Pharmacy and Pharmaceutical Sciences Commons^™

Epigenetic Regulation Of Immune Responses In Autoimmune Diseases And Cancer: Mechanisms And Therapeutic Implications, Faisal H. Al-Amier, Ammar B. Al-Asadi, Aljuboori M. Nafea, Karar M. Jaleel

Al-Esraa University College Journal for Medical Sciences

Immune tolerance balances immune responses with self-tolerance, a balance that is directive by epigenetic pathways. These mechanisms responsible for gene expression regulation and immune cell activity, and include DNA methylation, histone modifications, and non-coding RNAs. Disruption of mechanisms involved in the autoimmune disorder pathophysiology like systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis through the induction of long term inflammation and breakdown of immune tolerance. In cancer, epigenetic changes allow immune evasion and establish an immunosuppressive tumor microenvironment. Epigenetic markers have been used for diagnosis and prognosis, and epigenetic treatments have the potential to rebalance the immune system and improve …

Tumor Targeting With Peptide-Drug Conjugates: Showcasing Key Progress And Hurdles, Keykavous Parang, Thuy Do, Clare Dinh, Dorna Davanidavari, Max Foroughi, Troy Khong, Mahsa Moazen, Amir Nasrolahi Shirazi

Pharmacy Faculty Articles and Research

Peptide-drug conjugates (PDCs) are modular, targeted therapeutics composed of a homing peptide linked to a cytotoxic or modulating drug payload via a cleavable/non-cleavable linker. PDCs utilize peptide targeting to enhance the delivery of potent drugs to tumors, providing advantages such as superior tissue penetration, reduced immunogenicity, and simpler manufacture compared to antibody-drug conjugates (ADCs). A comparison of PDCs versus ADCs highlights that PDCs’ small size (~1-3 kDa) enables deeper tumor penetration and faster clearance, whereas ADCs (~150 kDa) benefit from prolonged circulation but suffer from limited tissue diffusion. This review surveys recent advances in PDC design and application. We discuss …

Host-Derived Interleukin-1Α Drives Tumor Immunosuppression By Reprogramming Tumor-Associated Myeloid Cells, Manikanda Raja Keerthi Raja, Gourab Gupta, Grace Atkinson, Katie Kathrein, Alissa R. Armstrong, R. Michael Gower, Igor Roninson Ph.D., Eugenia Broude, Mengqian Chen Ph.D., Hao Ji, Chang-Uk Lim, Hongjun Wang, Daping Fan, Peisheng Xu Ph.D., Hexin Chen

Faculty Publications

Myeloid cells are highly heterogeneous and play key roles in establishing an immunosuppressive tumor microenvironment (TME), but the mechanisms controlling their differentiation remain unclear. Using orthotopic murine breast cancer models, we investigated how interleukin-1α (IL-1α) influences this process. Deletion of host Il1α resulted in rejection of transplanted tumors. Single-cell RNA sequencing identified CX3CR1⁺ macrophages as the main source of IL-1α in the TME. Il1α deficiency disrupted monocyte–macrophage differentiation, reducing CX3CR1⁺ macrophages and increasing iNOS⁺ macrophages. Myeloid cells from Il1α⁻/⁻ hosts induced lower PD-1 and CTLA-4 expression in co-cultured CD8⁺ T cells than those from wild-type hosts. CellChat analysis showed …

From Fog To Function: An Occupational Therapist's Guide To Evaluating And Treating Cancer-Related Cognitive Impairments, Lauren E. Toner

Entry-Level Occupational Therapy Doctorate - Doctoral Capstone Symposium

Cancer – related cognitive impairment (CRCI) is a common side effect of cancer treatment that interferes with cancer survivors’ occupational performance, independence, and quality of life. Despite its high prevalence, CRCI remains under recognized and inconsistently addressed within oncology care. About 70% of individuals diagnosed with cancer report cognitive changes during or after treatment, yet many do not receive treatment. Occupational therapists are clinically trained to evaluate and treat functional cognition, activities of daily activities, instrumental activities of daily living, and client centered goals, positioning them as key providers in addressing CRCI. However, limited occupational therapy specific resources have hindered …

Development Of Tunable Rose Bengal Based-Nanogumbos As Potential Selective Chemotherapeutic Agents, William J.A. Russell

