Medicinal Chemistry and Pharmaceutics Commons^™

Development Of Long-Acting Antiviral And Antimicrobial Prodrug Nanoformulations, Srijanee Das

Theses & Dissertations

Over the past decade, the global burden of infectious diseases has increased substantively, underscoring the need for more effective treatment strategies. However, the discovery and development of new drugs with desirable safety, pharmacokinetics, and efficacy is a time consuming and costly process with great uncertainty around success rate. As an alternative to new drug development, prodrugs and novel drug delivery systems have increasingly been explored. Both serve to overcome the drug development challenges. Such drug formulations that permit extended dosing intervals of potent native drugs serve multiple purposes by promoting patient adherence to in improving treatment outcomes. This is especially …

Pharmacodynamic Effects Of Zsj-0228 On Complement Protein Deposition In The Kidneys Of Focal Segmental Glomerulosclerosis-Afflicted Mice., Braeden Pinkerton

Theses & Dissertations

Chronic inflammation, when left untreated, may result in significant morbidity and in severe cases, mortality. While glucocorticoids (GCs) are still being extensively used clinically as a class of very potent anti-inflammatory agents, they are also notorious for diverse adverse side effects. To mitigate these side effects, we have developed a polyethylene glycol (PEG)-based prodrug (ZSJ-0228) of dexamethasone (Dex). When tested on rodent models of Lupus Nephritis and Focal Segmental Glomerulosclerosis (FSGS), ZSJ-0228 was found to provide potent and sustained therapeutic efficacy without any detectable typical GC-associated side effects. Given ZSJ-0228’s transient renal exposure after systemic administration, it is yet to …

An Ultra Long-Acting Bictegravir Prodrug Nanocrystal With A Shape-Shifting Pharmacokinetic Tail, Mohammad Ullah Nayan

Theses & Dissertations

While antiretroviral therapy (ART) has significantly reduced human immunodeficiency virus type one (HIV-1) co-morbidities and mortality, adherence to daily oral therapy remains a key barrier to all therapeutic and preventative outcomes. Over the past years, the emergence of long-acting (LA) ART has gained considerable enthusiasm amongst people living with HIV (PLWH) and could potentially simplify dosing regimens and improve treatment outcomes. LA ART could also improve drug adherence, reduce viral transmission, and limit viral drug resistance and systemic toxicities. In response to these needs, a combination of two LA injectable nanocrystalline drugs (CABENUVA) was recently approved for bimonthly administration in …

Intramuscular Administration Of The Host-Derived Immunostimulant Cpdi-02 Increases Protection Of Outbred Mice And Piglets Against Dermal Mrsa Infection In A Curative Setting And Is Well Tolerated After Repeated Administration, Jason P. Stewart

Theses & Dissertations

Staphylococcus aureus is the most common cause of bacterial skin and soft tissue infections (SSTIs) and the leading cause of hospital-associated infections in the United States. The abundance of S. aureus infections is due, in part, to its virulence factors that suppress host immune system and the development of antibiotic resistance strains such as methicillin-resistant S. aureus (MRSA). In contrast to antibiotics, Host-Directed Therapeutics (HDTs), avoid the pitfalls of antibiotics by targeting the host for immune system rather than targeting the pathogen. This mechanism of action avoids selective evolutionary pressure, which leads to antibiotic resistance and helps the host immune …

Neuropilin-2 In Advanced Prostate Cancer And Its Targeting With Novel Small Molecule Inhibitors, Ridwan Islam

Theses & Dissertations

Despite the development of new therapies, clinical management of advanced metastatic castrationresistant prostate cancer (mCRPC) still remains challenging owing to the emergence of therapy resistance. Resistance to the therapies is driven by both AR and non-AR pathways. Non-AR pathway is characterized by a lineage switch that leads to the development of neuroendocrine-like (NE-like) prostate cancer (PCa), which has a fulminant clinical course due to the lack of effective treatment strategy. Therefore, novel molecular targets need to be identified to develop effective therapeutic regimen to improve the outcomes in advanced PCa patients including NE-like PCa. Recent investigation on advanced PCa patients …

Polymeric Nanocarriers For Delivery Of Small Molecules Inhibiting Tubulin Polymerization For The Treatment Of Pancreatic Cancer And Lung Metastatic Melanoma, Rajan Sharma Bhattarai

Theses & Dissertations

The aim of this thesis is to develop delivery systems for the novel small molecules which inhibit tubulin polymerization. One of the small molecules was modified to lipid conjugate to increase the lipophilicity of the molecules which in turn drastically improved the drug loading in amphiphilic polymeric system. The second molecule was conjugated to the amphiphilic polymeric backbone with pH sensitive Schiff’s linker for the tumor site specific delivery in lung metastatic melanoma model.

