Pharmaceutics and Drug Design Commons^™

Discovery Of Novel Tubulin Polymerization Inhibitors And Survivin Inhibitors As Potential Anticancer Agents, Min Xiao

Theses and Dissertations (ETD)

Melanoma is the most dangerous form of skin cancer and accounts for the majority of skin cancer death. Although considerable advances have been made in melanoma treatment in recent years, there are many problems associated with current therapies. Drug resistance to targeted therapies is almost inevitable after short term treatment. Immunotherapies generally have low response rate and the effects vary among patients. Therefore, the need to develop new and more effective treatment for melanoma is high.

The work presented here focuses on discovery of novel anticancer agents for melanoma by targeting two important cancer targets: tubulin and survivin. Microtubules play …

Overcoming Acquired Resistance To Braf Inhibitors By Novel Synergistic Drug Combination And Discovery Of Novel Smac Mimetics As Selective Survivin Inhibitors, Jin Wang

Theses and Dissertations (ETD)

The first part (Chapter 1 and 2) of this dissertation presents a novel combination study of melanoma therapy. Acquired clinical resistance to vemurafenib, a selective BRAFV600E inhibitor, arises frequently after short term chemotherapy. Since the inhibitions of targets in the RAFMEK-ERK pathway result in G0/G1 cell cycle arrest, vemurafenib-resistant cancer cells are expected to escape this cell cycle arrest and progress to subsequent G2/M phase. We hypothesized that a combined therapy using vemurafenib with a G2/M phase blocking agent will trap resistant cells and overcome vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values of …

Design, Development And Evaluation Of Erlotinib-Loaded Hybrid Nanoparticles For Targeted Drug Delivery To Nonsmall Cell Lung Cancer, Bivash Mandal

Theses and Dissertations (ETD)

The objective of this work was to design, develop and evaluate erlotinib-loaded coreshell type lipid albumin hybrid nanoparticles (CSLAHNPs) for targeted drug delivery to nonsmall cell lung cancer (NSCLC). Erlotinib (ETB) is a highly selective, potent and reversible inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR) which is overexpressed (50-90%) in NSCLC. ETB is marketed as film coated tablets for oral delivery. However, poor survival rate along with life-threatening adverse effects were reported from oral administration. Nanoparticulate delivery system of ETB might be advantageous to target the tumor cells, thereby increasing therapeutic efficacy and reducing off-targeting toxicities of ETB …

Design, Development, Characterization And Testing Of Cd22 Targeted Long Circulating Liposomal Drug Delivery Systems For B Cell Malignancies, Nivesh Kumar Mittal

Theses and Dissertations (ETD)

Hematological malignances of the B cells affect almost 130,000 people in the United States every year of which approximately 44,000 lose their lives. Therapies for B cell malignancies such as doxorubicin, have limitations due to dose related adverse effects such as neutropenia and cardiomyopathy. AD 198 is a novel PKC-delta activating agent that has cytotoxic superiority over doxorubicin by being able to circumvent resistance mechanisms developed by the cancer cells towards doxorubicin and being cadioprotective from the damage caused to cardiomyocytes by doxorubicin. Targeted delivery of AD 198 is crucial to moderate the non-specific interactions of the chemotherapeutic agent with …

Computer-Aided Drug Design And Discovery, Screening And Synthesis Of Small Molecule Inhibitors Of Nucleoside Transporters, Hilaire Colleen Playa

Theses and Dissertations (ETD)

Using prior biological data, pharmacophore models were made for hCNT1, hCNT3, hENT1, and hENT4. The hCNT3 and hCNT1 pharmacophore were used to select compounds for biological testing. The NBMPR analogue and dipyridamole analogue hENT1 pharmacophores were compared to each other and to a combined pharmacophore for hENT1. The dipyridamole analogue pharmacophore better predicted non-nucleoside small molecule inhibitors, and as such appears to be the better tool for aiding in the design of new small molecule inhibitors. The hCNT3 pharmacophore failed to select active compounds and as such must be redesigned. The hCNT1 pharmacophore succeeded in identifying two moderately active compounds …

Development Of A Novel Vaccine Adjuvant System Utilizing An In Situ Implant System To Modified Release, Qiuye Zhang

Theses and Dissertations (ETD)

Pulsatile release formulations for single dose vaccines have been studied for many years because of the advantages that they may provide to vaccine administration with a single dose instead of prime and booster shots.

