Pharmaceutics and Drug Design Commons^™

Biodegradable Hybrid Nanogels For Combination Chemotherapy, Swapnil Desale

Theses & Dissertations

Combination chemotherapy is commonly used to treat cancer, because such a therapy regimens usually involve sequential administration of multiple drugs and allow targeting different cell signaling pathway. The co-delivery of drug combination at a controlled ratio via the same vehicle is offering the advantages such as spatial-temporal synchronization of drug exposure, synergistic therapeutic effects and suppression of drug resistance. Undoubtedly, there are several molecular and pharmacological factors that determine the effectiveness of drug combinations. A rationally designed drug combination is required since certain drug ratios and the definitive exposure to the targets of interest can only be synergistic while others …

Antiviral Peptide Nanocomplexes As Potential Therapeutics For The Treatment Of Infectious Diseases, Jinjin Zhang

Theses & Dissertations

Hepatitis C Virus (HCV) is recognized as a major burden in global public health, which can be further exacerbated by several cofactors such as human immunodeficiency virus (HIV). Currently, there is no vaccine for HCV. The emergence of potent and highly specific direct-acting antivirals (DAA) has marked a new era in HCV therapy, however, the remaining issues like affordability, genotype dependency, and potential resistance still necessitate the development of additional therapeutic approaches to be used instead or in combination with DAA.

Recently, the antiviral peptide C5A (in our studies designated as p1) and its cationic derivative p41 have been identified …

Using A Cost Benefit Analysis To Support The Development Of A Comprehensive Business Model For A Pre-Filled, Pre-Labeled, Pre-Diluted, Sterilely Packaged, Ready-To-Use, Syringe-Based Anesthesia Delivery System, Lance B. Kennedy

Doctoral Projects

The foundation of Certified Registered Nurse Anesthetists’ (CRNAs) entire profession is built on the ability to provide anesthetic services using a variety of medications in the safest, most efficient, cost-effective way possible. The purpose of this capstone is to address, via a comprehensive cost benefit analysis, whether pre-filled syringe drug trays are a more cost-effective way to address problems as compared to vial-filled drug trays and to implement the necessary transitions in order to improve outcomes. There are a number of identifiable problems related to anesthesia medication delivery via vial-filled medication, including increased cost of healthcare, decreased patient safety to …

Development And Evaluation Of Amphotericin B Loaded Iron Oxide Nanoparticles For Targeted Drug Delivery To Systemic Fungal Infections, Pavan Balabathula

Theses and Dissertations (ETD)

A targeted nanotheronostic drug delivery system to diagnose and treat life threatening invasive fungal infections (IFIs) such as cryptococcal meningitis was designed, developed, characterized, and evaluated. To address the development processes, first, iron oxide nanoparticles (IONP) (34-40 nm) coated with bovine serum albumin (BSA), loaded and targeted with amphotericin B (AMB) (AMB-IONP) was formulated by applying a layer by layer approach. Several designs (A, B, C, D, & E) of AMB-IONP were developed and their physicochemical properties such as drug loading with HPLC method, particle size, poly dispersity index (PDI), and ζ-potential using dynamic light scattering (DLS) technique, morphology with …

Development Of Oral Vaccines Against Lyme Disease, Rita Raquel Dos Anjos De Carvalho E Melo

Theses and Dissertations (ETD)

Lyme Disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States and Europe. If left untreated, it can lead to permanent damage to the nervous and musculoskeletal systems. In some cases, patients that receive the recommended antibiotic therapy develop a debilitating health condition associated with substantial health care costs. Despite current preventive measures, the incidence and the geographic distribution of Lyme Disease continues to increase. Recent estimates from CDC suggest that the true number of cases of Lyme Disease in the US is approximately 300,000 per year. Yet, there is currently no vaccine …

Optimization Of Lead Spectinamide Compounds As Novel Anti-Tuberculosis Agents With A Pharmacometric Approach, Ashit Rasendu Trivedi

Theses and Dissertations (ETD)

In an effort to combat the global Tuberculosis pandemic, Dr.Richard E. Lee and his group at St.Jude Children’s Research Hospital designed a novel series of anti-tuberculosis agents, spectinamides – semi-synthetic analogs of spectinomycin. Spectinamides are a potent inhibitor of mycobacterial ribosomes and overcome efflux mediated drug resistance in M. tb. Spectinamides have shown an excellent in vitro activity, which makes them well suited for further lead optimization and preclinical development. We hypothesized that through pharmacokinetic (PK) and pharmacodynamics (PD) model-based dosing optimization studies, we could strategically guide the selection and refinement of more potent and effective anti-TB spectinamides. Biopharmaceutical in …

Pamam Dendrimers As Promising Nanocarriers For Rnai Therapeutics, Prashant Kesharwani, Sanjeev Banerjee, Umesh Gupta, Mohd Cairul Iqbal Mohd Amin, Subhash Padhye, Fazlul H. Sarkar, Arun K. Iyer

