Absolute Quantification And Identification Of Rna From Rna-Lipid Nanoparticles Using High Resolution Mass Spectrometry, Jason C. Funderburk

Theses and Dissertations

RNA therapeutics are a rising drug category with potential use for a range of conditions encompassing infectious diseases to therapies for cancer, diseases, and genetic disorders. RNA-lipid nanoparticles (RNA-LNPs) are the prominent delivery method for these therapeutics approved products include mRNA vaccines and polyneuropathy treatments. The emergency use authorizations and orphan drug status of current RNA-LNP drugs has allowed approval without finalization of the regulatory analytical procedures for quality monitoring. The objective of the study was to develop an LC-MS assay to simultaneously measure identity and concentration of two therapeutically relevant intact RNA constructs extracted from RNA-LNPs to enhance quality …

Absolute Quantification And Identification Of Rna From Rna-Lipid Nanoparticles Using High Resolution Mass Spectrometry, Jason C. Funderburk, Yasir A. Alshehry, Matthew S. Halquist Phd, Sandro R.P. Da Rocha Phd

Graduate Research Posters

Background

RNA therapeutics are a rising drug category with potential use for a range of conditions encompassing infectious diseases to therapies for cancer, diseases, and genetic disorders. RNA-lipid nanoparticles (RNA-LNPs) are the prominent delivery method for these therapeutics approved products include mRNA vaccines and polyneuropathy treatments. The emergency use authorizations and orphan drug status of current RNA-LNP drugs has allowed approval without finalization of the regulatory analytical procedures for quality monitoring. The objective of the study was to develop an LC-MS assay to simultaneously measure identity and concentration of two therapeutically relevant intact RNA constructs extracted from RNA-LNPs to enhance …

Hafnium Oxide-Based Nanoheterostructures For Catalytic Radiosensitization And Enhanced X-Ray Radiotherapy, Marlen Dariela Calix Quezada

Theses and Dissertations

Orthovoltage X-ray beams are attractive for surface and intra-operative radiotherapy. Yet, their clinical utility is constrained by rapid attenuation and the limited dose that can be delivered without harming healthy tissue. High-Z hafnium oxide (HfO₂) nanoparticles can boost local energy deposition through the photoelectric effect, while catalytic surface defects accelerate water radiolysis. Harnessing both mechanisms in a single nano-heterostructure could enable potent radiosensitization at diagnostic-range energies.

This thesis develops and evaluates HfO₂-based nanoheterostructures, both bare and Au-decorated, as catalytic radiosensitizers.

Two types of HfO₂ were evaluated, one was synthesized following a specific route and the …

Levofloxacin Incorporated Extracellular Matrix Nanoparticles For Pulmonary Cystic Fibrosis Infections, Raahi Patel

Theses and Dissertations

Cystic fibrosis (CF) is a progressive genetic disorder that affects around 40,000 people in the United States. CF is characterized by a mutation in the CFTR protein that causes dysregulated ion transport across epithelial cells, producing viscous mucus in the lung that increases bacterial invasion, causing persistent infections and subsequent inflammation. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most common infections in CF patients that are resistant to antibiotics. One antibiotic approved to treat these infections is levofloxacin (LVX) that functions to inhibit bacterial replication, but can be further developed into tailorable particles. Nanoparticles are an emerging inhaled …

Proposing An Rna Interference (Rnai)-Based Treatment For Human Immunodeficiency Virus (Hiv) By Analyzing The Post-Transcriptional Gene Targeting Of Sars-Cov-2, Hepatitis C Virus, And A549 Lung Cancer Cells, Arjun Jagdeesh

UROP Posters

Human Immunodeficiency Virus (HIV) is a retrovirus that infects CD4+ T cell lymphocytes in humans, leading to the development of Acquired Immunodeficiency Syndrome (AIDS) if left untreated. While current treatment methods, including antiretroviral combination treatments, effectively limit HIV replication, HIV can evade these treatments due to its high mutation rate. Long-term antiretroviral treatment can also be toxic to patients, meaning patients would benefit from a new mechanism of HIV treatment. RNA interference (RNAi) is an antiviral pathway found in mammals, plants, and insects that involves a small-interfering RNA that is incorporated into a protein complex called the RNA-induced Silencing Complex …

A Highly Conductive, Flexible, And 3d-Printable Carbon Nanotube-Elastomer Ink For Additive Bio-Manufacturing, Andy Shar, Phillip Glass, Daeha Joung Ph.D.

UROP Posters

The synthesis of a highly conductive, flexible, 3D-printable, and biocompatible ink has been of great interest in the field of bio-based additive manufacturing. Various applications include ultra-sensitive, microscale tactile sensors, patient-customizable scaffolds for cardiac and nerve tissue regeneration, and flexible electrocardiogram (ECG) electrodes. Here, a novel elastomeric carbon nanocomposite is presented consisting of amino-functionalized carbon nanotubes (CNT-NH₂) homogenously dispersed in a one-part room-temperature vulcanizing (RTV) silicone matrix. The use of acetone as a swelling solvent aids in electrical percolation through the elastomer matrix. CNT-NH₂ ratios can be tuned to fit various needs; higher tensile strength is favored …

Comparison Of Free Versus Encapsulated Drugs On 3t3 Differentiation, Simon H. Friedrich, Gabriel Volpe

UROP Posters

The scope of this project was to design, synthesize and test targeted nanoparticles containing hydrophobic and hydrophilic drugs that promote browning in adipose tissue. For hydrophilic drugs the use of liposomes and their hydrophilic core is more useful than the PLGA nanoparticles which have hydrophobic cores. The inhibition of the FOXO1 pathway and modulation of autophagy in adipose tissue can promote browning of white adipose tissue, or an energy burning state where excess energy is burned as heat instead of stored in the cell. If successful, these drugs would offer an alternative treatment for obesity where changes to the patient's …

Overcoming Mechanisms Of Acquired And Innate Doxorubicin Resistance Using Nanomedicine And Tumor-Associated Macrophage Immunotherapy, Rashed M. Almuqbil

Theses and Dissertations

ABSTRACT

Overcoming Mechanisms of Acquired and Innate Doxorubicin Resistance Using Nanomedicine and Tumor-Associated Macrophage Immunotherapy

By Rashed M. Almuqbil, Pharm.D.

