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Repurposing Of Small Molecule Inhibitor Ym-155 Inhibits High-Risk Neuroblastoma Growth By Directly Inhibiting Survivin Protein, Danielle Crystal Rouse

Theses and Dissertations

High-risk neuroblastoma (NB) is an aggressive pediatric tumor which develops from the extracranial sympathetic nervous system and accounts for almost 15% of all childhood cancer-related deaths. Current therapies include high-dose chemotherapy and radiation which have long-term toxic side-effects. Despite these intensive therapies, the overall survival rate of NB is less than 50%. Therefore, developing novel therapeutic approaches by directly targeting the molecular mechanisms that drives NB progression is very important. In the present study, we analyzed genomic datasets of 1235 NB patients and discovered that overexpression of survivin coding gene BIRC5 strongly correlates with poor overall and event-free survival of …

Self-Emulsified Nanoemulsion As Permeation Enhancer And Its Application For Intranasal Delivery Of Insulin, Kanyaphat Bunchongprasert

Theses and Dissertations

This study aimed to investigate the permeation enhancing property and safety of self-emulsified nanoemulsion (SEN) and use these findings to enhance insulin absorption through the nasal route.

The first part of the project was to identify the factors affecting cytotoxicity and permeation enhancement of SEN on Madin-Darby Canine Kidney (MDCK) cells, a widely used paracellular model. Twenty-six fatty acid esters (FAEs) commonly used in SEN were investigated. Among the FAEs (mono-, di-, and triesters), fatty acid monoesters (FAME) are the main excipient causing cytotoxicity and opening tight junction. The cytotoxicity of FAME in SEN was reduced with the presence of …

Development Of Nanoliposomes For The Treatment Of Braf V600e Mutated Parent And Vemurafenib-Resistant Melanoma, Yige Fu

Theses and Dissertations

Melanoma is one of the most aggressive and deadliest types of skin cancer. Currently, off-target toxicities and the rapid resistance development of metastatic melanoma mainly restrict the efficiency of the treatments. This thesis presents efforts towards developing liposomes to address current problems of BRAF-mutant metastatic melanoma.

EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF V600E Mutated Parent and Resistant Melanoma

In order to address off-target toxicities of the targeted therapy of MEK inhibitor trametinib (TMB), we developed a physically stable EphrinA1-mimicking peptide (YSA) anchored TMB-loaded PEGylated nanoliposomes (YTPLs). The YTPLs were evaluated in BRAFV600E-mutated parent cell lines (A375 and …

Development And Characterization Of Bilayer Abuse Deterrent Extended Release Tablet Using Various Model Drugs For Opioids Overdose Crisis, Ankit Soni

Theses and Dissertations

The objective of present study is to develop bilayer abuse-deterrent extended-release tablets (ADERTs) using various model drugs for opioids overdose crisis. Bilayer ADERTs using various model drugs were fabricated by direct compression; consists of extended-release drug layer and pH modifying layer. To develop extended-release layer, various hydrophilic polymers evaluated for their abuse deterrent potential. Based on significantly higher viscosity at 100RPM and lower syringe-ability data, it was found that HPMC K100M could be used as abuse deterrent polymer. Along HPMC K100M, various diluents were evaluated for their abuse deterrent potential. Tablet formulations prepared with various type of diluents using metformin …

Qbd Approach For Development Of Ivermectin-Loaded Gastro Retentive Sustained Release Tablets As Mass Drug Administration For Malaria Transmission Control, Zhangjie Xi

Theses and Dissertations

Malaria is a life-threatening disease with a high prevalence worldwide. Mass drug administration (MDA) of ivermectin have been shown to prevent the transmission of malaria. The objective of this investigation is to develop ivermectin-loaded gastro retentive sustained release tablets (GRSRTs), which have the potential to avoid not only frequent administration of MDA but also fluctuation of ivermectin in systemic circulation. Based on the outcomes from screening various materials to be the suitable matrix forming polymer and bio-adhesive polymer mixture of GRSRTs, HPMC K100M, Carbopol 934p and sodium alginate:chitosan (1:1) were selected as formulation variables. Eight formulations of ivermectin-loaded GRSRTs were …

Exploring Efficacy Of An Anti-Malarial Nanomedicine In Non-Small Cell Lung Cancer Treatment, Vineela Parvathaneni

Theses and Dissertations

New drug and dosage form development faces significant challenges, especially in oncology, due to longer development cycle and associated scale-up complexities. Repurposing of existing drugs with potential anti-cancer activity into new therapeutic regimens provides a feasible alternative. In this project, amodiaquine (AQ), an anti-malarial drug, has been explored for its anti-cancer efficacy through formulating inhalable nanoparticulate systems using high-pressure homogenization (HPH) with scale-up feasibility and high reproducibility. A 32 multifactorial design was employed to better understand critical processes and formulation parameters so as to ensure product quality with improved anticancer efficacy in non-small cell lung cancer (NSCLC). Optimized AQ loaded …

