Pharmacy and Pharmaceutical Sciences Commons^™

Development Of Macromolecular Prodrugs For The Treatment Of Chronic Inflammatory Pain, Laura Weber

Theses & Dissertations

Chronic pain afflicts millions of people worldwide. Particularly, the inflammatory conditions in the incurable disease rheumatoid arthritis (RA) generate persistent pain in its sufferers, for which a number of different analgesics have been prescribed, such as glucocorticoids (GCs) and opioids. However, administration of these pain- mitigating pharmaceutics is implicated in the development of adverse systemic effects due to their non-specific tissue distribution and quick excretion, eliciting the need for high dosing frequencies. To address this issue, this thesis is focused on the development of prodrugs based on a macromolecular design approach to instill preferential inflammation-targeting and retentive properties to common …

Developing Of Micellar Drug Carriers For The Treatment Of Breast Cancer Bone Metastasis, Tong Liu

Theses & Dissertations

Breast cancer (BC) remains one of the most frequently diagnosed cancer worldwide. Bone is one of the most common sites and often the first clinical indication of metastatic progression of BC. Current treatments including radiation, surgery, and chemotherapy are rarely curative with limited effect in overall survival. The challenge is true especially for patients with triple-negative BC that are not responsive to receptor-targeted therapy, or patients who had exposure to chemotherapy before and might already gain the resistance to some of the drugs.

Here we took advantage of the aminobisphosphonate, alendronate (ALN), that can bind to the bone mineral efficiently …

Development Of Novel Therapies For The Treatment Of Inflammatory Bowel Disease, Shrey Kanvinde

Theses & Dissertations

Inflammatory bowel disease (IBD) is a chronic and remittent inflammation of the gastrointestinal tract (GIT). Despite extensive research efforts, there is no cure nor a well-defined pathogenesis for IBD. Loss of epithelial barrier function, increased colonic immune cell infiltration and upregulation of pro-inflammatory cytokines are the hallmarks of IBD. Despite treatments like painkillers, aminosalicylates, steroids, and biologics, almost 70% patients require surgery at least once in their life time. The main limitation with most of the current treatments is they are either absorbed systemically or administered systemically resulting in adverse side effects. As a result, there is a huge unmet …

Polymeric Nanocarriers Delivering Anticancer Agents For The Treatment Of Chemoresistant Prostate Cancer And Lung Metastatic Melanoma, Ruinan Yang

Theses & Dissertations

The aims of this thesis is to first develop novel combination chemotherapies of two anticancer agents and their appropriate drug delivery platforms to treat chemoresistant prostate cancer, and second develop a polymeric conjugate of a biodegradable polymer and novel tubulin destabilizer to treat lung metastatic melanoma.

In Chapter 1, a general introduction of polymeric nanocarriers including polymeric micelles and polymer drug conjugates for cancer therapy was given. In Chapter 2, we described a combination therapy of paclitaxel (PTX) polymer conjugate and cyclopamine (CYP) polymer conjugate, which had the potential to treat chemoresistant prostate cancer. We first synthesized mPEG-b-PCC-g-PTX-g-DC (P-PTX) …

Next Generation Of Translational Long-Acting Cabotegravir, Tian Zhou

Theses & Dissertations

Recent development of long-acting antiretroviral therapeutic regimens has opened a new chapter for HIV/AIDS management. Cabotegravir (CAB), as one of the very first long-acting antiretroviral regimens, has drawn tremendous attention. However, the remaining challenges include suboptimal dosing intervals, large injection volume, injection site reactions, lack of tissue penetration, etc. As one of the pioneers in this field, our lab was successful in harnessing mononuclear phagocytes as “Trojan horses” for antiretroviral drug delivery and transportation to viral reservoirs. We proposed this targeted delivery strategy could address the limitations of current CAB formulation. To this end, we developed folic acid decorated CAB …

Absolute Oral Bioavailability Of Creatine Monohydrate In Rats: Debunking A Myth, Eman A. Alraddadi, Ryan Lillico, Jonathan L. Vennerstrom, Ted M. Lakowski, Donald W. Miller

Journal Articles: Pharmaceutical Sciences

Creatine is an ergogenic compound used by athletes to enhance performance. Supplementation with creatine monohydrate (CM) has been suggested for musculoskeletal and neurological disorders. Until now, little is known about its pharmacokinetic profile. Our objective was to determine the oral bioavailability of CM and the influence of dose on oral absorption. Rats were dosed orally with low dose (10 mg/kg) or high dose (70 mg/kg)