Pharmaceutical Sciences Faculty Publications

Therapeutics based on RNA interference mechanisms are highly promising for the management of several diseases including multi-drug resistant cancers. However, effective delivery of siRNAs and oligonucleotides still remains challenging. In this regard, hyper-branched, PAMAM dendrimers having unique three-dimensional architecture and nanoscale size, with cationic surface charge can potentially serve as siRNA condensing agents as well as robust nano-vectors for targeted delivery. In addition, their surface functionality permits conjugation of drugs and genes or development of hybrid systems for combination therapy. Thus far, in vitro cellular testing of dendrimer-mediated siRNA delivery has revealed great potential, with reports on their in vivo …

Cysteine And Arginine-Rich Peptides As Molecular Carriers, Amir Nasrolahi Shirazi, Naglaa Salem El-Sayed, Dindayal Mandal, Rakesh Tiwari, Kathy Tavakoli, Matthew Eteshem, Keykavous Parang

Pharmacy Faculty Articles and Research

A number of linear and cyclic peptides containing alternative arginine and cysteine residues, namely linear (CR)₃, linear (CR)₄, linear (CR)_5, cyclic [CR]₄, and cyclic [CR]₅, were synthesized. The peptides were evaluated for their ability to deliver two molecular cargos, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI) and fluorescence-labeled lamivudine (F′-3TC), intracellularly in human leukemia cancer (CCRF-CEM) cells. We investigated the role of cyclization and the number of amino acids in improving the transporting ability of the peptides. The flow cytometry studies suggested that the synthesized peptides were able to work efficiently as …

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 …

Daun Jambu Biji (Psidium Guajava L.) Sebagai Antikanker Payudara, Dwitiyanti Dwitiyanti

Pharmaceutical Sciences and Research

Guava leaves are used as a cytotoxic. Previous research has demonstrated that guava leaves contained 61.71% of quersetin and has potential as an cytotoxic. The aim of this study was to determine the cytotoxic activity of 70% ethanol extract of guava leaves against cancer cells T47D. The method used direct counting (viable cell count) to obtained LC50 value. This study used a test solution with six concentrations that were 130.62; 67.98; 35.98; 18.43; 9.56 and 5 µg/ml. The LC50 value from the 70% ethanol extract of guava leaves was 27.54 µg/ml. The results suggested the extract of guava leaves has …

Uji Toksisitas Akut Dan Efek Antiinflamasi Ekstrak Metanol Dan Ekstrak N-Heksana Daun Pepaya (Carica Papaya L), Tahara Dilla Santi

Pharmaceutical Sciences and Research

The acute toxicity test and antiinflammatory effect of methanolic and n-hexane extracts Carica papaya L leaf have been studied. The results of phytochemical screening show that papaya leaf contains alkaloid, steroid, and flavonoid compound. Flavonoid and alkaloid extracted from methanolic extract of papaya leaf and steroid extracted from n-hexane extract of papaya leaf. The acute toxicity test of methanolic and n-hexane extracts Carica papaya L leaf have been studied on rat with giving a single dose of samples. The aim of this work was to investigate the behavioral responses (pharmacological profile), the development of body weight and mortality for 14 …

Enzim Papain: Aspek Green Chemistry Pada Reaksi Knoevenagel, Laurentius Haryanto, Antonius Herry Cahyana

Pharmaceutical Sciences and Research

Green chemistry aspect is the chemical approach that has been studied in the past two decade. One of the principles is the development of green synthesis process that is friendly for the environment. This research showed that papain can be used as catalyst for Knoevenagel reaction with 3 kinds of substituted-benzaldehyde and malononitrile as substrates in aqueous medium. The best reaction condition with 80% yield was reached by utilizing of 25 mg papain/mmol substrate. Reaction was conducted at ambient temperature and pressure for 30 min. Products were as yellowish to yellow needle crystals and successfully characterized by melting point, UV-Vis, …

Skrining Fitokimia Dan Aktivitas Antioksidan Fraksi Etanol Alga Merah Eucheuma Spinosum, Bina Lohita Sari, Nurulia Susanti, Sutanto Sutanto

Pharmaceutical Sciences and Research

The red alga, Eucheuma spinosum from South Bangka Waters was shown to contain antioxidant activity. Natural antioxidants from algae are known to play an important role against various diseases and aging processes. The study objective was to investigate phytochemical screenings and antioxidant activity of ethanol fractions Euchema spinosum from south Bangka waters. Antioxidant activities of fresh algae (FA), dry algae (DA), and algae product (AP) were determined with DPPH (1,1-diphenyl-2-picrylhydrazyl) assay. Extraction was conducted using 70% ethanol in acidic environment for 24 hours. Then, the extract was evaporated using rotary evaporator. Dry extract was fractionated with ethanol - n - …