The aim of this work is to develop novel formulations based on an In Situ Implant (ISI) systems to provide a modified vaccine release and altered immune response, which could act as a booster administration. This type of system was selected because ISI systems are used for long acting administration of various drugs and ease of administration. A typical ISI system is comprised of hydrophilic organic …

Glioma: A Tale Of Corticosteroids, Thiopurines And Proposed Novel Antiglioma Small Molecules, Amira Ahmed

Theses and Dissertations (ETD)

Glioma is a brain tumor that arises from glial cells or glial progenitor cells, and represents 80% of malignant brain tumor incidence in the United States. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor malignancy with fewer than 8% of patients with GBM surviving for 3 years. Over the past 10 years, despite improvement in diagnosis and therapies for cancer, the survival rate for high-grade glioma patients remains unchanged. The main focus of this dissertation is to investigate two therapeutic agents that are related to increase tumor resistance or increase secondary tumor incidence, which might play a role …

A Series Of Pharmaceutical Technology Concepts Applied To Pediatric Formulations, Hao Lou

Theses and Dissertations (ETD)

Pediatric formulations have received great attention from regulatory agencies in the United States and Europe. Since solid dosage forms such as tablets and capsules will not be able to improve pediatric patients’ compliance, customized pediatric formulations are needed. In response, formulators in the pharmaceutical industry have made significant effort into developing various pediatric formulations. However, developing satisfactory pediatric formulations is a process that is guided by case by case basis. The objective of this current study was to apply the scientific pharmaceutical technology concepts into developing modern pediatric formulations. We have shown that the drug delivery design will be affected …

Nanotherapies For Treating Prostate Cancer, Michael Danquah

Theses and Dissertations (ETD)

Current prostate cancer treatment remains ineffective primarily due to ineffectual therapeutic strategies and numerous tumor-associated physiological barriers which hinder efficacy of anticancer agents. Therefore, the focus of this study was to investigate a new combination therapy approach for treating prostate cancer and develop polymeric nanocarriers to facilitate anticancer drug and nucleic acid delivery.

It was hypothesized that simultaneously targeting androgen-androgen receptor (AR) and X-linked inhibitor of apoptosis protein (XIAP) signaling pathways would be effective in treating prostate cancer. The effect of bicalutamide (antiandrogen) and embelin (XIAP inhibitor) on the growth of prostate cancer cells in vitro and in vivo was …

Effect Of Compression Force On Agglomeration Of Micronized Active Pharmaceutical Ingredients: Techniques To Prevent Api Agglomeration During Compression, Suresh Potharaju

Theses and Dissertations (ETD)

Micronization is one of the common processes for size reduction to increase surface area of poorly soluble Active Pharmaceutical Ingredient’s (API). This size reduction improves the dissolution rate and permeability thereby increasing the bioavailability for hydrophobic API’s.

Tablets and capsules are the most marketed and easy to manufacture solid dosage forms. During manufacturing of tablets, high compression forces are applied uniaxially on the powder bed to get a coherent consolidated compact with good tensile strength. So, diluents are required to mix with API’s and compress into tablets. When this mixture is compressed into tablets, there is a possibility of agglomeration …

Development Of The Sustained Release Analgesic Formulations For Rodents And A Novel In Vitro Model For Parenteral Formulations With The Character Of A Level A Ivivc, Jin Xu

Theses and Dissertations (ETD)

Laboratory animals are often subjected to various painful surgical procedures such as laparotomy, thoracotomy or orthopedic procedures as well as non-surgical procedures such as the induction of arthritis. Any procedure that causes pain in humans is assumed to cause pain in animals too. It is the ethical obligation of all research personnel to reduce or preferably eliminate pain and distress by using analgesics. Furthermore, the Institutional Animal Care and Use Committee (IACUC) requires that appropriate anesthetics and/or analgesics must be used to minimize or eliminate pain and distress for animals undergoing painful procedures.