Design And Synthesis Of Non-Xanthone Structural Analogs Of Α-Mangostin, Maryam Foroozmehr

Theses and Dissertations

α-Mangostin belongs to a class of polyphenolic compounds called xanthones. The potential pharmacological effects such as anti-bacterial and anti-cancer effects of α-mangostin have made it an important natural product for medicinal chemistry evaluation. During this thesis research, we have designed and synthesized a series of non-xanthone analogs of α-mangostin for medicinal chemistry evaluation. A commercially available starting material, methyl-4-methoxysalicylate was used to synthesize these non-xanthone analogs. The analogs were designed as more flexible derivatives compared to the tricyclic motif within α-mangostin yet retain the hydroxybenzoate scaffold. Through a one-pot chemical synthesis, with relatively high yield (70%), we prepared eight different …

Double-Coated Biodegradable Poly (Butyl Cyanoacrylate) Nanoparticulate Delivery Systems For Brain Targeting Of Doxorubicin Via Oral Administration, Neeraj Kaushal

Theses and Dissertations

Primary brain cancer cells grow within the brain or cancer cells can metastasis from different site of the body into brain. The major hurdle in the treatment of brain cancer is the presence of blood-brain barrier (BBB). Additionally, acquired multidrug-resistant (MDR) impedes the success of long-term chemotherapy. Therefore, the objective of this investigation is to evaluate the brain targeting potential of orally administered poly(butyl cyanoacrylate) nanoparticulate delivery systems (PBCA-NPDS), double-coated with Tween 80 and polyethylene glycol (PEG) 20000 for brain delivery of doxorubicin, that does not cross the BBB by itself. And, evaluate the MDR reversal potential of PBCA-NPDS. Doxorubicin-loaded …

A Timecourse Based Dermatotoxicity Evaluation Of Mechlorethamine On Damage And Repair Related Protein Expression In The Mouse Ear Vesicant Model, Ganming Mao

Theses and Dissertations

Mechlorethamine (HN2) is a type of nitrogen mustard alkylating agent that has been widely applied as an anticancer drug. HN2 is an analog of the corrosive reagent sulfur mustard, which is highly reactive with skin and organisms exposed to HN2 develop significant skin irritation, edema, erythema, and disruption of the dermal-epidermal junction (DEJ). These pathological affects lead to tissue damage, activate wound repair mechanisms and, if unresolved, result in necrosis. The purpose of the present study was to evaluate the time-dependent effects of HN2 on the expression of three different proteins using immunohistochemistry (IHC) and previously prepared and preserved formalin-fixed …

Particle Shape Engineering For Improved Drug Delivery To Peripheral Lungs By Non-Invasive Route, Snehal Shukla

Theses and Dissertations

Inhalation of therapeutics has been gaining importance owing to immense advantages offered by pulmonary route and have attracted significant advancements in the pharmaceutical field. However, pulmonary drug delivery has been challenging because of the complexity of the respiratory tract and the existing defense mechanism. The pulmonary drug delivery has experienced advances in approaches and strategies to combat the existing challenges by tailoring the physicochemical properties of the delivery carriers and enabling both localized as well as systemic delivery. Pulmonary drug delivery is governed by several biophysical parameters of the delivery carriers such as particle size, shape, density, charge, and surface …

Preformulation Studies For The Preparation Of Amorphous Solid Dispersions, Hemanth Kumar Mamidi

Theses and Dissertations

The major challenges in the formulation of amorphous solid dispersions (ASDs) using hot-melt extrusion (HME) are the selection of an ideal polymeric carrier, optimization of HME processing conditions, and screening of the physical stability of the ASDs. Addressing these challenges using traditional approaches require extensive experimentation and large amounts of active pharmaceutical ingredients (API) which may not be feasible during the initial stages of product development. Therefore, there is a need to develop material-sparing techniques for the successful formulation of ASDs. The objective of the present study was to develop material-sparing techniques that can be used as pre-formulation tool during …

Selective Toxicity Of Mx106-4c, A Survivin Inhibitor, To Abcb1 Positive Multidrug Resistant Colon Cancer, Zining Lei

Theses and Dissertations

Multidrug resistance (MDR) is a major challenge in colon cancer chemotherapy, which is typically mediated by the overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1 (P-gp, MDR1). The application of ABCB1 inhibitors to overcome ABCB1-mediated MDR has been disappointing in the clinical settings. As an alternative approach, a synthetic analog of survivin inhibitor MX106, MX106-4C, was identified as a potent collateral sensitivity (CS) agent that selectively exerted more than 10-fold cytotoxicity on ABCB1 positive MDR colon cancer cell lines compared to cell lines with low ABCB1 expression. Biochemical assays revealed that MX106-4C did not affect the ATPase activity or the …