Application Of Ichip To Grow “Uncultivable” Microorganisms And Its Impact On Antibiotic Discovery, Rinzhin T. Sherpa, Caretta J. Reese, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

Purpose. Antibiotics have revolutionized modern medicine, allowing significant progress in healthcare and improvement in life expectancy. Development of antibiotic resistance by pathogenic bacteria is a natural phenomenon; however, the rate of antibiotic resistance emergence is increasing at an alarming rate, due to indiscriminate use of antibiotics in healthcare, agriculture and even everyday products. Traditionally, antibiotic discovery has been conducted by screening extracts of microorganisms for antimicrobial activity. However, this conventional source has been over-used to such an extent that it poses the risk of “running out” of new antibiotics. Aiming to increase access to a greater diversity of microorganisms, …

Role Of Macrophages In Muscle Transfection With Pdna/Pluronic Formulation, Vivek Mahajan

Theses & Dissertations

Non-ionic amphiphilic block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), Pluronics, arranged in a tri-block structure PEO-PPO-PEO, have raised a considerable interest in skeletal muscle Gene Therapy. Previous studies have demonstrated that co-administration of Pluronics with naked plasmid DNA (pDNA) by direct i.m. injection enhanced transgene expression not only in muscle but also in distal lymphoid organs (spleen and lymph nodes) and this response was strain-dependent; not observed in athymic (BALB/c nu/nu) mouse; suggesting a role of immune cells in gene transfer to skeletal muscles. Therefore, we first evaluated the role of inflammation and inflammatory cells, on muscle …

Polymeric Nanocarriers For Treatment Of Melanoma And Genetically Modified Mesenchymal Stem Cells To Improve Outcome Of Islet Transplantation, Vaibhav Mundra

Theses & Dissertations

Melanoma is a lethal malignancy with limited treatment options for advanced metastatic stages. New targeted therapeutic options with discovery of BRAF and MEK inhibitors have shown significant survival benefit. Despite the recent progress, inefficient tumor accumulation and dose limiting systemic toxicity remains pressing challenges for treating metastatic melanoma and there is a need for drug delivery approach to improve therapeutic index of chemotherapeutics. Nanoparticle based drug delivery represents promising approach to enhance efficacy and reduce the dose limiting systemic toxicity. Nanoparticles can be formulated either by physical encapsulation of drugs or by covalent conjugation of drugs to the polymeric backbone. …

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 …

Computational Modeling Of Rna-Small Molecule And Rna-Protein Interactions, Lu Chen

Dissertations and Theses (Open Access)

The past decade has witnessed an era of RNA biology; despite the considerable discoveries nowadays, challenges still remain when one aims to screen RNA-interacting small molecule or RNA-interacting protein. These challenges imply an immediate need for cost-efficient while predictive computational tools capable of generating insightful hypotheses to discover novel RNA-interacting small molecule or RNA-interacting protein. Thus, we implemented novel computational models in this dissertation to predict RNA-ligand interactions (Chapter 1) and RNA-protein interactions (Chapter 2).

Targeting RNA has not garnered comparable interest as protein, and is restricted by lack of computational tools for structure-based drug design. To test the potential …

Molecular Overlap In The Regulation Of Sk Channels By Small Molecules And Phosphoinositides, Miao Zhang, Xuan-Yu Meng, Ji-Fang Zhang, Meng Cui, Diomedes E. Logothetis

Pharmacy Faculty Articles and Research

Phosphatidylinositol 4,5-bisphosphate (PIP2) directly interacts with the small-conductance Ca2+-activated K+ 2-a (SK2-a) channel/calmodulin complex, serving as a critical element in the regulation of channel activity. We report that changes of protein conformation in close proximity to the PIP2 binding site induced by a small-molecule SK channel modulator, NS309, can effectively enhance the interaction between the protein and PIP2 to potentiate channel activity. This novel modulation of PIP2 sensitivity by small-molecule drugs is likely not to be limited in its application to SK channels, representing an intriguing strategy to develop drugs controlling the activity of the large number of PIP2-dependent proteins.

Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors, Bruno Ramos-Molina, Adam N. Lick, Amir Nasrolahi Shirazi, Donghoon Oh, Rakesh Tiwari, Naglaa Salem El-Sayed, Keykavous Parang, Iris Lindberg

Pharmacy Faculty Articles and Research

Cationic cell-penetrating peptides have been widely used to enhance the intracellular delivery of various types of cargoes, such as drugs and proteins. These reagents are chemically similar to the multi-basic peptides that are known to be potent proprotein convertase inhibitors. Here, we report that both HIV-1 TAT47-57 peptide and the Chariot reagent are micromolar inhibitors of furin activity in vitro. In agreement, HIV-1 TAT47-57 reduced HT1080 cell migration, thought to be mediated by proprotein convertases, by 25%. In addition, cyclic polyarginine peptides containing hydrophobic moieties which have been previously used as transfection reagents also exhibited potent furin inhibition in vitro …