Honors College Theses

As cancer remains one of the greatest threats to the global population, the development of chemotherapeutic agents that are selective and tunable is of critical importance. Herein, a series of Rose Bengal (RB)-based GUMBOS, a group of uniform materials based on organic salts, were synthesized via counterion exchange between [Na]₂[RB] and three organic cations: tetrabutylphosphonium bromide [TBP][Br], tetraphenylphosphonium chloride [TPP][Cl], and 1-dodecyl-3-methylimidazolium chloride [C₁₂MIm][Cl]. The resulting GUMBOS were characterized through FT-IR, ESI-MS, NMR, and UV-Vis Spectroscopy. Partition coefficient studies indicated all GUMBOS exhibited hydrophobic physiochemical characteristics. These hydrophobic RB-based GUMBOS …

Clinical Outcomes With Perioperative Nivolumab By Nodal Status In Patients With Stage Iii Resectable Nsclc: Phase 3 Checkmate 77t Exploratory Analysis, Mariano Provencio, Mark M Awad, Jonathan D Spicer, Annelies Janssens, Fedor Moiseyenko, Yang Gao, Yasutaka Watanabe, Aurelia Alexandru, Florian Guisier, Nikolaj Frost, Fabio Franke, T Jeroen Nicolaas Hiltermann, Jie He, Fumihiro Tanaka, Shun Lu, Cinthya Coronado Erdmann, Padma Sathyanarayana, Phuong Tran, Vipul Devas, Tina Cascone

Faculty, Staff and Student Publications

Individuals with non-small-cell lung cancer (NSCLC) with metastases to the ipsilateral mediastinum or subcarinal lymph nodes (N2 disease) have poor long-term survival. This exploratory analysis from the randomized phase 3 CheckMate 77T study assessed clinical outcomes by nodal status in individuals with stage III NSCLC who received neoadjuvant nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab (nivolumab) versus neoadjuvant chemotherapy followed by surgery and adjuvant placebo (placebo). Here we show that among patients with N2 disease, nivolumab versus placebo improved event-free survival (1-year rate, 70% versus 45%; hazard ratio, 0.46 (95% confidence interval, 0.30–0.70)) and pathological complete response rate …

Implementing A Standardized App-Led Multidisciplinary Medication Review And Reconciliation To Improve Medication Safety Before Systemic Cancer Therapy: An Ambulatory Oncology Quality Improvement Initiative, Sarah R. Hines

DNP Projects

Background

Adult patients initiating systemic cancer therapy frequently present with pre-existing polypharmacy related to chronic comorbidities and cancer-related symptom management. The addition of anticancer therapies and supportive care medications further increases medication burden and the risk of medication-related harm. Although national organizations and institutional policies recommend comprehensive medication review before treatment initiation, implementation remains inconsistent in ambulatory oncology practice.

Purpose

To implement and evaluate a standardized Advanced Practice Provider (APP)-led multidisciplinary medication review and reconciliation process designed to identify medication medication-related safety risks before initiation of systemic cancer therapy in adult oncology patients receiving care in an ambulatory infusion center. …

Multidrug Resistance: Are We Still Afraid Of The Big Bad Wolf, Abdulelah Alhazza, Adenike Oyegbesan, Emira Bousoik, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

After the era of multidrug resistance (MDR) against cytotoxic chemotherapy, the development of resistance against newly developed molecularly targeted drugs also seems inevitable. While the mechanisms involved in resistance against these two categories of anticancer drugs are different, the principles are similar: inherent resistance (also known as primary resistance) is a result of heterogeneity in cancer cells where a subpopulation of the cells do not show a favorable initial response to the drug, while acquired resistance (or secondary resistance), as the name suggests, is developed after repeated treatments due to the plasticity of cancer cells. Despite the introduction of a …

Engineering Lipid–Polymer Nanoparticles For Sirna Delivery To Cancer Cells, Arthur Manda, Abdulelah Alhazza, Hasan Uludağ, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

Background: RNA interference (RNAi) is a powerful tool that can target many proteins without the expensive and time-consuming drug development studies. However, due to the challenges in delivering RNA molecules, the potential impact of RNAi approaches is yet to be fully realized in clinical settings. Lipid nanoparticles (LNPs) have been the most successful delivery system for nucleic acids, but targeted delivery to a solid tumor still eludes the developed LNPs. We hypothesized that specially designed low-molecular-weight PEIs can partially or completely replace the ionizable lipids for more accommodating vehicles due to the structural flexibility offered by polymers, which could …