The oral administration route is the most …

Discovery Of Dihydroartemisinin And Dasatinib Drug Combination To Cure Pooroutcome Bcr-Abl+ Acute Lymphoblastic Leukemia, Harpreet Singh

Theses and Dissertations (ETD)

Oncogenic signaling by the Philadelphia chromosome-encoded BCR-ABL fusion kinase initiates and drives both Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Food and Drug Administration (FDA)- approved BCR-ABL-specific kinase inhibitors (BCR-ABL–KIs) imatinib, dasatinib and nilotinib induce prolonged remissions in CML but poor leukemia-reduction and relapse-control in Ph+ ALL. The relative primary BCR-ABL–KI-resistance in Ph+ ALL patients carrying predominantly BCR-ABLWT disease cannot be attributed to drug-resistant BCR-ABL mutations (BCR-ABLMUTANTS), and remains poorly understood.

We established a cell-based platform to evaluate the modulation of anti-Ph+ ALL activity of drugs by both tumor-extrinsic cytokines normally present in the leukemia …

Investigation Of Enhancement Of Furosemide Solubilization With Cyclodextrins And A Novel Octenyl Succinate Anhydride Starch, Rui Zhu

Theses and Dissertations (ETD)

Solubility behavior is one of the most challenging aspects for drug commercialization and often the main reason of drug that do not reach to its full potential. Now nearly 60% new chemical entities possess solubility problems, whereas practically no drug products with less than 10 µg/ml solubility in 70’s or 80’s. There is an ever increasing need to develop new formulation techniques and exicipients with novel mechanisms of action. Various techniques have been applied to enhance the drug solubility such as co-solvents, particle size reduction, lipid based drug delivery systems, nanosuspension, use of surfactants, salt formation, cyclodextrin complexes and solid …

Investigations Of Pharmacokinetic Challenges In Premature Infants, Yi Zhang

Theses and Dissertations (ETD)

Premature infants (gestational age less than 37 weeks) are considered a vulnerable patient population due to their immaturity at birth. Currently, off-label prescribing is common in younger pediatric populations, especially in premature neonates and infants, which is a primary group receiving intensive care. Unique pharmacokinetic (PK) challenges—such as limited blood volume and frequency of blood sample collections, rapid growth and continuous developmental changes, complexity of pediatric studies as well as scientific, practical, and ethical concerns— lead to the current lack of PK information and empirical dosing in premature neonates and infants. In this research, several approaches were investigated to overcome …

Development Of Co-Processed Plasticized Cellulose Acetate For Sustained Release Matrix Tablets, Yinqi Zhou

Theses and Dissertations (ETD)

Cellulose Acetate (CA) is a polymer extensively used in pharmaceutical applications. Because of the hydrophobic nature and good film properties of CA, it is a good polymer candidate for sustained release matrix tablets. Sustained release matrix tablets of cellulose acetate can be prepared by direct compression or wet granulation methods. However, previous studies showed that a large amount of CA was required to achieve the desired sustained release profile for a sparingly soluble drug and it was difficult to formulate a highly water soluble drug by using CA as the retarding agent. Some studies concluded that CA is very sensitive …

Preclinical Study Of Potential Antiglioma Novel Tetrahydroisoquinoline Analogs: Pharmacokinetics And Mechanism Of Action, Fei Ma

Theses and Dissertations (ETD)

Gliomas, the tumors of glial cells, account for 80% of primary malignant brain tumors. In 2011, there were about 18,300 new cases of maligant gliomas in the United States alone. Patients with glioblastoma multiforme or anaplastic astrocytoma, the two major types of malignant gliomas, have a median survival of 14 months or 2 to 3 years, respectively. Therefore novel treatments for malignant glioma are urgently needed.

