Pharmacy and Pharmaceutical Sciences Commons^™

Self-Assembled Ternary Polypeptide Nanoparticles With Improved Biostability For Drug Delivery In Cancer Therapy, Preye Mike Agbana

Theses and Dissertations--Pharmacy

Cancer remains a real and present threat to global health. In the United States, according to cancer statistics, almost 40% of people will be diagnosed with cancer at some point in their lifetime. Conventional chemotherapy has become the mainstay for cancer treatment option. However, chemotherapeutic agents are plagued with problems such as poor aqueous solubility, chemical degradation, Bio instability, and off-site toxicity due to non-specificity. New drug modalities are needed to tackle the ever-growing burden on cancer. In recent times, the promise of nanotechnology has aided to develop drug delivery vehicles to facilitate the administration of potent chemotherapeutics. Nanoformulations such …

Investigation Of Folate-Poly(Glutamic Acid)/Polyethylenimine/Dna Complexes For In Vitro Gene Delivery, Caleb Akers

Theses and Dissertations--Pharmacy

Gene therapy is currently being studied as a treatment for a variety of indications, including cancer, infectious disease, and cardiovascular diseases, among others. While many of the early treatments in the field involved the use of viral delivery methods, various safety, ethical, and financial concerns limit the potential uses of this methodology. As such, more recent research has focused on developing non-viral delivery platforms to alleviate some of the issues inherent in viral delivery. Recently, the release of the COVID-19 vaccines from Pfizer and Moderna represents a promising use of non-viral delivery as both utilized a lipid-based delivery vector.

Despite …

Frontiers In The Self-Assembly Of Charged Macromolecules, Khatcher O. Margossian

Doctoral Dissertations

The self-assembly of charged macromolecules forms the basis of all life on earth. From the synthesis and replication of nucleic acids, to the association of DNA to chromatin, to the targeting of RNA to various cellular compartments, to the astonishingly consistent folding of proteins, all life depends on the physics of the organization and dynamics of charged polymers. In this dissertation, I address several of the newest challenges in the assembly of these types of materials. First, I describe the exciting new physics of the complexation between polyzwitterions and polyelectrolytes. These materials open new questions and possibilities within the context …

Quality By Design Based Optimization Of Anti-Inflammatory Nanoemulgels For Local Treatment Of Burn Wounds, Leah Dickey

Electronic Theses and Dissertations

Burns are some of the most traumatizing and damaging skin injuries, with the potential of causing extensive internal damage that increases the risk of chronic wound development. Oral and topical analgesics in combination with antibiotics can provide temporary relief and improve wound healing progress for both mild and severe burns. However, recurrent systemic exposure to pain relievers and antibiotics has been associated with adverse side effects including nausea, drowsiness, abdominal pain, etc., and increased risk of new infections or even ulcers. Local and targeted drug delivery systems, such as nanomedicine, have gained attention as potentially more effective alternatives to improve …

Modulation Of Immune Homeostasis In Neurodegenerative Diseases, Pravin Yeapuri

Theses & Dissertations

Modulating the immune system via. transformation of CD4+ T cell effector to regulatory (Teff to Treg) or promoting microglial clearance of abnormal disease proteins are attractive therapeutic strategies to restore immunological balance in neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease (AD). In the past decade, we defined a safe and effective pathway for Treg induction through the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF was developed in PD animal models and early phase I human studies demonstrating proof-of-concept efficacy for ameliorating disease signs and symptoms. Despite the recorded efficacy, the medicine’s short half-life, limited bioavailability, and injection site reactions …

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 …

The Use Of Spectral Imaging To Reveal Inorganics And Organics Identity In The Biological Samples, Qamar Alshammari

Pharmaceutical Sciences (PhD) Dissertations

The wavelength is used to identify the exact location and quantify the number of molecules in the spectral imaging system. It aids in identifying materials and studying their quantities by examining how they interact with light. A traditional spectrometer provides spectrum information of chemical compounds, while standard imaging provides the intensity at each pixel of the image. Spectral imaging (SI) combines these two aspects by equipping intensity and spectral data for each pixel. In biomedical research, it is important to assess the inorganics/organics molecules to understand drug activity, cellular toxicity, and distribution. Using the microscopy technique, we found for the …