Machine Learning And Protein Engineering Approaches To Understanding Kinesin-5 Activity, Jason Eden Sanchez

Open Access Theses & Dissertations

Cancer is a term describing a collection of diseases that result in uncontrolled cell growth. Cancer has manifold etiologies and underlying cancers are rouge biochemical pathways involving many different proteins. In the current work, two approaches are used to enhance knowledge of kinesin-5, a potential cancer target involved in cell division. Kinesin-5 promotes cell division by cross-linking and separating microtubules in dividing cells. The first approach uses machine learning (ML) to identify small molecule inhibitors for kinesin-5. Though decades of research have uncovered classes of small-molecules which inhibit kinesin-5 in vitro and in vivo, no candidates have reached phase III …

Studies To Understand The Stability And Liabilities Of Legumain-Cleavable Antibody-Drug Conjugates, Michele Yi

Undergraduate Honors Theses

Antibody-drug conjugates (ADCs) offer targeted drug delivery of potent cytotoxic payloads, minimizing systemic toxicity. However, the stability of the linker is integral to ensure that there is minimal off-target payload release and little systemic toxicity. This study analyzes the physical and biological stability of our new legumain-cleavable vs traditional cathepsin-cleavable antibody-drug conjugates (ADCs), with a focus on hydrophobicity, thermal stability, aggregation, and biological payload release. Our findings indicate that decreased hydrophobicity of the legumain-cleavable ADCs compared to cathepsin-cleavable ADCs is correlated with decreased aggregation (predicting lower uptake by liver macrophages and therefore slower clearance and less systemic toxicity) and lower …

Optimization Of Localized Photothermal Therapy Utilizing Liposomal Formulation Of Ir-820 Photoactive Dye, Dinesh Shrestha, Viswanathan Sundaram, Shoukath Sulthana, Danyel Manteufel, Shelby Metcalf, Santosh Aryal

Pharmacy Faculty Publications and Presentations

Current phototherapeutic approaches in cancer treatment include photothermal (PTT) and photodynamic (PDT) therapy, which harness light energy for the activation of a photoactive molecule resulting in the destruction of cancer cells. In PTT, generated local heat kills abnormal cells; whereas, in PDT, a series of biochemical reactions generating reactive oxygen species is responsible for cellular damage. However, a major concern arises in the cellular delivery of an optimal amount of a photoactive molecule required for the desired effect. In this work, we employed IR-820, a new Indocyanine green dye, in a liposomal formulation to maximize its delivery to cancer cells …

Synthesis Of Tu100 Analogs And Biological Assays, Feyisope Tonye Oladapo

College of Graduate Studies: Theses & Dissertations

TU100 (14-methyl-5H-5,12-epiminobenzo[4,5]cyclohepta[1,2-b]naphthalene-6,11,13(12H)-trione) exhibits exceptional chemotherapeutic properties. It operates via a distinct mechanism that triggers cell death to create cytotoxic effects while concurrently inhibiting topoisomerase I and II. Its efficacy rivals that of well-known chemotherapeutic drugs like Daunorubicin. The distinctive characteristics of TU100 have led to initiatives aimed at creating structurally similar compounds to discover even more effective bioactive alternatives.

The analog synthesis incorporated quinoxaline or its derivatives (diphenyl quinoxaline, dipyridinyl quinoxaline, and dibenzophenazine-10,13-dione) that have been shown to have promising chemotherapeutic effects. Synthesizing the hetero naphthoquinones required a multi-step synthetic process, so quinoxaline/ derivatives intermediates are first prepared, then the …

Discovering Therapeutic Strategies In Colorectal Cancer Via Synthetic Lethal Genetic Screens On Patient-Derived Organoid Models, Sana Khalili

Theses and Dissertations

Precision medicine is a revolutionary approach of targeting genetic alterations that are present only in tumor cells to find vulnerabilities that can be targeted with therapy. Identifying genetic dependencies in human colon cancer could help identify effective treatment strategies. Genome-wide CRISPR-Cas9 dropout screens can reveal all genetic dependencies, some of which could be exploited as therapeutic targets using existing drugs.