Up-Regulation Of Fibroblast Growth Factor (Fgf) 21 Via Ap-1 Activation Attenuates Cisplatin-Induced Hepatotoxicity, Yue Zhang

Theses and Dissertations

Fibroblast growth factor (Fgf in rodents and FGF in human) 21 plays important roles in the maintenance of sugar, lipid and energy homeostasis. Fgf/FGF21 can be up-regulated via activation of peroxisome proliferator-activated receptors (PPARs), aryl hydrocarbon receptor (AhR), glucocorticoid receptor (GR), and activating transcription factor (ATF) 4. Recent studies also demonstrated that Fgf/FGF21 plays cytoprotective roles against chemical-induced toxicities, such as of dioxins, acetaminophen, and alcohols. Cisplatin (cis-diamminedichloroplatinum, CDDP) is a widely used chemotherapeutic drug. However, numerous adverse effects have been noted during CDDP therapy, which largely limit its clinical applications. This study was designed to determine the regulation of …

Structure Based Optimization Of Benzimidazole 4-Carboxamide Scaffold Led To Picomolar Poly(Adp-Ribose) Polymerase Inhibitors, Griffin J. Coate

Theses and Dissertations

Poly(ADP-ribose) polymerase 1 (PARP1) is one of several proteins in the PARP superfamily consisting of 17 proteins with a conserved ART domain. Out of the 17 total proteins, 6 show clear evidence of catalytic activity. These 6 proteins are comprised of PARP1 through PARP4 as well as TNKS1 and TNKS2. PARP1 is thoroughly characterized and has been implicated for its role in various forms of cancer. Due to the role PARP1 plays in the DNA repair pathway, targeting PARP1 for inhibition has led to two distinct anticancer strategies. The first focusing on combinatorial drug therapy with a DNA damaging anticancer …

Gm-1111 Preserves Phagocytic Function Of Macrophages Exposed To Prolonged Hyperoxia Via Interruption Of Hmgb1-Mediated Signaling, Leanne Daley

Theses and Dissertations

Supraphysiological levels of oxygen (i.e. hyperoxia) are used to treat patients with respiratory distress. Prolonged exposure to hyperoxia can impair alveolar macrophage functions and increase susceptibility to ventilator-associated pneumonia (VAP). Hyperoxia-induced alveolar macrophage dysfunction is, in part, mediated by high airway levels of the pro-inflammatory mediator, high mobility group box-1 (HMGB1). An early generation glycosaminoglycan (GAG), 2-O, 3-O desulfated heparin (ODSH), attenuates hyperoxia-compromised innate immunity by preventing the binding of HMGB1 with receptors that activate pro-inflammatory pathways. In this study, we investigated whether the next generation GAG, GM-1111, can attenuate hyperoxia-compromised macrophage function. GM-1111 (100μM) prevented hyperoxia-induced (95% O2 for …

Chemical Space Exploration Around Thieno[3,2-D]Pyrimidin-4(3h)-One Scaffold Led To A Novel Class Of Highly Active Clostridium Difficile Inhibitors, Xuwei Shao

Theses and Dissertations

Clostridium difficile infection (CDI) is the leading cause of healthcare-associated infection in the United States. Therefore, development of novel treatments for CDI is a high priority. Toward this goal, we began in vitro screening of a structurally diverse in-house library of 67 compounds against two pathogenic C. difficile strains (ATCC BAA 1870 and ATCC 43255), which yielded a hit compound, 2-methyl-8-nitroquinazolin-4(3H)-one (2) with moderate potency (MIC = 312/156 µM). Optimization of 2 gave lead compound 6a (2-methyl-7-nitrothieno[3,2-d]pyrimidin-4(3H)-one) with improved potency (MIC = 19/38 µM), selectivity over normal gut microflora, CC50s >606 µM against mammalian cell lines, and acceptable stability in …

Development Of Abuse Deterrent Formulations Using Hot Melt Extrusion, Pavan Kumar Nukala

Theses and Dissertations

In recent years prescription drug diversion, misuse, abuse represent a growing problem for the United States. Oral ingestion, snorting, injection are most commonly employed routes of abuse. To circumvent this problem hot melt extrusion (HME) was employed to prepare abuse deterrent formulation (ADF). Abuse Deterrent Immediate Release Egg-Shaped Tablet Using 3D Printing Technology: Quality by Design to Optimize Drug Release and Extraction. In current work, we developed egg-shaped tablet (egglet) using fused deposition modeling (FDM) 3D printing. Drug-loaded polymeric filaments (1.5 mm) were prepared using HME followed by printing into egglets of different sizes and infill densities. Based on printability, …