The Enzymatic Activity Of Apobe3g Multimers, Yangang Pan, Karen Zagorski, Luda S. Shlyakhtenko, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

APOBEC3G (A3G) belongs to the family of cytosine deaminases that play an important role in the innate immune response. Similar to other, two-domain members of the APOBEC family, A3G is prone to concentration-dependent oligomerization, which is an integral for its function in the cell. It is shown that oligomerization of A3G is related to the packing mechanism into virus particle and, is critical for the so-called roadblock model during reverse transcription of proviral ssDNA. The role of oligomerization for deaminase activity of A3G is widely discussed in the literature; however, its relevance to deaminase activity for different oligomeric forms of …

Flupirtine Derivatives As Potential Treatment For The Neuronal Ceroid Lipofuscinoses, Joelle Makoukji, Fadi Saadeh, Karl Albert Mansour, Sally El-Sitt, Jamal Al Ali, Nihar Kinarivala, Paul C. Trippier, Rose-Mary Boustany

Journal Articles: Pharmaceutical Sciences

OBJECTIVE: Neuronal Ceroid Lipofuscinoses (NCL) are fatal inherited neurodegenerative diseases with established neuronal cell death and increased ceramide levels in brain, hence, a need for disease-modifying drug candidates, with potential to enhance growth, reduce apoptosis and lower ceramide in neuronal precursor PC12 cells and human NCL cell lines using enhanced flupirtine aromatic carbamate derivatives in vitro.

METHODS: Aromatic carbamate derivatives were tested by establishing growth curves under pro-apoptotic conditions and activity evaluated by trypan blue and JC-1 staining, as well as a drop in pro-apoptotic ceramide in neuronal precursor PC12 cells following siRNA knockdown of the

RESULTS: Retigabine, the benzyl-derivatized …

Novel Therapeutic Strategies For Treatment Of Castration-Resistant Prostate Cancer, Matthew A. Ingersoll

Theses & Dissertations

Prostate cancer (PCa) remains the most commonly diagnosed solid tumor and is the third leading cause of cancer-related death in United States men. While androgen deprivation therapy is the current standard-of-care treatment for metastatic PCa, most patients eventually relapse and develop castration-resistant (CR) tumors, for which there is currently no effective treatment. Therefore, synthesis of novel therapeutic agents and identification of alternative target proteins are necessary to improve treatment. Herein, I investigate the efficacy of novel imidazopyridine and statin derivatives as alternative therapeutic compounds. These molecules not only inhibit androgen receptor signaling, but also block activation of the AKT axis, …

Development Of C5ar-Targeted Nanoparticles For Delivery Of Vaccines, Shailendra Bharadwaj Tallapaka Venkata Sesha

Theses & Dissertations

Since the early attempts of Benjamin Jesty at inducing immunity against smallpox and the pioneering work of Edward Jenner, vaccination has been, and continues to remain, the principal method of protection from diseases. However, most of the successful vaccines have been against pathogens that do not have major mechanisms to evade the immune system. So far, many life-threatening diseases like hepatitis C, HIV infection, malaria etc., have been resistant to existing vaccination strategies. Thus, there is an urgent need to develop new vaccination strategies that can generate long-lived protective immunity against such pathogens.

The purpose of this thesis is to …

Development Of Cxcr4 Inhibitors For Topical Treatment Of Psoriasis, Suthida Boonsith

Theses & Dissertations

Psoriasis is a chronic inflammatory skin disease that is often associated with systemic comorbidities and impaired skin barrier function. There are several treatment options including topical treatment with immunosuppressants, phototherapy, and systemic therapies using small molecules and biological agents. However, none of them can be regarded as a perfect solution due to their toxicity during chronic use. Recently, the CXCR4/SDF-1 axis was found to play an important role in the pathogenesis of psoriasis. AMD3100, a small molecule CXCR4 antagonist can selectively bind to CXCR4 and inhibit skin inflammation, reduce angiogenesis and infiltration of inflammatory cells. Unfortunately, AMD3100 can only be …

Nano-Assembly Of Amyloid Β Peptide: Role Of The Hairpin Fold., Sibaprasad Maity, Mohtadin Hashemi, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

Structural investigations have revealed that β hairpin structures are common features in amyloid fibrils, suggesting that these motifs play an important role in amyloid assembly. To test this hypothesis, we characterized the effect of the hairpin fold on the aggregation process using a model β hairpin structure, consisting of two Aβ(14-23) monomers connected by a turn forming YNGK peptide. AFM studies of the assembled aggregates revealed that the hairpin forms spherical structures whereas linear Aβ(14-23) monomers form fibrils. Additionally, an equimolar mixture of the monomer and the hairpin assembles into non-fibrillar aggregates, demonstrating that the hairpin fold dramatically changes the …

