Pharmaceutics and Drug Design Commons^™

A Robust Delivery System For Rna Therapeutics, Suleyman Bozal

University Scholar Projects

The field of RNA therapeutics is currently undergoing both transformation and expansion. Specifically, research in lipid nanoparticle (LNP) based RNA therapeutics is gaining significant traction. Other research into mechanisms of gene regulation and manipulation, including siRNA and the CRISPR/Cas9 system have demonstrated the potential of RNA-based disease treatment. This work identifies a delivery system which can regulate expression of green fluorescent protein (GFP) in human embryonic kidney cells (HEK293) stably expressing GFP.

Analysis of siRNA-induced gene knockdown demonstrates that the current siRNA-LNP formulation is equally as effective as a commercially available transfection reagent, Lipofectamine RNAiMAX (RNAiMAX), which is designed specifically …

A Robust Delivery System For Rna Therapeutics, Suleyman Bozal

Honors Scholar Theses

The field of RNA therapeutics is currently undergoing both transformation and expansion. Specifically, research in lipid nanoparticle (LNP) based RNA therapeutics is gaining significant traction. Other research into mechanisms of gene regulation and manipulation, including siRNA and the CRISPR/Cas9 system have demonstrated the potential of RNA-based disease treatment. This work identifies a delivery system which can regulate expression of green fluorescent protein (GFP) in human embryonic kidney cells (HEK293) stably expressing GFP.

Analysis of siRNA-induced gene knockdown demonstrates that the current siRNA-LNP formulation is equally as effective as a commercially available transfection reagent, Lipofectamine RNAiMAX (RNAiMAX), which is designed specifically …

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 Macromolecular Prodrug Conjugates For The Treatment Of Inflammatory Diseases, Gang Zhao

Theses & Dissertations

Inflammation is the complex biological response to the stimuli triggered by various factors like pathogens, damaged cells, or irritants. Constant uncontrolled acute inflammation may become chronic conditions, leading to significant tissue damage, contributing to a series of chronic inflammatory diseases. Our lab has been working on the different types of inflammatory diseases and has developed multiple macromolecular prodrug conjugates for the better therapeutic efficacy and reduced toxicity. The general approach we have taken is to incorporate small molecules containing monomers into water-soluble and biocompatible polymers, such as N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers. The superior and the sustained efficacy of those macromolecular …

Development Of Approaches Of Tumor Trapping Enhanced Bb2r-Targeted Radiopharmaceuticals For Prostate Cancer, Wenting Zhang

Theses & Dissertations

The Gastrin-Releasing Peptide Receptor (BB2r) has been intensively investigated as a cancer target over the years. Numerous diagnostic and therapeutic BB2r-targeted agents have been developed for various solid tumors, including prostate cancers, due to the high expression level of BB2r on neoplastic relative to normal tissues. The development of those targeted agents have mainly utilized the modified c-terminal of bombesin(BBN), a peptide that has nanomolar binding affinity to human BB2r. However, a major issue that hinders the clinical translational potential of low-molecular weight, receptor-targted agents, is their short residence time at tumor tissues due to the intrinsically high diffusion and …

Synthesis And Characterization Of A Long-Acting Emtricitabine Prodrug Nanoformulation, Ibrahim M. Ibrahim

Theses & Dissertations

The introduction of highly active antiretroviral therapy led to a paradigm shift in the management of HIV/AIDS changing a disease considered “a death sentence” to “a manageable chronic disease”. Nevertheless, challenges exist for successful treatment of HIV, including patient adherence to the complex daily regimens and the inability of current formulations to target viral sanctuaries. Introduction of nanoformulated antiretroviral therapy (ART) is a promising alternative to tackle these challenges. Our laboratory has been focusing on developing long-acting (LA) nanoformulated antiretrovirals and has succeeded in developing LA integrase inhibitors. However, challenges for this approach extend to a range of short-acting hydrophilic …

Human Immunodeficiency Virus Theranostics, Christopher J. Woldstad

Theses & Dissertations

RATIONALE: Long-acting slow effective release antiretroviral therapy (LASER ART) was developed to improve patient regimen adherence, prevent new infections, and facilitate drug delivery to human immunodeficiency virus cell and tissue reservoirs. However, maintenance of sustained plasma drug levels, for weeks or months, after a single high-level dosing, could improve regimen adherence but, at the same time, affect systemic toxicities. Of these, the most troubling are those that affect the central nervous system (CNS) In an effort to facilitate LASER ART development, “multimodal imaging theranostic nanoprobes” were created. These allow combined bioimaging, drug pharmacokinetics and tissue biodistribution tests in animal …