Chapter 1 discusses the tumor microenvironment for the solid tumor especially focusing on Pancreatic Ductal Adenocarcinoma (PDAC). Further the drug delivery system currently researched for addressing …

Utilizing Proteolysis-Targeting Chimeras To Target The Transcriptional Cyclin-Dependent Kinases 9 And 12, Hannah King

Theses & Dissertations

Cyclin-dependent kinases (CDKs) are a family of serine-threonine kinases involved in various cellular functions, such as regulating the cell cycle and gene transcription. CDK9, a transcriptional CDK, regulates highly expressed enhancer-associated oncogenic transcription factors, including the oncogene Myc. CDK9 is responsible for the transcription and stabilization of Myc; consequently, it was a validated target for pancreatic cancer treatment.

As such, we developed a panel of aminopyrazole based proteolysis targeting chimera where we identified PROTAC 2 as a selective degrader of CDK9 (DC₅₀ = 158 ± 6 nM). PROTAC 2 was capable of cereblon mediated proteasomal degradation of CDK9 while …

Long-Acting Nanoformulated Antivirals For The Treatment And Prevention Of Hiv-1 And Hbv Infections, Dhruvkumar M. Soni Dr.

Theses & Dissertations

While antiretroviral therapy (ART) has revolutionized treatment and prevention of human immunodeficiency virus type one (HIV-1) infection, regimen adherence, viral mutations, drug toxicities, stigma and pill fatigue are limitations. These have led to the development of long acting (LA) ART. These include, but are not limited to, implantable devices, new chemical entities, prodrug modifications and nanoformulations. To these ends, this thesis focues on the transformation of nucleoside reverse transcriptase inhibitors (NRTIs) into LA parenterals, While elusive, data from our laboratories demonstrated that modifications to the PROdrug and nucleoTide technology (ProTide) enables improvements in drug apparent half-life and tissue and cell …

Next Generation Aryl Hydantoins As Antischistosomal Agents, Derek A. Leas

Theses & Dissertations

Schistosomiasis, also known as “snail fever,” is both an acute and chronic disease spread by trematode flukes from the tropical parasitic worm genus Schistosoma. The flukes are spread via diseased freshwater snails, which release the parasites into the water column where they find a new human host. According to the World Health Organization (WHO), 99 million people were treated for schistosomiasis in 2017. The primary treatment used to combat schistosomiasis is the drug praziquantel (PZQ), but due to high drug pressure and widespread administration, its effectiveness has eroded because of rising drug resistance. Furthermore, PZQ is active against adult but …

Delivery Of Small Molecule And Rna Using Synthetic Polymeric Micelles And Multifunctional Exosomes For The Treatment Of Type 1 Diabetes, Yang Peng

Theses & Dissertations

Type 1 diabetes is one of the most challenging chronic autoimmune diseases. The destruction and dysfunction of insulin-secreting β cells are the results of inflammatory infiltration and the synergistic effect of multiple immune cells. The aim of this dissertation is to develop novel and reliable therapeutic approaches to advance the treatment of T1D: including chemical modification of a broad-spectrum immunosuppressant, co-application of small molecule based immune intervention and siRNA based β cell preservative therapy, and administration of a PI3K-δ/γ dual inhibitor to specifically target immune cells, utilizing synthetic polymeric micelles or natural produced multi-functional exosomes derived from human bone marrow …

Computational Studies And Design Of Pparγ And Glut1 Inhibitors, Suliman Almahmoud

Theses & Dissertations

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. PPARγ is a target for insulin-sensitizing drugs, and it plays a significant function in prostate cancer. PPARγ antagonists have anti-proliferative effects in a broad range of hematopoietic and epithelial cell lines. The ligand binding domain (LBD) of PPARγ is large and has orthosteric and allosteric binding sites. Several PPARγ-ligand co-crystal structures show two bound molecules, one to the orthosteric pocket and a second to the allosteric …

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 …

Development Of A Long-Acting Nanoformulation Of Dolutegravir For Prevention And Treatment Of Hiv-1 Infection, Brady Sillman