Targeted Delivery Of Drug Combinations Via Nanocarriers For Cancer Treatment, Kruti Soni

Theses & Dissertations

Combination therapy is preferred over monotherapy to treat cancer as it can show better therapeutic outcomes and also delay the onset of resistance by targeting multiple cell-survival pathways in cancer cells. Rationally developed combinations with monoclonal antibodies and small molecule drugs in the form of antibody-drug conjugates or antibody nanoparticle conjugates allow us to take advantage of the cellular targeting of the potent cytotoxic agents, thereby widening the scope for dose reduction while maintaining the required therapeutic response. This can in turn improve patient tolerability by reducing the off target toxicities. For the therapy of ErbB2 positive breast cancer, the …

Delivery Of Small Molecule And Rna For The Treatment Of Type 1 Diabetes And Prostate Cancer, Di Wen

Theses & Dissertations

The aim of this thesis is to develop combination therapy using a small molecule and RNA including siRNA, shRNA, or miRNA inhibitor for the treatment of type 1 diabetes and prostate cancer. New amphiphilic biodegradable polymers capable of co-delivering small hydrophobic molecules and RNAs or human bone marrow-derived mesenchymal stem cell (hBMSC) for co-delivery of an shRNA and a miRNA inhibitor were used as drug delivery platform. The drug delivery properties were evaluated in vitro and in vivo islet transplantation, subcutaneous and orthotopic prostate cancer models.

In Chapter 1, an overview of prostate cancer, the role of miRNA and …

A Novel Pathway For Amyloids Self-Assembly In Aggregates At Nanomolar Concentration Mediated By The Interaction With Surfaces., Siddhartha Banerjee, Mohtadin Hashemi, Zhengjian Lv, Sibaprasad Maity, Jean-Christophe Rochet, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

A limitation of the amyloid hypothesis in explaining the development of neurodegenerative diseases is that the level of amyloidogenic polypeptide in vivo is below the critical concentration required to form the aggregates observed in post-mortem brains. We discovered a novel, on-surface aggregation pathway of amyloidogenic polypeptide that eliminates this long-standing controversy. We applied atomic force microscope (AFM) to demonstrate directly that on-surface aggregation takes place at a concentration at which no aggregation in solution is observed. The experiments were performed with the full-size Aβ protein (Aβ42), a decapeptide Aβ(14-23) and α-synuclein; all three systems demonstrate a dramatic preference of the …

Chemosensitization Effect Of Sp1017 On Multiple Myeloma, Hangting Hu

Theses & Dissertations

Multiple myeloma (MM) is a hematological malignancy of plasma cells that are predominantly located in bone marrow (BM). Despite recent improvements in MM treatment by introduction of several novel agents includingimmunomodulatory drugs, proteasome inhibitors and the use of the drug combinations, MM remains incurable and almost all patients eventually relapse or become refractory to the current treatment regimens. So the current challenge of MM treatments is to maintain treatment response, prevent relapse and eventually prolong survival.

Here we demonstrated that Pluronic block copolymers ((Pluronic L61: Pluronic F127 = 1:8 w/w, SP1017) significantly increase cytotoxicity of proteasome inhibitors (Bortezomib, BTZ or …

Polymeric Nanocarriers For Delivery Of Small Molecules And Mirnas For The Treatment Of Liver Fibrosis And Pancreatic Cancer, Virender Kumar

Theses & Dissertations

The aim of this thesis is to develop combination therapy of small molecules and miRNAs for treating liver fibrosis and pancreatic cancer. New amphiphilic biodegradable polymers capable of carrying small hydrophobic molecules and hydrophilic anionic nucleic acids were synthesized, characterized and evaluated in vitro and in vivo liver fibrosis and pancreatic cancer mouse models.

In Chapter 1, an overview of liver fibrosis, current treatments and the role of miRNAs in liver fibrosis as well as the design of their delivery systems is given. Further, a general introduction to pancreatic cancer and role of miRNAs in pancreatic cancer is given. In …

Development Of Cxcr4-Inhibiting Nanoparticles For The Treatment Of Metastatic Cancer, Yan Wang

Theses & Dissertations

Metastasis is the main cause of cancer mortality and morbidity, leading to several million deaths every year. Less than 20% of pancreatic cancer (PC) patients are candidates for surgery due to spread beyond the pancreas. Desmoplasia presents substantial barriers to perfusion, diffusion, and convection of antitumor therapeutics into the PC tissues. We focus on developing novel therapies that regulates tumor microenvironment, chemosensitizing tumor to therapeutics and preventing metastasis.