Exploiting Modulation Of The Blood-Brain And Blood-Tumor Barrier Permeability By Translational Focused Ultrasound For Therapeutic Delivery To Cns Metastases, Tasneem A. Arsiwala

Graduate Theses, Dissertations, and Problem Reports

Transcranial low-intensity focused ultrasound is a unique technology to modulate the integrity of tight endothelial junctions and transiently increase BBB/BTB permeability to enhance therapeutic delivery. Despite promising early studies, present literature lacks agreement on key experimental conditions, which restricts our knowledge and the technique's widespread translation. This dissertation first provides a critical review of the current gaps in knowledge regarding the universal use of LiFUS in preclinical and clinical use. We then identify key parameters for translational and predictable opening of the BBB using a 3T MRI coupled with a clinical device. Our investigation highlights that passive permeability of the …

Development Of Once-A-Year Injectable Formulation Of Cabotegravir For Prevention And Treatment Of Hiv Infection, Tanmay Abhay Kulkarni

Theses & Dissertations

Long-acting cabotegravir (CAB) extends antiretroviral drug (ARV) dosing to monthly for maintenance of human immunodeficiency virus type one (HIV-1) suppression and to every other month for prevention of viral transmission. However, injection dose volumes, site reactions, and clinical oversights that are required remain obstacles towards broad usage. To meet these needs, surfactant coated hydrophobic and lipophilic CAB prodrugs were created with controlled prodrug dissolution, hydrolysis and drug tissue penetration. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18, and 22 added carbon chains were synthesized then nanoformulated as NMCAB, NM2CAB, and NM3CAB. These nanocrystal formulations were tested …

Complexation Of Glycoalkaloid Α- Tomatine With Sterols And Its Potential Application As An Anti-Cancer Drug, Bishal Nepal

Dissertations

Glycoalkaloids (GAs) are secondary metabolites found mostly in higher plant species and some marine invertebrates. They are known to form complexes with 3β-hydroxy sterols such as cholesterol causing membrane disruption. So far the visual evidence showcasing the complexes formed between glycoalkaloids and sterols has been mainly restricted to some earlier studies using Brewster angle microscopy. This study aimed to develop a method for topographic and morphological analysis of sterol-glycoalkaloid complexes. Langmuir-Blodgett (LB) transfer of monolayers comprising of glycoalkaloid tomatine, sterols, and lipids in varying molar ratios onto mica followed by AFM examination was performed. The AFM method used required minimal …

The Antioxidant And Antimicrobial Activities Of Cornsilk Extract Encapsulated In Polysaccharide Nanoparticles, Maryam Mady

Theses and Dissertations

Corn silk possess antibacterial and antioxidant activities due to its phenolic compounds but they are of low bioavailability that requires some innovative techniques to develop such active ingredients in a safe and less toxic manner. Accordingly, silk extract SE was encapsulated in chitosan nanoparticles CS NPs, which is a natural and abundant polymer derived from chitin. Among 15 experimental trials via design expert software, the optimum formula of SE x\CS NPs was prepared at 800 rpm, 5hrs. on magnetic stirrer, and by CS: TPP ratio was 2.5:1. Then SEM showed the majority of particles size diameter in the range of …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Tools And Antimicrobial Agents, David Salehi

Pharmaceutical Sciences (MS) Theses

Cell-penetrating peptides containing arginine as positively charged residues and tryptophan or diphenylalanine as hydrophobic residues were synthesized. The synthesis was accomplished through the Fmoc solid-phase peptide synthesis in the presence of HBTU and DIPEA. The side-chain protected linear peptides were cleaved from the resin and cyclized in the presence of DIC and HOAt in the solution phase overnight. MALDI-TOF mass spectrometry was used to characterize the peptides.

