy; or c) selective Pneumocystis jirovecii (pj) dihydrofolate reductase (pjDHFR) inhibitors for pneumocystis pneumonia (PCP) infection.

The work in this dissertation is centered on identifying structural features that are necessary for inhibition of tubulin polymerization or thymidylate synthase as well as for inhibition of one or more of the receptor tyrosine kinases (RTKs)- vascular endothelial growth factor receptor-2 (VEGFR2), epidermal growth …

A Quantitative Study Of Drug Recrystallization In Drug-In-Adhesive Transdermal Patches Using Vibrational Spectroscopy, Yi Li

Electronic Theses and Dissertations

Drug-in-adhesive (DIA) transdermal patches are an important type of transdermal drug delivery system (TDDS). The drugs used in the DIA system are frequently present in metastable forms, such as amorphous solids or supercooled liquids. These drug states are thermodynamically unstable and tend to undergo recrystallization. Recrystallization of the active pharmaceutical ingredient can adversely affect the efficacy of transdermal products. This dissertation demonstrates a systematic approach to quantify the crystalline content of the API in DIA systems. This approach uses a novel method of preparing calibration standards and a spectroscopic method to reliably predict crystalline content in DIA patches. Spectroscopic tools, …

The Development Of Hybrid Process Control Systems For Fluidized Bed Pellet Coating Processes, Hanzhou Feng

Electronic Theses and Dissertations

The conventional basic control for pharmaceutical batch processes has several drawbacks. The basic control often uses constant process settings discovered by trial and error. The rigid process operation provides limited process understanding and forgoes the opportunities of process optimization. Product quality attributes are measured by the low efficient off-line tests, therefore these cannot be used to monitor and inform the process to make appropriate adjustments. Frequent reprocessing and batch failures are possible consequences if the process is not under effective control. These issues raise serious concerns of the process capability of a pharmaceutical manufacturing process.

An alternative process control strategy …

Modeling And Prediction Of Amorphous Solid Dispersion Formation Using A Molecular Descriptor, Kevin Deboyace

Electronic Theses and Dissertations

Poor aqueous solubility of an active pharmaceutical ingredient (API) is a significant hurdle during drug development. Delivering a drug in its amorphous solid-state is a potential method to overcome this issue, since the amorphous form has increased apparent aqueous solubility. However, the amorphous state is only metastable, and is thermodynamically driven to recrystallize. As a result, pure amorphous drugs are seldom used in marketed products. Intimately mixing a drug in its amorphous form with a polymer, known as an amorphous solid dispersion (ASD), has the potential to significantly extend the physical stability of the amorphous form, while maintaining the benefit …

Development Of A Lectin-Fc Fusion Protein With Antiviral And Anti-Cancer Activity., Matthew William Dent

Electronic Theses and Dissertations

This thesis describes the development of a novel lectin-Fc fusion protein and its antiviral and anti-cancer activity. The molecule, Avaren-Fc (AvFc), is a fusion of a variant of the actinomycete lectin actinohivin (Avaren) and the Fc region of human IgG1, and is selective for the terminal α1,2-mannose residues found at the ends of high-mannose-type glycans that can be found on the surface of certain heavily glycosylated viruses and cancer cells. Here, AvFc was found to be able to neutralize simian immunodeficiency virus as well as Hepatitis C virus with nanomolar IC₅₀ values. Furthermore, AvFc recognizes a number of cell …