Medicine and Health Sciences Commons^™

Development And Evaluation Of Therapeutics In The Setting Of Radiation Injury, Karin Emmons Thompson

Theses and Dissertations (ETD)

The possibility of an incident involving radiation exposure is at the forefront of public attention in the current global environment. With a greater number of entities possessing nuclear weapons and increased demand for nuclear power, the concern for uncontained exposure to radiation is increasing. In light of these developments, the need for treatments that may be easily stored and administered to large numbers of people who have been exposed to high doses of total body irradiation (TBI) is more urgent than ever before.

Our goal was to identify and develop novel, drug-like small molecules that would exhibit radiomitigating activity for …

Development And Evaluation Of Paclitaxel-Loaded Liposomal Formulations For Targeted Drug Delivery To Breast Cancer, Vinayagam Kannan

Theses and Dissertations (ETD)

The objective of this work was to develop and evaluate paclitaxel-loaded liposomal formulations for targeted drug delivery to breast cancer. The liposomal formulation was optimized to maximize drug loading and physical stability. Cholesterol and saturated lipid content showed a negative influence on paclitaxel loading. Short-term stability studies showed that optimum drug-lipid ratio is necessary for adequate physical stability. Biodistribution studies in mouse xenografts bearing MDA-MB-231 breast cancer using near infrared fluorescence imaging showed that the accumulation of tumor vasculature targeted long-circulating liposomes (LCL) in the tumor was significantly less than non-targeted LCL at 48 h. The accumulation of these liposomes …

Therapeutic Gene Delivery To Human Pancreatic Islets For Treatment Of Diabetes And The Effect Of Tfo On Liver Fibrosis Induced By Bile Duct Ligation, Ravikiran Panakanti

Theses and Dissertations (ETD)

Ex vivo gene transfer can improve the outcome of islet transplantation for treating Type I diabetes. Earlier we have shown co‑expression of human vascular endothelial growth factor (hVEGF) and human interleukin‑1 receptor antagonist (hI‑1Ra) after transfection of plasmid DNA encoding these two genes. Due to poor transfection efficiency of plasmid DNA and the better known islet transduction efficiency of adenoviral (Adv) vectors, in this study, we constructed Adv‑hVEGF‑hIL‑1Ra by cloning hVEGF and hIL‑1Ra coding sequences and polyA signal under separate cytomegalovirus (CMV) promoters in Adenoquick plasmid (Ad 13.1). There was dose and time dependent expression of these genes after transduction …

Design Of Lipid And Polymeric Carriers For Nucleic Acid Delivery, Lin Zhu

Theses and Dissertations (ETD)

The objectives of the study were to investigate and develop lipid and polymeric carriers for nucleic acid delivery. These included: i) to develop novel cationic lipids for plasmid, oligonucleotide, and siRNA delivery; ii) to develop a novel polymeric delivery system, polyethylene glycol (PEG) based bio–conjugate, for oligonucleotide delivery; iii) to develop a novel bio–conjugate delivery system for siRNA delivery.

In Chapter 2, we discussed the barriers and strategies of nucleic acid delivery, as well as summarized the commonly used lipids, polymers, and the corresponding carriers in terms of their characteristics, applications, advantages and limitations.

Cationic lipids are most commonly used …

Tdiscovery And Development Of Novel Therapeutic Agents For Advanced Melanoma, Zhao Wang

Theses and Dissertations (ETD)

Malignant melanoma is the most dangerous form of skin cancer and accounts for about 75% of skin cancer deaths. Once diagnosed at the metastatic stage, it has a very poor prognosis with a median survival rate of 6 months and a 5-year survival rate of less than 5%. In addition, melanoma has become an important public health hazard owing to its rising incidence, which has been well documented over the past 50 years. Currently there is no effective way to treat melanoma. It is highly resistant to existing chemotherapy, radiotherapy, and immunotherapy. Over the past 30 years, only two drugs …