A novel series of tetrahydroisoquinoline derivatives with antiglioma activity has been undergoing drug metabolism/pharmacokinetics (DMPK)-guided lead optimization. EDL-291 was result from structure modification of last generation compound EDL-155. Its preclinical pharmacokinetics were characterized in …

Compound 49b: A Novel Beta-Adrenergic Receptor Agonist In The Treatment Of Diabetic Retinopathy, Kimberly Williams-Guy

Theses and Dissertations (ETD)

Diabetic retinopathy is the leading cause of blindness in working Americans. While there are therapeutic regimens for the disease, more effective methods are needed. We have previously shown that a non-specific beta-adrenergic receptor agonist, isoproterenol, was effective in preventing functional and morphological changes associated with diabetic retinopathy in the rat. Isoproterenol also produced left ventricle remodeling suggesting it entered the systemic circulation. We therefore synthesized various novel beta-adrenergic receptor compounds and screened these compounds in vitro for their ability to reduce markers of inflammation and apoptosis. Of the various compounds tested, Compound 49b was able to reduce both inflammation and …

Development And Evaluation Of Nano‑Scale Systems For Targeted Delivery To Treat Liver Fibrosis, Ningning Yang

Theses and Dissertations (ETD)

Excessive deposition of ECM is the common characteristic of liver fibrosis. During hepatic fibrosis, various inflammatory cytokines are released and trigger the activation of quiescent HSCs. The activated HSCs play the major role in producing extra amount collagen. It becomes very crucial to focus on HSCs to find out therapeutics, such as inhibiting collagen synthesis, inhibiting activation to myofibroblasts, or controlling inflammation.

To control excessive collagen synthesis, one triplex forming oligonucleotides (TFO), was systemically administrated to prevent type I collagen mRNA transcription. To enhance circulation time and targeted delivery efficiency, TFO was conjugated to M6P‑HPMA and showed efficient targeted delivery …

Preclinical Pharmacology Of The Mdm2 Antagonist Nutlin-3a, Fan Zhang

Theses and Dissertations (ETD)

Nutlin-3a is an MDM2-p53 interaction antagonist that is under investigation in preclinical models for a variety of pediatric malignancies, including neuroblastoma, retinoblastoma, leukemia, and rhabdomyosarcoma. In the current research, we conducted preclinical pharmacology studies of nutlin-3a to evaluate the synergistic effect of the nutlin-3a and topotecan combination on neuroblastoma cell growth, to assess the effect of nutlin-3a on breast cancer resistance protein (BCRP), and to characterize the disposition of nutlin-3a in the mouse plasma and multiple tissues.

Activating the p53 pathway might offer a new therapy for neuroblastoma. In the first part of the study, we assessed the effect of …

The Design And Synthesis Of Autotaxin Inhibitors And Analogs Of Lysophosphatidic Acid, Renuka Niranjan Gupte

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) is a naturally occurring bioactive phospholipid. It has a wide array of biological effects like cell proliferation, survival, migration, apoptosis invasion, wound healing and angiogenesis. Autotaxin (ATX) was identified as an autocrine tumor cell motility factor from A2058 melanoma conditioned medium. ATX has lysophospholipase D enzyme activity and is responsible for the cleavage of lysophophatidylcholine (LPC) leading to the generation of LPA. Antagonists of Autotaxin would have a potential therapeutic application in cancer research. Chapter 1 is an introduction of LPA and autotaxin. It provides the background and significance of the research. Chapter 2 explores the synthesis …

Rna Interference For Improving The Outcome Of Islet Transplantation And Polymeric Micelle‑Based Nanomedicine For Cancer Therapy, Feng Li

Theses and Dissertations (ETD)

Ex vivo gene transfer has been used to improve the outcome of islet transplantation for treating type I diabetes. RNA interference is an effective approach for reducing gene expressions at the mRNA level. The application of RNA interference to improve the outcome of islet transplantation was reviewed in Chapter 2, where I summarized biological obstacles to islet transplantation, various types of RNAi techniques, combinatorial RNAi in islet transplantation, and different delivery strategies.