Gene therapy is emerging as a promising new therapeutic agents for cancer treatment. A targeted, systemic, effective and safe gene delivery system should be developed. CXCR4/SDF-1 axis plays a crucial role in …

Design, Synthesis, And Evaluation Of Aryl Hydantoins And Ureas As Antischistosomal Agents, Chunkai Wang

Theses & Dissertations

Schistosomiasis is a tropical parasitic disease caused by infections with flukes of the genus Schistosoma, affecting as many as 440 million individuals worldwide, with 779 million living at risk of infection. A new drug for schistosomiasis is urgently needed as praziquantel (PZQ) is currently the drug of last resort and the development of resistance cannot be ignored, particularly in view of its large-scale use in many endemic countries. Furthermore, PZQ is active against adult but not juvenile schistosomes; this may be an important factor in the frequently observed treatment ‘failures’ in areas endemic for schistosomiasis.

The introduction of PZQ in …

Treatment Of A Chemoresistant Neuroblastoma Cell Line With The Antimalarial Ozonide Oz513., Don W. Coulter, Timothy R. Mcguire, J. Graham Sharp, Erin M. Mcintyre, Yuxiang Dong, Xiaofang Wang, Shawn Gray, Gracey R. Alexander, Nagendra K. Chatuverdi, Shantaram Joshi, Xiaoyu Chen, Jonathan L. Vennerstrom

Journal Articles: Pharmacy Practice

BACKGROUND: Evaluate the anti-tumor activity of ozonide antimalarials using a chemoresistant neuroblastoma cell line, BE (2)-c.

METHODS: The activity of 12 ozonides, artemisinin, and two semisynthetic artemisinins were tested for activity against two neuroblastoma cell-lines (BE (2)-c and IMR-32) and the Ewing's Sarcoma cell line A673 in an MTT viability assay. Time course data indicated that peak effect was seen 18 h after the start of treatment thus 18 h pre-treatment was used for all subsequent experiments. The most active ozonide (OZ513) was assessed in a propidium iodide cell cycle flow cytometry analysis which measured cell cycle transit and apoptosis. …

Near Infrared Fluorescent Nanoparticles Derived From Hyaluronic Acid Improve Tumor Contrast For Image-Guided Surgery., Tanner K. Hill, Sneha S. Kelkar, Nicholas E. Wojtynek, Joshua J. Souchek, William M. Payne, Kristina Stumpf, Frank C. Marini, Aaron M. Mohs

Journal Articles: Pharmaceutical Sciences

Tumor tissue that remains undetected at the primary surgical site can cause tumor recurrence, repeat surgery, and treatment strategy alterations that impose a significant patient and healthcare burden. Intraoperative near infrared fluorescence (NIRF) imaging is one potential method to identify remaining tumor by visualization of NIR fluorophores that are preferentially localized to the tumor. This requires development of fluorophores that consistently identify tumor tissue in different patients and tumor types. In this study we examined a panel of NIRF contrast agents consisting of polymeric nanoparticle (NP) formulations derived from hyaluronic acid (HA), with either physically entrapped indocyanine green (ICG) or …

Stability And Kinetics Of Dna Pseudoknots: Formation Of T∗A•T Base-Triplets And Their Targeting Reactions, Calliste Steffensmeier

Theses & Dissertations

Pseudoknots have been found to play important roles in the biology of RNA. These stem-loop motifs are considered to be very compact and the targeting of their loops with complementary strands is accompanied with lower favorable free energy terms. We used a combination of spectroscopic (UV, CD and fluorescence), calorimetric (DSC, PPC and ITC) and kinetic (SPR) techniques to investigate: 1) Local base-triplet formation in pseudoknots; 2) energetic contributions for the association of pseudoknots with their complementary strands; and 3) the kinetic rates as a function of targeting strand length.