The cytotoxicity of the synthesized peptides was determined in CCRF-CEM (human, lymphoblast peripheral blood), and HEK-293 (human, embryonic epithelial kidney healthy) cells using the MTS assay. A concentration of 10 µM was found …

Nebulizer-Based Systems To Improve Pharmaceutical Aerosol Delivery To The Lungs, Benjamin M. Spence

Theses and Dissertations

Combining vibrating mesh nebulizers with additional new technologies leads to substantial improvements in pharmaceutical aerosol delivery to the lungs across therapeutic administration methods. In this dissertation, streamlined components, aerosol administration synchronization, and/or Excipient Enhanced Growth (EEG) technologies were utilized to develop and test several novel devices and aerosol delivery systems. The first focus of this work was to improve the poor delivery efficiency, e.g., 3.6% of nominal dose (Dugernier et al. 2017), of aerosolized medication administration to adult human subjects concurrent with high flow nasal cannula (HFNC) therapy, a form of continuous-flow non-invasive ventilation (NIV). The developed Low-Volume Mixer-Heater (LVMH) …

Investigation Of Novel Mitoneet Ligand Nl-1 As A Therapeutic For Cerebral Ischemia And Reperfusion Injury, Pushkar Saralkar

Graduate Theses, Dissertations, and Problem Reports

Cerebral ischemia reperfusion injury, a common type of stroke, is a neurodegenerative disorder which is the leading cause of permanent disability in the United States. The underlying pathophysiology of ischemic stroke involves an occlusion in the vasculature supplying oxygen and glucose to the brain tissue, leading to infarction and eventual necrosis in the brain. MitoNEET is an outer mitochondrial protein that plays a role in the cellular bioenergetics and its redox physiology. Although its endogenous ligands are under investigation, mitoNEET binds molecules with a thiazolidinedione moiety, such as NL-1. This dissertation investigates NL-1 as a potential cytoprotective agent, and its …

Rilpivirine-Associated Aggregation-Induced Emission Enables Cell-Based Nanoparticle Tracking, Insiya Mukadam

Theses & Dissertations

Antiretroviral therapy (ART) has improved the quality and duration of life for people living with human immunodeficiency virus (HIV) infection. However, limitations in drug efficacy, the emergence of viral mutations and the paucity of cell-tissue targeting remain. We posit that to maximize ART potency and therapeutic outcomes newer drug formulations that reach HIV cellular reservoirs need to be created. In a step towards achieving this goal we discovered the aggregation-induced emission (AIE) property of the non-nucleoside reverse transcriptase inhibitor Rilpivirine (RPV) and used it as a platform for drug cell and subcellular tracking. RPV nanocrystals were created with endogenous AIE …

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 …

Development Of Cxcr4-Inhibiting Rna Delivery Vectors For The Treatment Of Metastatic Pancreatic Cancer, Yu Hang

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is a growing medical problem associated with extensive metastasis and high mortality. Late diagnosis and complexity of the tumor microenvironment (TME) with severe hypoxia, desmoplasia, and hypovascular nature contributes to poor effectiveness of conventional chemotherapies. RNA interference (RNAi) holds great potential in the treatment of multiple genetic and acquired diseases, including PDAC. CXCR4/CXCL12 chemokine axis plays a pivotal role in PDAC TME remodeling to promote tumor proliferation, angiogenesis, metastasis, and chemoresistance. This project developed polymeric AMD3100 (PAMD) derivatives as dual-function vectors capable of simultaneously delivering small RNAs and blocking CXCR4/CXCL12 signaling.

Administration route plays pivotal role …

Ligand-Installed Polymeric Nanocarriers For Combination Chemotherapy, Xinyuan Xi

Theses & Dissertations

Combination chemotherapy remains the mainstay of cancer treatment because such strategy targets different cell signaling pathways to decrease the likelihood of developing protective mechanisms by cancer cells, thereby delaying the onset of recurrence and prolonging the survival. The co-delivery of binary drug combination via a single nanocarrier provides benefits in reducing dose-limiting toxicities, improving the pharmacokinetic properties of the cargo, spatial-temporal synchronization of drug exposure, and synergistic therapeutic effects. Rational design of such regimen is crucial for maximizing the therapeutic effects since only certain drug ratios exposed to the target might be synergistic while other ratios exert additive or even …