Upregulation of inducible nitric oxide synthase (iNOS) and subsequent product of radical nitric oxide (NO) impair islet β cell function. Therefore, we hypothesized that iNOS gene silencing could …

Pharmacokinetic And Pharmacodynamic Studies Of A Novel Spectinamide Series Of Antituberculosis Agents, V. N. R. Pavan Kumar Vaddady

Theses and Dissertations (ETD)

Spectinamides are novel amide derivatives of the antibiotic spectinomycin that have emerged as a new class of agents to treat tuberculosis. These agents showed potent in vitro activity against Mycobacterium tuberculosis (MTB) compared to spectinomycin and in a preliminary in vivo study in interferon gamma (IFN‑γ) knockout mice, spectinamide Lee1329 reduced the lung bacillary load of TB comparable to streptomycin. We hypothesized that the application of an iterative pharmacokinetics and pharmacodynamics (PK/PD) guided approach would facilitate the optimization of these lead compounds suitable for further development.

A series of in vitro experiments including parallel artificial membrane permeability assay (PAMPA), microsomal …

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 …

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 …

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 …

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 …

A Pharmacokinetics And Pharmacodynamics (Pk/Pd) Guided Approach To Lead Optimization Of Nitrofuranylamide Anti-Tuberculosis Agents, Nageshwar Rao Budha

Theses and Dissertations (ETD)

Currently used treatment strategies for tuberculosis (TB) involve administration of multiple drug combinations for a minimum of 6-9 months. However, these prolonged regimens do not always achieve sterilization, as evidenced by post-therapy relapse in a subgroup of treated individuals. In an effort to develop novel therapeutic agents for TB a new class of chemical agents, nitrofuranylamides, is being developed at the University of Tennessee Health Science Center. We hypothesized that the application of an iterative pharmacokinetics and pharmacodynamics (PK/PD) guided approach would facilitate the optimization of nitrofuranylamide lead compounds suitable for further development.

First, we examined the biopharmaceutic properties and …

Controlled Release Of Insulin And Modified Insulin From A Novel Injectable Biodegradable Gel, Om Anand

Theses and Dissertations (ETD)

The objective of the study was to develop a controlled release dosage form of
insulin, which can provide basal concentrations of insulin in diabetic rats for 1 to 2 weeks after a single subcutaneous injection.
A biodegradable injectable drug delivery gel was prepared by dissolving a
biodegradable polymer, polylactic-co-glycolic acid (PLGA), in biocompatible
plasticizer(s), triethyl citrate (TEC) and/or acetyl triethyl citrate (ATEC). Insulin was
then loaded into the blank gel to form an insulin suspension in the polymer solution.
After the insulin-loaded gel was injected subcutaneously, the plasticizer(s) dissolved in the aqueous media and were gradually taken away from the …

Structure- And Ligand-Based Design Of Novel Antimicrobial Agents, Kirk Edward Hevener

Theses and Dissertations (ETD)

The use of computer based techniques in the design of novel therapeutic agents is a rapidly emerging field. Although the drug-design techniques utilized by Computational Medicinal Chemists vary greatly, they can roughly be classified into structure-based and ligand-based approaches. Structure-based methods utilize a solved structure of the design target, protein or DNA, usually obtained by X-ray or NMR methods to design or improve compounds with activity against the target. Ligand-based methods use active compounds with known affinity for a target that may yet be unresolved. These methods include Pharmacophore-based searching for novel active compounds or Quantitative Structure-Activity Relationship (QSAR) studies. …