In this dissertation, I comprehensively characterized genetic dependencies present in a colon cancer organoid avatar, and validated tumor-specific selectivity of select pharmacologic agents. I identified all somatic mutations, all expressed genes, and conducted a genome-wide CRISPR dropout screen to elucidate …

Selective And Brain-Penetrant Acss2 Inhibitors Target Breast Cancer Brain Metastatic Cells, Emily Esquea, Lorela Ciraku, Riley Young, Jessica Merzy, Alexandra Talarico, Nusaiba Ahmed, Mangalam Karuppiah, Anna Ramesh, Adam Chatoff, Claudia Crispim, Adel Rashad, Simon Cocklin, Nathaniel Snyder, Joris Beld, Nicole Simone, Mauricio Reginato, Alexej Dick

Kimmel Cancer Center Faculty Papers

Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeline to identify novel brain-penetrant ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, and excretion (ADME) property predictions. We identified compounds AD-5584 and AD-8007 that were validated for specific binding affinity to ACSS2. Treatment of BCBM cells with AD-5584 and AD-8007 leads to …

Assessment Of In-Vitro And In-Vivo Pre-Clinical Pharmacokinetics Of Epz015666; A Novel Small Molecule For Medulloblastoma Treatment, Pratiksha U. Kshirsagar

Theses & Dissertations

Group 3 medulloblastoma (MB) has the worst prognosis of the MB subgroups associated with elevated MYC expression and a 5-year survival rate of

Quantitation of EPZ was performed on a Shimadzu LC-MS/MS system utilizing electrospray ionization operated in positive mode. The validated assay was linear from 0.2 to 500 ng/mL. Metabolic stability studies demonstrated slow intrinsic clearance of EPZ in mouse and human liver microsomes, suggesting no CYP-mediated metabolism. Additionally, EPZ exhibited low binding affinity to plasma and brain proteins and high apparent permeability across artificial membranes, indicating efficient membrane penetration. Drug transporter studies identified EPZ as a substrate of …

Neoadjuvant Versus Adjuvant Therapy For Stage Iiib-Iiid Melanoma, Bhumik Patel, Sangnya Upadhyaya

Rowan-Virtua Research Day

The treatment landscape for advanced stage melanoma is rapidly evolving due to advancements in our understanding of melanoma biology and the emergence of novel therapies. This necessitates a comprehensive review to guide clinicians in adopting evidence based and patient centric approaches to treat stage IIIB-IIID melanoma. A literature review was conducted to synthesize current information on the most optimal treatment available. Data available from different clinical trials found that neoadjuvant therapy was a more effective treatment compared to adjuvant therapies alone. Furthermore, neoadjuvant therapy with combination therapy was more efficacious in producing a complete pathological response compared to monotherapy. A …

Bcl2 Mediated Targeted Drug Delivery For The Treatment Of Kidney Fibrosis And Stomach Cancer, Humayra Afrin

Open Access Theses & Dissertations

Apoptosis, the programmed death of cells, is primarily regulated by a delicate balance between pro-apoptotic and anti-apoptotic signals. The Bcl-2 (B-cell lymphoma 2) family of proteins acts as anti-apoptotic agents, promoting cell survival. Dysregulation of these proteins is a common occurrence in conditions such as cancer and fibrosis, where overexpression of anti-apoptotic members can foster tumor cell survival and fibroblast activation. In this study, our aim was to explore the therapeutic potential of Bcl-2 inhibitors, both as a small molecule (specifically Navitoclax (Navi)), inhibitor and as Bcl-2 siRNA, for targeted treatment. Intravenous administration of Navi often leads to thrombocytopenia, necessitating …

Synthesis And Characterization Of Polymeric Nanoparticles To Enhance Celleullar Drug Delivery, Rahma Aly

Chemistry Theses

Medicines in the form of nanoparticles called nanomedicines, stand at the forefront of revolutionary advancements in healthcare, offering precise drug delivery and diagnostic capabilities. A recent example of nanomedicine in the clinic is the COVID-19 vaccine, which helped prevent death during the pandemic. While the potential benefits are immense, a myriad of challenges complicate their seamless integration into clinical practice. The design and fabrication of nanoparticles demand meticulous attention to biocompatibility and toxicity. Interactions with biological systems are complex, requiring a delicate balance between therapeutic efficacy and safety. The reticuloendothelial system's rapid clearance of nanoparticles, their instability in physiological environments, …

Targeting Strategies To Optimize The Therapeutic Potential Of Gold Compounds Against Her2-Positive Breast Cancers, Afruja Ahad