Development Of Fluorescent Hyaluronic Acid Nanoparticles For Intraoperative Tumor Detection, Nicholas E. Wojtynek

Theses & Dissertations

Surgical resection remains to be the primary treatment for the majority of solid tumors, including breast cancer. The complete removal of the primary tumor, local metastases, and metastatic lymph nodes dramatically improve a patient’s treatment outcome and prognosis. Nevertheless, surgeons are limited to tactile and visual cues in distinguishing malignant and healthy tissue. This can result in a positive surgical margin (PSM), which occurs when tumor goes undetected and is left behind in the surgical cavity. PSMs decreases a patient’s prognosis and necessitate additional treatment in the form of surgery, radiation, and chemotherapy. An emerging imaging modality, known as fluorescence-guided …

Engineering Hyaluronic Acid For Biomedical Applications, Deep S. Bhattacharya

Theses & Dissertations

This work presents research using the naturally available non- sulfated carbohydrate glycosaminoglycan hyaluronic acid (HA) for the synthesis of different chemical derivatives of HA for evaluation of binding kinetics with CD44 and P- selectin proteins for applications in fluorescence image-guided surgery. Chemical derivatives of HA such as deacetylated HA (deHA), sulfated HA (sHA), and deacetylated and sulfated HA (s-deHA) were synthesized by modulating sulfating and deacetylating reagents to alter binding specificities to CD44. Modified HA derivatives and CD44 biophysical interactions were assessed by fluorescence polarization. In silico techniques were also used to determine binding using molecular docking and MM-PBSA approaches. …

Theranostics For Antiretroviral Biodistribution And Pharmacokinetics, Brendan M. Ottemann

Theses & Dissertations

RATIONALE: Our laboratories birthed the field of human immunodeficiency virus (HIV) theranostics. The new field allows simultaneous detection (diagnostics) and treatment (therapeutic) for the identification, treatment and inevitable elimination of virus in cell and tissue compartments. By employing theranostics, antiretroviral drugs (ARVs) can be tracked in lymph nodes, gut, spleen and liver. Cellular viral reservoirs including CD4+ T cell populations and mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) along with subcellular endosomal structures can now be targeted for drug delivery bringing therapeutics to areas where virus replicates. The overarching idea rests in improving precision targeted ARV delivery. …

Synthesizing Galactose Modified Polymeric Nanoparticles For Biofilm Inhibition Of Pseudomonas Aeruginosa, Tyler R. Flockton

Theses and Dissertations

Treating patients with antibiotics is becoming harder with the increase in antibiotic resistance. This is due to the widespread antibiotic use in clinical and agricultural settings. With antibiotic resistance outpacing new drugs making it to the market, developing new options to treat bacterial infections is and will be important. We created sugar modified nanoparticles to inhibit the biofilm formation of Pseudomonas aeruginosa.

P. aeruginosa is a gram-negative opportunistic pathogen that infects its host that has a compromised immune system. This makes it one of the most significant bacterial infection in hospitals. P. aeruginosa uses biofilms as an attack mechanism …

Synthesis And Characterization Of Long-Acting Rilpivirine Prodrugs, James R. Hilaire

Theses & Dissertations

Antiretroviral therapy (ART) requires lifelong daily dosing to suppress viral replication, restore or maintain immune function and improve quality of life. As an alternative, long-acting (LA) antiretrovirals (ARVs) aim to deliver therapeutic drug concentrations over an extended period, ultimately requiring monthly or even more extended dosing intervals. Specifically, the success of recent clinical trials examining LA cabotegravir and rilpivirine (CAB and RPV LA) highlight the advent of these novel HIV-1 therapeutics. Further optimization of LA dosage forms are required and rests upon improving dosing frequency, injection volumes and tissue distribution to viral compartments. To this end, we report the synthesis …

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 …

Mechanisms And Thermodynamics Of The Influence Of Solution-State Interactions Between Hpmc And Surfactants On Mixed Adsorption Onto Model Nanoparticles, Salin Gupta Patel