We investigated a set of DNA pseudoknots with sequence: d(TCTCT …

Long-Acting Antiretroviral Nanoformulation Development And Subcellular Trafficking, Dongwei Guo

Theses & Dissertations

The introduction of nanoformulated antiretroviral therapeutic regimens is a promising alternative to standard once a day oral treatment of HIV infection. Our lab has pioneered this effort and was successful in harnessing mononuclear phagocytes (monocytes, dendritic cells and macrophages) as nanoformulated drug carriers. The approach was developed as Trojan horses for drug transport, delivery and distribution to sites of viral replication in order to facilitate microbial elimination in HIV sanctuaries. However, the remaining challenges for current antiretroviral nanoformulations include to formulate a broad range of hydrophilic short-acting drugs, and to elucidate the mechanism of sequestered nanoparticles in macrophages at the …

Block Copolymer Based Magnetic Nanoclusters For Cancer-Theranostics: Synthesis, Characterization And In Vitro Evaluation, Hemant M. Vishwasrao

Theses & Dissertations

“There is plenty of room at the bottom”. In this visionary lecture in 1959 Prof. Richard Feynman spoke of the interesting ramifications of working with matter at the atomic scale. Since then, scientists have worked relentlessly towards realizing his vision. The influence of nanobiotechnology on material science and polymer chemistry has given rise to a new field called ‘theranostics’, combining drug delivery and diagnostics within the same nanostructures, thereby enabling simultaneous diagnosis, targeted drug delivery and continued therapy monitoring. Iron oxide nanoparticles (MNPs) are one such class of MRI contrast agents that can be converted into theranostic nanomedicines for cancer …

Factors And Outcomes Associated With Potentially Inappropriate Medication Use In Rural Community-Dwelling Older Adults, Marcia Y. Shade

Theses & Dissertations

Potentially inappropriate medications (PIMs) use in older adults is a significant public health concern. The use of PIMs to avoid may lead to negative outcomes such as adverse drug events. Prior conceptual analysis of PIMs use and observation of health-related factors in rural adults led to the design of this dissertation study. A sample was recruited from a population of rural community-dwelling older adults to examine the following specific aims: 1) Describe the use of PIMs to avoid, 2) Explore individual demographic characteristics (age, gender, income, education, and rural home location), health experience (comorbidity, number of medications and health providers), …

Guidance For The Practical Management Of The Heparin Anticoagulants In The Treatment Of Venous Thromboembolism., Maureen A. Smythe, Jennifer Priziola, Paul P. Dobesh, Diane Wirth, Adam Cuker, Ann K. Wittkowsky

Journal Articles: Pharmacy Practice

Venous thromboembolism (VTE) is a serious and often fatal medical condition with an increasing incidence. Despite the changing landscape of VTE treatment with the introduction of the new direct oral anticoagulants many uncertainties remain regarding the optimal use of traditional parenteral agents. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance based on existing guidelines and consensus expert opinion where guidelines are lacking. This specific chapter addresses the practical management of heparins including low molecular weight heparins and fondaparinux. For each anticoagulant a list of the most common practice related questions were created. Each question was addressed using a …

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 …

Apobec3g Interacts With Ssdna By Two Modes: Afm Studies., Luda S. Shlyakhtenko, Samrat Dutta, Jaspreet Banga, Ming Li, Reuben S. Harris, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

APOBEC3G (A3G) protein has antiviral activity against HIV and other pathogenic retroviruses. A3G has two domains: a catalytic C-terminal domain (CTD) that deaminates cytidine, and a N-terminal domain (NTD) that binds to ssDNA. Although abundant information exists about the biological activities of A3G protein, the interplay between sequence specific deaminase activity and A3G binding to ssDNA remains controversial. We used the topographic imaging and force spectroscopy modalities of Atomic Force Spectroscopy (AFM) to characterize the interaction of A3G protein with deaminase specific and nonspecific ssDNA substrates. AFM imaging demonstrated that A3G has elevated affinity for deaminase specific ssDNA than for …

Direct Oral Anticoagulants For The Prevention Of Stroke In Patients With Nonvalvular Atrial Fibrillation: Understanding Differences And Similarities., Paul P. Dobesh, John Fanikos

Journal Articles: Pharmacy Practice

The presence of atrial fibrillation (AF), the most common sustained cardiac arrhythmia, significantly increases the risk for stroke. Current guidelines recommend that the vitamin K antagonist warfarin or direct oral anticoagulants (DOACs), such as the approved direct thrombin inhibitor dabigatran and the approved direct factor Xa inhibitors apixaban, rivaroxaban, and edoxaban, should be used for thromboprophylaxis in patients with nonvalvular AF at risk for stroke or systemic embolic events (SEE). Warfarin, the mainstay of stroke prevention in AF, increases the risk of major bleeding. Furthermore, warfarin therapy comes with several limitations including frequent monitoring and the need for dose adjustments, …