Development, Evaluation And Application Of Insulin Solution And Film Dosage Forms For Sublingual Administration, Anuja Paprikar

Theses and Dissertations

The major barrier for sublingual absorption of large molecules like insulin is low permeability owing to the hydrophilic nature of insulin. One approach to overcome this barrier is to sublingually co-administer insulin with permeation enhancers (HPβCD and poloxamer 188). In vitro performance of permeation enhancers was screened across cellulose acetate membrane to select the concentrations of both enhancers, which were further evaluated across four models (MatTek tissue model, MDCK cell line, rat and porcine esophagus). The insulin solution with combination of HPβCD (5%) and poloxamer 188 (0.5%) indicates higher permeation as compared to that of only insulin across all the …

Nvestigation Of Dissolution And Dispersion Behavior Of Ritonavir From Amorphous Solid Dispersion, Nitprapa Siriwannakij

Theses and Dissertations

The aim of this study was to develop ritonavir amorphous solid dispersion (ASD) formulation, investigate its aqueous dissolution and dispersion behavior, and predict potential pharmacokinetic parameters by in-silico modeling. The binary/ternary ASDs of ritonavir with PVPVA or HPMCAS-MG in the absence or presence of surfactants were prepared by using the hot-melt extrusion method. The amount of ritonavir was fixed at 20 %w/w, while amount of polymer and surfactant in the formulation was varied. The film-casting technique was used to confirm the miscibility of drug and polymer in the absence and presence of surfactant in different formulations. PXRD and DSC analyze …

Oil/Water Nanoemulsion Biodistribution In Mice Upon Intravenous Administration, Jiayi Chen

Theses and Dissertations

The present study aimed to explore the biodistribution of O/W nanoemulsions (NE) upon intravenous administration. Three NEs were prepared with distinctive droplet sizes: SE (29 ± 1 nm), ME (214 ± 2 nm) and LE (883 ± 16 nm) without overlapping of the size distribution. Kolliphor® HS15 was used as the only surfactant for these three NEs, so that their droplets had similar surface structure. The NEs droplet size was stable under room temperature for minimum 3 days in phosphate buffer saline (PBS) and in mice plasma in vitro for 4-hour at 37°C. A lipophilic fluorescent dye, 1, 1’-dioctadecyl-3, 3, …

Agal Antigen And Rutinose Glycosides As Model Compounds For The Design Of Classical And Conformational Glycomimetics, Dhwani Ashish Mehta

Theses and Dissertations

αGal or Galili epitope (αGal(1→3)βGal(1→4)GlcNAc) is a natural trisaccharide associated with cell-surface glycoproteins of certain mammalian and non-mammalian cells. The saccharide is not expressed by humans and anti-αGal antibodies account for ~1% of the total circulating antibodies in sera as a result of our constant exposition to the antigen from food and intestinal flora. Our interest in αGal relies on its involvement in a variety of pathologies including red meat allergy, hyperacute xenotransplant rejection, and parasitic and bacterial infections. In particular, we have an interest in developing structurally simple glycomimetics for engaging in high-affinity binding αGal-recognizing receptors such as the …

Chemical Synthesis And Evaluation Of Azotochelin Analogs As Anticancer Agents And Their Ability To Reverse Anticancer Drug Resistance, Nishant Karadkhelkar

Theses and Dissertations

Cancer has been plaguing the humanity for several decades. In the meanwhile, multi-drug resistance (MDR) is causing abatement of effective therapeutic drugs, necessitating discovery of new class of anticancer agents. Natural products have been proved to be a promising source of structurally new anticancer agents. A specific class of bacterial secondary metabolites, named siderophores have been explored as potential anticancer agents. Enterobactin is one of the most studied siderophores as a potential anticancer agent. Azotochelin is a structurally similar but structurally simpler siderophore compared to enterobactin. Our research project focused on the evaluation of the structure activity relationship assessment of …

Intranasal Delivery Of Insulin By Nanoemulsion System, Darshana Mahendrakumar Shah

Theses and Dissertations

The main objective of this research was to develop an o/w nanoemulsion dosage form of insulin for intranasal delivery where insulin is loaded into the oil phase of the nanoemulsion for enhanced absorption. When loaded into the lipid droplets (oil phase), insulin can be protected from enzymatic degradation, can permeate through the mucus gel barrier in a comparatively efficient manner and can be absorbed through transcellular permeation along with paracellular route. To incorporate lipophilicity to insulin molecule, several complexes of insulin with various amphiphiles were developed to load it into the oil phase. The cytotoxicity of these amphiphiles and the …