Theses and Dissertations--Pharmacy

Nanoparticulate drug delivery systems (NDDS) such as nanocrystals, nanosuspensions, solid-lipid nanoparticles often formulated for the bioavailability enhancement of poorly soluble drug candidates are stabilized by a mixture of excipients including surfactants and polymers. Most literature studies have focused on the interaction of excipients with the NDDS surfaces while ignoring the interaction of excipients in solution and the extent to which the solution-state interactions influence the affinity and capacity of adsorption. Mechanisms by which excipients stabilize NDDS and how this information can be utilized by formulators a priori to make a rational selection of excipients is not known.

The goals of …

Nutritional Transporter Mediated Drug Delivery For Cancer, Siddharth S. Kesharwani

Electronic Theses and Dissertations

Recent advancements in nanotechnology have unfolded novel opportunities in medicine, especially in targeted therapeutics and imaging for cancer. However, the majority of the existing nanotechnologies for cancer suffer from shortcomings such as (i) rapid elimination from the systemic circulation before reaching the cancer tissue. (ii) poor tumor accumulation, targeting, and penetration due to inadequate vasculature and extensive extracellular matrix in the tumor. Thus, overcoming these two limitations of nanotechnology is of considerable interests for cancer researchers. In this dissertation, we demonstrate the feasibility of glucose-modified nanoparticles (GLU-NPs) as an efficient cancer targeted-delivery system for enhancing the systemic circulation time and …

Delivery Of Microrna With Cxcr4-Targeted Nanoparticles In Metastatic Cancer Treatment, Ying Xie

Theses & Dissertations

Metastasis is the main contributor to cancer-associated deaths. Inhibition of CXCR4 emerged as one promising approach in metastatic cancer therapy. MiRNAs represent a new class of therapeutics for cancer treatment through RNA interference-mediated gene silencing. Polymeric CXCR4 antagonist (PCX) is a dual-functional polycation to inhibit CXCR4 and deliver nucleic acids. This dissertation hypothesized that blockade of CXCR4 by PCX combined with delivery of miRNA cooperatively enhances metastatic cancer therapy.

In chapter 1, an overview of CXCR4 inhibition, miRNA delivery and CXCR4 targeted nanomedicine in cancer therapy is given.

Chapter 2 reports that PCX can effectively deliver miR-200c mimic and that …

Bacterial Lps At The Immune Modulating Component In Juzen-Taiho-To, Diego Montenegro

Dissertations, Theses, and Capstone Projects

Juzen-taiho-to (JTT) is an immune-boosting herbal formulation with an ideal balance of safety and efficacy. For example, JTT is clinically used in Japan to stimulate the immunological functions of cancer patients undergoing chemotherapy and radiation. Although the clinical effects of JTT are recognized, the active compounds and mechanism of action are unknown. The studies conducted previously in our laboratory associated several phytosterols and plant glycolipids with the potent immunostimulatory activity of JTT: namely, β-sitosteryl β-D-glucoside (BSSG), glucocerebroside (GluCer), digalactosyldiacylglycerol (DGDG) and monogalactosyldiacylglycerol (MGDG). However, these compounds, when further purified, exhibited little or no immunostimulatory activity. This suggested that the immunostimulatory …

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 …

One-Pot Syntheses And Characterizations Of “Click-Able” Polyester Polymers For Potential Biomedical Applications, James F. Beach Ii

Electronic Theses & Dissertations

In this study, a synthetic polyester polymer was designed using polyethylene glycol, sorbitol, glutaric acid and 4-pentynoic acid as monomers. The synthesis was carried out using standard melt polymerization technique and catalyzed by Novozyme-435, an enzyme suitable for polyesterification of biocompatible compounds. The progress of the reaction was monitored with respect to time and vacuum exposure, with samples being subjected to standard characterization protocols. Polymers with high molecular weight and water solubility were chosen for further modification into folate-functionalized polymeric nanoparticles for targeted drug delivery to cancer cells. This was achieved by employing a solvent diffusion method, wherein the polymer …