Theses & Dissertations

Dolutegravir (DTG) is a potent human immunodeficiency virus type 1 (HIV-1) integrase strand-transfer inhibitor (INSTI) with a high barrier to viral drug resistance. However, opportunities to improve its profile abound. These include extending the drug’s apparent half-life, increasing penetrance to “putative” viral reservoirs, and reducing inherent toxicities. These highlight, in part, the need for long-acting, slow effective release antiretroviral therapy (LASER ART) delivery schemes. A long-acting (LA) DTG was made by synthesizing a hydrophobic and lipophilic prodrug encased with poloxamer (P407) surfactant. This modified DTG (MDTG) reduced systemic metabolism and polarity, increased lipophilicity and membrane permeability, improved encapsulation, and formed …

Development Of Long-Acting Nanoformulated Abacavir Protides, Zhiyi Lin, Howard E. Gendelmant

Theses & Dissertations

Combination antiretroviral therapy (cART) for treatment of human immunodeficiency virus (HIV) infection demands life-long regimen adherence. Treatment interruptions lead to a lack of virologic control and the emergence of viral mutations and drug resistance. To address these, our laboratory developed long-acting (LA) parenteral administered nanoformulated abacavir prodrug (NMABC) by formulating myristoylated abacavir (MABC) with poloxamer 407 as stabilizer, which sustained ABC levels for up to 2 weeks with low levels of active drug metabolite (CBV-TP). To more significantly extend the apparent half-life of ABC and improve its antiretroviral activities, we developed second generation long-acting ABC prodrugs by ProTide technologies. This …

Development Of Chloroquine-Containing Hpma Copolymers For Drug Delivery, Fei Yu

Theses & Dissertations

Abstract

Development of Chloroquine-containing HPMA Copolymers for Drug Delivery

Fei Yu, Ph.D.

University of Nebraska Medical Center, 2018

Supervisor: David Oupický, Ph.D.

Synthetic polymers have been extensively explored for improved delivery of anticancer agents. Polymers can be designed as either carriers of existing drugs or as polymeric drugs with intrinsic pharmacological activity. Advantages of such polymeric drugs include common positive features of polymer-drug conjugates, such as targeted delivery of drugs, altered pharmacokinetic and biodistribution, improved drug safety, but also favorable pharmacological activities due to multivalent receptor-ligand interactions.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are safe drugs that have been in clinical …

Development Of Macromolecular Prodrug Conjugates For The Diagnosis And Treatment Of Musculoskeletal Diseases, Xin Wei

Theses & Dissertations

Macromolecular prodrug conjugate is a promising strategy for better diagnosis and treatment of musculoskeletal diseases. Our lab has pioneered this effort and has successfully developed multiple prodrug formulations. The general approach we have taken is to incorporate active ingredient (AI, including imaging probe or therapeutic agents) containing monomers into water-soluble and biocompatible polymers, such as N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers. Structural parameters of these polymeric prodrugs, such as molecular weight (MW), drug loading, prodrug activation mechanism and the selection of drug payload may greatly affect therapeutic efficacy and the safety of the macromolecular prodrugs. To investigate the impact of these …

Development Of Neurotensin-Based Radiopharmaceuticals For Neurotensin-Receptor-1-Positive Tumors Targeting, Yinnong Jia

Theses & Dissertations

The neurotensin receptor 1 (NTR1) is overexpressed in many cancers, due to its role as a growth pathway. These NTR1-positive cancers include pancreatic, colon, prostate and breast cancers. In the radiopharmaceutical field, the overexpression of NTR1 in cancer has prompted the development of NTR1-targeted diagnostics and therapeutics. The neurotensin (NT) peptide exhibits low nanomolar affinity for NTR1 and has been the paradigm for NTR1-targeted agents. Since the 1980’s, radiolabeled NT analogs have been developed and evaluated for targeting NTR1-positive cancers. Since native NT is rapidly degraded in vivo by a variety of peptidases, a tremendous amount of effort has been …

Development Of Polymer Peptide Conjugates For Enhanced Pancreatic Cancer Imaging, Wen Shi

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US with very poor prognosis. All clinically available biomarkers and diagnostic tools either fail to detect early stage PDAC or suffer from low specificity and sensitivity. There is an urgent need for diagnostic agents with greater efficacy for PDAC detection and staging. Nanomaterials such as N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers can effectively target tumors, and offer novel opportunities for the development of effective diagnostic agents for cancer. However, a major problem of many nanomaterials-based diagnostics is their opsonization and sequestration by the mononuclear phagocyte system (MPS), leading …