Transcriptional Regulation Of Azole Antifungal Resistance And Tolerance In Candida Glabrata, Kelly E. Caudle

Theses and Dissertations (ETD)

Azole antifungal resistance has emerged as a significant problem in the management of infections caused by fungi including Candida species. In recent years, Candida glabrata has become the second most common cause of mucosal and invasive fungal infections in humans second to Candida albicans. Not only are systemic C. glabrata infections characterized by high mortality rates, treatment failures to the azole class of antifungals, the most widely used antifungal for treatment of Candida infections, have been reported. Contributing to this problem, C. glabrata exhibits intrinsic reduced susceptibility to the azole antifungals, and the development of high-level azole resistance …

The Design And Synthesis Of Novel Antimicrobial Agents For Use In The Battle Against Bacterial Resistance, Joshua Randal Brown

Theses and Dissertations (ETD)

There is an ever increasing need to develop new antimicrobial agents with novel mechanisms of action. These new agents will help to combat the steady rise of antibiotic-resistant bacteria which are becoming more and more difficult to treat due to the dwindling number of antibiotics available to treat such organisms. This body of work brings to light the many ways in which medicinal chemistry plays a vital role in the discovery of novel antimicrobial agents. Chapter 1 is an introduction into antimicrobial agents. It provides a brief history of the discovery of antimicrobial agents, and delves into reasons why new …

Discovery Of Quinic Acid Derivatives As Oral Anti-Inflammatory Agents, Kui Zeng

Theses and Dissertations (ETD)

Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. Cat’s claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB). Herein, we described the synthesis and biological testing of novel QA derivatives. Inhibition of NF-κB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-κB response element. A549- NF-κB cells were stimulated with TNF-α (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at …

Tamoxifen: Mechanisms Of Resistance, Cyrus Mccoy Adams

Theses and Dissertations (ETD)

The role of estrogen in breast cancer has been recognized for decades. The selective estrogen receptor modulator tamoxifen was the first targeted therapy for the treatment of breast cancer. It was also the first drug approved by the FDA for the reduction of breast cancer risk. While tamoxifen has extended the lives of countless patients with breast cancer, resistance to tamoxifen remains a significant clinical problem. Work over the last two decades has greatly enhanced our understanding of the molecular mechanisms by which breast cancer cells may become resistant to tamoxifen treatment. Here I review our current understanding of the …

Population Pharmacokinetics Of Therapeutic Monoclonal Antibodies: Examples And Estimation Method Performance Differences, Nathanael Le Dirks

Theses and Dissertations (ETD)

Over the past two decades, there has been an increase in the research and development and therapeutic application of monoclonal antibodies (mAbs). An application of pharmacokinetic (PK) and pharmacodynamic concepts that has likely contributed to the success of the pre-clinical and clinical drug development of therapeutic mAbs is population PK, which attempts to quantify the typical disposition characteristics and sources of PK variability (such as between-subject, within-subject, and inter-occasion variability) within study populations. Population PK also attempts to identify and quantify the impact of covariates on systemic drug exposure and assess their potential implications for clinical dosing. The general theme …

Synthesis Of Novel Cannabinoid Ligands And Their Use As Anti-Glioma And Anti-Inflammatory Agents, Steven Neal Gurley

Theses and Dissertations (ETD)

Following the discovery of the cannabinoid receptors, research in the field of cannabinoids has grown exponentially over the last two decades. Cannabinoids have been shown to have tremendous therapeutic potential in the treatment of several pathological conditions ranging from inflammation to asthma, multiple sclerosis, Parkinson’s disease, epilepsy, glaucoma, septic shock, hemorrhagic shock, and cancer. Our research has focused on two major conditions for which cannabinoids hold great promise for drug development, namely, cancer and inflammation.

Our focus in the field of cancer has been on the devastatingly lethal brain tumor glioblastoma multiforme. Due to the high expression of the CB2 …