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 …

Iron-Containing Nanoparticles For The Treatment Of Chrionic Biofilm Infections In Cystic Fibrosis, Leisha M. A. Martin

Nanoscience and Microsystems ETDs

Cystic fibrosis (CF) is the most common genetic disease resulting in the morbidity and mortality of Caucasian children and adults worldwide. Due to a genetic mutation resulting in malfunction of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, CF patients produce highly viscous mucus in their respiratory tract. This leads to impairment of the mucociliary clearance of inhaled microbes. In addition to reduced microbial clearance, anoxic environmental conditions in the lungs promote biofilm-mode growth of the pathogenic bacterial species Pseudomonas aeruginosa. Chronic infections of P. aeruginosa begin in early childhood and typically persist until respiratory failure and death result. The …

Synthesis And Antiproliferative Activities Of Conjugates Of Paclitaxel And Camptothecin With A Cyclic Cell-Penetrating Peptide, Naglaa Salem El-Sayed, Amir Nasrolahi Shirazi, Muhammad Imran Sajid, Shang Eun Park, Keykavous Parang, Rakesh Tiwari

Pharmacy Faculty Articles and Research

Cell-penetrating peptide [WR]5 has been previously shown to be an efficient molecular transporter for various hydrophilic and hydrophobic molecules. The peptide was synthesized using Fmoc/tBu solid-phase chemistry, and one arginine was replaced with one lysine to enable the conjugation with the anticancer drugs. Paclitaxel (PTX) was functionalized with an esterification reaction at the C20 hydroxyl group of PTX with glutaric anhydride and conjugated with the cyclic peptide [W(WR)4K(bAla)] in DMF to obtain the peptide-drug conjugate PTX1. Furthermore, camptothecin (CPT) was modified at the C(20)-hydroxyl group through the reaction with triphosgene. Then, it was conjugated with two functionalized cyclic peptides through …

The Landscape Of Cellular And Gene Therapy Products: Cost, Approvals, And Discontinuations, Vaishali Shukla, Enrique Seoane-Vazquez, Souhiela Fawaz, Lawrence M. Brown, Rosa Rodriguez-Monguio

Pharmacy Faculty Articles and Research

Background The past 10 years witnessed a significant increase in the approval of cellular and gene therapy products worldwide. The US Food and Drug Administration (FDA) approved 3 gene therapy products within the last 4 months of 2017. The objective of this study was to examine the approval characteristics, discontinuations and cost of all cellular and gene therapy products approved worldwide. Data and Methods We conducted an electronic search of approved cell and gene therapy products from the databases of the main drug regulatory agencies including the US Food and Drug Administration, the European Medicines Agency (EMA), the Korea Ministry …

The Impact Of Concomitant Empiric Cefepime On Patient Outcomes Of Methicillin-Resistant Staphylococcus Aureus Bloodstream Infections Treated With Vancomycin, Evan J. Zasowski, Trang D. Trinh, Safana M. Atwan, Marina Merzlyakova, Abdalhamid M. Langf, Sahil Bhatia, Michael J. Rybak

Faculty Publications & Research of the TUC College of Pharmacy

Background: Data suggest that vancomycin + β-lactam combinations improve clearance of methicillin-resistant Staphylococcus aureus(MRSA) bloodstream infections (BSIs). However, it is unclear which specific β-lactams confer benefit. This analysis evaluates the impact of concomitant empiric cefepime on outcomes of MRSA BSIs treated with vancomycin.

Methods: Retrospective cohort study of adults with MRSA BSI from 2006 to 2017. Vancomycin + cefepime therapy was defined as ≥24 hours of cefepime during the first 72 hours of vancomycin. The primary outcome was microbiologic failure, defined as BSI duration ≥7 days and/or 60-day recurrence. Multivariable logistic regression was used to evaluate the association between …

The Pharmabiotic For Phenylketonuria: Development Of A Novel Therapeutic, Chloé Elizabeth Lebegue

Senior Theses

Phenylketonuria, now known as phenylalanine hydroxylase (PAH) deficiency, is a genetic disorder of metabolism affecting approximately one in every 15,000 infants born in the United States. Patients have nonfunctional PAH enzyme secondary to one or more genetic mutations. The enzyme deficit results in destructive supraphysiologic blood phenylalanine levels upon consumption of the essential dietary amino acid phenylalanine. Current standards of care mitigate signs and symptoms of the disorder, but do not approach a cure. The methods for creating a prototype pharmabiotic as an innovative treatment strategy for PAH deficiency are described herein.