Dissertations, Theses, and Capstone Projects

The overexpression of HER2 accounts for 20-30% of breast cancer tumors and not only serves as a marker for poor predictive clinical outcomes but also as a target for treatment. Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies (mAbs) with the efficacy of chemotherapeutic drugs to provide targeted treatment without toxicity to normal tissue. Most of the ADCs currently in the clinic for cancer chemotherapy are based on complex organic molecules. In contrast, the conjugation of metallodrugs to mAbs has been overlooked when there is enormous potential in this area with the resurgence of metal-based drugs as prospective cancer …

Investigating The Use Of Serious Games For Cancer Control Among Children And Adolescents: Scoping Review, Sunghak Kim, Ebling Library, Olufunmilola Abraham

Pharmacy Practice and Science Faculty Publications

Background: Effective health care services that meet the diverse needs of children and adolescents with cancer are required to alleviate their physical, psychological, and social challenges and improve their quality of life. Previous studies showed that serious games help promote people’s health. However, the potential for serious games to be used for successful cancer control for children and adolescents has received less attention.

Objective: This scoping review aimed to map the use of serious games in cancer prevention and cancer care for children and adolescents, and provide future directions for serious games’ development and implementation within the context of cancer …

Application Of Interpretable Machine Learning Methods To Study The Disease Characteristics And Healthcare Expenditures In Hodgkin’S Lymphoma, Zasim Azhar Dil Hasan Siddiqui

Graduate Theses, Dissertations, and Problem Reports (ETD)

Hodgkin’s lymphoma (HL) is a rare malignancy of lymphocytes that predominantly occurs in young adults aged 20-30 years or elderly individuals aged 65-75 years. Despite its low incidence, there were an estimated 223,512 HL survivors in the US in 2020. Hodgkin’s lymphoma shows a favorable prognosis among young adults, with a high cure rate of 85-90%; however, older adults experience poor prognosis, with a 5-year overall survival rate of 40-55% in patients over 60 years. HL survivors incur high total and out-of-pocket (OOP) healthcare expenditures, averaging $78,183 and $4,180 per patient in the first year after diagnosis, highlighting a considerable …

Treatment Patterns And Clinical And Economic Burden In Patients With Merkel Cell Carcinoma: Statistical And Machine Learning Approaches, Yves Mbous

Graduate Theses, Dissertations, and Problem Reports (ETD)

Although considered a rare form of nonmelanoma skin cancer, Merkel Cell Carcinoma incidence rate has increased to 0.74 per 100,000 and projections expect this number to steadily rise over the next decades and to reach an average of 3,285 cases per year in 2025. MCC incidence increases significantly with age. Among those aged 40-44, it is 0.44, it rises to 1.0/100,000 in the 60-64 age group and soars to 9.8/100,000 among those ≥85 years and above. Due to the small number of cases, MCC is often managed using institutional practices or provider preferences. Formal clinical trials that enroll early stage …

Discovery Of Novel Hit Molecules Targeting Parp1 Using Structure-Based Design, Shahrazad Polk

Dissertations (2016-Present)

In the United States of America alone, cancer is the second highest cause of death. While there have been many remarkable breakthroughs in cancer research, there is still a need for the development of new therapies that target the different mechanisms of cancer cells. Therefore, the focus of our research is identifying novel hit molecules targeting Poly (ADP-ribose) polymerase 1. Poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme that has many distinct functions in the body. PARP1 has four domains: zinc fingers also known as the DNA binding domain, BRCT domain, WGR domain, and the ART catalytic domain. Its most …

Tigit Contributes To The Regulation Of 4-1bb And Does Not Define Nk Cell Dysfunction In Glioblastoma, Kyle B. Lupo, Sandra Torregrosa-Allen, Bennett D. Elzey, Sagar Utturkar, Nadia A. Lanman, Aaron A. Cohen-Gadol, Veronika Silvova, Mackenzie Mcintosh, Karen E. Pollok, Sandro Matosevic

Purdue University Libraries Open Access Publishing Fund

TIGIT is a receptor on human natural killer (NK) cells. Here, we report that TIGIT does not spontaneously induce inhibition of NK cells in glioblastoma (GBM), but rather acts as a decoy-like receptor, by usurping binding partners and regulating expression of NK activating ligands and receptors. Our data show that in GBM patients, one of the underpinnings of unresponsiveness to TIGIT blockade is that by targeting TIGIT, NK cells do not lose an inhibitory signal, but gains the potential for new interactions with other, shared, TIGIT ligands. Therefore, TIGIT does not define NK cell dysfunction in GBM. Further, in GBM, …