DNA molecular cloning techniques were utilized to engineer …

Systematic Literature Review Of Quetiapine For The Treatment Of Psychosis In Patients With Parkinsonism, Jack J. Chen, Henry Hua, Lilian Massihi, Ivan Portillo, Azita Alipour, William Ondo, Khashayar Dashtipour

Library Articles and Research

Objective:

The purpose of this article was to determine the efficacy and tolerability of quetiapine compared with placebo or other interventions for psychosis in parkinsonism.

Methods:

Participants with a diagnosis of parkinsonism participated in randomized controlled trials (RCTs) investigating the efficacy and tolerability of quetiapine for psychotic symptoms within a defined follow-up period. The authors conducted searches on PubMed, Cochrane Controlled Register of Trials, and EMBASE for articles published from January 1991 to October 2017. Study methodology and patient- and treatment-level data were independently extracted and summarized by using descriptive statistics. Studies underwent quality assessment for risk of bias.

Results: …

Novel Flexible Heteroarotinoid, Sl-1-39, Inhibits Her2-Positive Breast Cancer Cell Proliferation By Promoting Lysosomal Degradation Of Her2., Hongye Zou, Mary B. Sevigny, Shengquan Liu, David T. Madden, Maggie C. Louie

Faculty Publications & Research of the TUC College of Pharmacy

SL-1-39 [1-(4-chloro-3-methylphenyl)-3-(4-nitrophenyl)thiourea] is a new flexible heteroarotinoid (Flex-Het) analog derived from the parental compound, SHetA2, previously shown to inhibit cell growth across multiple cancer types. The current study aims to determine growth inhibitory effects of SL-1-39 across the different subtypes of breast cancer cells and delineate its molecular mechanism. Our results demonstrate that while SL-1-39 blocks cell proliferation of all breast cancer subtypes tested, it has the highest efficacy against HER2+ breast cancer cells. Molecular analyses suggest that SL-1-39 prevents S phase progression of HER2+ breast cancer cells (SKBR3 and MDA-MB-453), which is consistent with reduced expression of key cell-cycle …

Small Peptide Ligands For Targeting Egfr In Triple Negative Breast Cancer Cells, Hanieh Hossein-Nejad-Ariani, Emad Althagafi, Kamaljit Kaur

Pharmacy Faculty Articles and Research

The efficacy of chemotherapy for cancer treatment can be increased by targeted drug delivery to the cancer cells. This is particularly important for triple negative breast cancer (TNBC) for which chemotherapy is a major form of treatment. Here we designed and screened a library of 30 peptides starting with a previously reported epidermal growth factor receptor (EGFR) targeting peptide GE11 (YHWYGYTPQNVI). A direct peptide array-whole cell binding assay, where the peptides are conjugated to a cellulose membrane, was used to identify four peptides with enhanced binding to TNBC cells. Next, the four peptides were synthesized as FITC-labelled soluble peptides to …

Synthesis, Biological Evaluation And Molecular Modeling Studies Of Novel Chromone/Aza-Chromone Fused Α-Aminophosphonates As Src Kinase Inhibitors, S. Bapat, N. Viswanadh, M. Mujahid, Amir Nasrolahi Shirazi, Rakesh Tiwari, Keykavous Parang, M. Karthikeyan, M. Muthukrishnan, Renu Vyas

Pharmacy Faculty Articles and Research

A series of novel chromone/aza-chromone fused α-aminophosphonate derivatives were synthesized in good yields using silica chloride as the catalyst. All the synthesized compounds were tested for their c-Src kinase inhibitory activity. Aza-chromone compound showed Src kinase inhibition with an IC50 value of 15.8 µM. The compounds were subjected to molecular docking and dynamics simulations to study the atomic level interactions with an unphosphorylated proto-oncogenic tyrosine protein kinase Src (PDB code 1Y57) as well as phosphorylated tyrosine protein kinase Src (PDB code 2H8H). Docking and molecular dynamic results revealed phosphorylated Src tyrosine kinase protein better results than unphosphorylated tyrosine Src kinase …

Car T Cells As A Patentable Therapeutic, Mckenzie List

Honors Program Theses

The development of a therapeutic to treat a particular disease is a complicated process that incorporates numerous components such as drug discovery, clinical trials, FDA approval and patentability. In the last two decades, cancer research and development has shifted from identifying small molecule therapeutic agents to focusing research on a novel approach designated as immunotherapy. Today, immunotherapy has progressed from a twentieth century scientific theory into an innovative treatment to cancer. In particular, CAR T cells have demonstrated therapeutic properties for certain types of cancers, but these living cells are not compatible with the traditional therapeutic model. First, the drug …

Inhibition Of Cancer Stem Cells By Glycosaminoglycan Mimetics, Connor P. O'Hara

Theses and Dissertations

Connor O’Hara July 29, 2019

Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics

In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.¹ The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.² As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).³ The 5-year survival rate …