Characterization Of Epithelial Growth Factor Transcripts Identified In Crotalus Atrox Venom, Ivan Lopez, Ying Jia

Research Symposium

Epithelial Growth Factor (EGF) is the primary source in regeneration and stimulation of essential fibroblasts cells commonly found in epithelium. Studies have shown that snake venom components are becoming a growing factor in treating illnesses such as cancer, muscular dystrophy, chronic pain, blood pressure, blood clotting, etc. EGF in human cells contains a promising quaternary structure that can bind to snake venom metalloproteinases, proposing a means of activating biochemical responses through protein-protein interactions to regulate unwanted cellular functions. This supports promising research in achieving a greater understanding of regulation along cellular pathways through ligands, increasing the likelihood of targeting unwanted …

Assessment Of Adherence To National Comprehensive Cancer Network Guideline Recommended Anticoagulant Therapy In The Management Of Patients With Cancer-Associated Venous Thromboembolic Disease, Ghufran Hassoun Naeemah, Ayad Ali Hussein Ameen

Maaen Journal for Medical Sciences

Background: Venous thromboembolism (VTE), a vascular disorder, is a serious and sometimes fatal problem, ranking as the second-deadliest complication for people with cancer. VTE includes pulmonary embolism, superficial vein thrombosis, deep vein thromboembolism, and internal vein thrombosis. It is important to note that cancer patients have almost nine times higher odds of dying from this illness. Objective: The Najaf Cancer Center conducted a study to evaluate the effectiveness of oncologist strategies in the prevention and treatment of cancer-associated venous thromboembolism (VTE). The primary objective was to measure the adherence of VTE patients to anticoagulant therapy recommended by the NCCN guidelines. …

Design, Molecular Modelling And Synthesis Of Novel Benzothiazole Derivatives As Bcl-2 Inhibitors, Amira Khalil, Hoda S. Ismail, Dalal A. Abou El Ella, Deena S. Lasheen, Rabah A. Taha

Pharmacy

Apoptosis plays a crucial role in cancer pathogenesis and drug resistance. BCL-2 family of enzymes is considered as one of the key enzymes which is involved in apoptosis. When there is disruption in the balance between anti-apoptotic and pro-apoptotic members of the BCL-2 family apoptosis is dysregulated in the affected cells. Herein, 33 novel benzothiazole-based molecules 7a-i, 8a-f, 9a-b, 12a-e, 13a-d, 14a,b, and 17a-j were designed, synthesized and tested for their BCL-2 inhibitory activity. Scaffold hopping strategy was applied in designing of the target compounds. Compounds 13c and 13d showed the highest activity with IC50 values equal to 0.471 and …

Isolation And Total Synthesis Of Sigma-2 Ligands From Marine Cyanobacteria, Andrea Hough

Electronic Theses and Dissertations

Cyanobacteria have been studied for over 50 years as a source of new antibiotics, antiviral, and anticancer drugs. The research described in this dissertation investigates marine cyanobacteria as a source of natural products with activity within the central nervous system and with cytotoxicity against breast cancer cells. Barbamide (1) is a known cyanobacterial metabolite that has been re-isolated from a variety of species and collection sites suggesting broad utility as a signaling molecule. Utilizing the psychoactive drug screening program, we screened barbamide for CNS activity and found that barbamide exhibited affinity for the kappa opioid receptor (KOR) and …

Design, Synthesis, And Evaluation Of Oleyl-Wrh Peptides For Sirna Delivery, Mrigank S Rai

Pharmaceutical Sciences (MS) Theses

The delivery of nucleic acid therapeutics across various cell membranes has always been one of the major challenges. Cell-penetrating peptides (CPPs) containing arginine (R), tryptophan (W), and histidine (H) have been promising for siRNA delivery. Therefore, to enhance siRNA delivery and efficient silencing of the STAT3 gene, herein, we hypothesized to use of fatty acylation with oleyl chain to our newly designed cell-penetrating peptide (WRH) to evaluate their silencing efficiency in breast and ovarian cancer cells. Therefore, the oleyl conjugated (WRH)_n (n=1-4) peptides were synthesized using Fmoc/tBu solid-phase peptide chemistry, followed by purification using Reverse-Phase High-Performance Liquid Chromatography (RP-HPLC), …