Director: Sandro R.P. da Rocha, PhD

Cancer is a leading cause of death worldwide. The available treatment for solid tumors may include surgery, radiotherapy, immunotherapy, and chemotherapy or a combination of all those regimens. Chemotherapy is widely used in the treatment of both lung cancers and breast cancer, including metastases, irrespective of type and stage. The poor rates of survival can be attributed to late diagnosis, and due to the development of acquired and innate chemoresistance. Lung tumors are intrinsically …

Copper Sulfide Manganese Nanoparticles For Multimodality Imaging And Therapy, Ali S. Gawi Ermi

Theses and Dissertations

Abstract

COPPER SULFIDE MANGANESE NANOPARTICLES FOR MULTIMODALITY IMAGING AND THERAPY

By Ali S. Gawi Ermi, MSc

Inorganic nanoparticles (NPs) are compatible with metal-based multi-modality molecular imaging and targeted therapy. Copper sulfide nanoparticles (CuS NPs) are attractive photoacoustic and photothermal agents and are amenable to incorporation of radionuclides and paramagnetic elements to facilitate image-guided therapy. The aim of this work is to develop manganese (Mn)- doped CuS NP, intrinsically radiolabeled with radionuclides such as (Zirconium-89 (⁸⁹Zr), Copper-64/67 (^64/67Cu) and Manganese-52/55 (^52/55Mn)). This novel approach combines Photoacoustic (PA), Positron emission tomography (PET), Single-photon emission computed tomography …

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) …

Live Cell Biomass Tracking For Basic, Translational, And Clinical Research, Graeme Murray

Theses and Dissertations

Single cell mass is tightly regulated throughout generations and the cell cycle, making it an important marker of cell health. Abnormal changes in cell size can be the first indication of dysfunction in response to environmental stimuli such as cytotoxic drugs. Described here is the further development of high-speed live cell interferometry (HSLCI) to concurrently measure the changes in single cell mass of thousands of cells over time. Critically, the high-throughput nature of HSLCI provides realistic pictures of tumor heterogeneity. This throughput enabled HSLCI to correctly predict in vivo carboplatin sensitivity of three triple negative breast cancer patient derived xenografts, …

Dendrimer-Based Antibiotics For The Treatment Of Bacterial Biofilm In Cystic Fibrosis (Cf), Younan Ma

Theses and Dissertations

Pseudomonas aeruginosa (PA) is the predominant pathogen in chronic lung infections of cystic fibrosis (CF) patients. The most important mechanism of adaptation of PA to host defense and antibiotic treatment is the formation of biofilms within the mucus layer covering the lung bronchi. The effectiveness of antibiotics such as aminoglycosides is significantly attenuated by their limited penetration through thick mucus and embedded biofilm matrix in patients’ lung. Inhaled tobramycin (Tobra), which is the most commonly used antibiotics in the treatment of PA infections for CF patients, is usually found to be in very high concentration in patients’ lung, and yet …

Enhancing Chemosensitivity Of Lung Cancers By Manipulating The Tumor Microenvironment: Local Lung Delivery And Nanocarrier-Based Therapies, Hanming Zhang

Theses and Dissertations

Cancer is the second leading cause of death in United States causing an estimated six hundred thousand death in 2019. Among different types of cancer, lung cancer is the leading cause of cancer related death in both male and female. While targeted therapy and immunotherapy have shown promising clinical outcomes, currently there remain a significant proportion of patients who do not benefit from these strategies or who cannot tolerate them, making Pt based doublet chemotherapy still an indispensable component in almost all stages of treatment. However, partially due to the poor tumor distribution of small molecule drug, the development of …

Formulation And Validation Of Nanoparticle Controlled Delivery For Chemotherapeutic Drug Products, Shani L. Levit

Theses and Dissertations

Taxol, a formulation of paclitaxel (PTX), is one of the most widely used anticancer drugs, particularly for treating recurring ovarian carcinomas following surgery. Clinically, PTX is used in combination with other drugs such as lapatinib (LAP) to increase treatment efficacy. Delivering drug combinations with nanoparticles has the potential to improve chemotherapy outcomes. In this study, we use Flash NanoPrecipitation, a rapid, scalable process to encapsulate weakly hydrophobic drugs (logP in vitro. Encapsulating either PTX or LAP into nanoparticles increases drug potency. When PTX and LAP are co-loaded in the same nanoparticle, they have a synergistic effect that is greater than …

Development Of Dexamethsone Sodium Phosphate Loaded Nanoparticles For Treating Corneal Allograft Rejection, Vineet R. Kulkarni

Theses and Dissertations

Corneas are the most commonly transplanted tissue worldwide, with approximately 80,000 transplantations performed in the United States in 2018 alone. Corneal transplantation is used to restore the vision due to opaque corneas in various diseases such as fungal keratitis, keratoconus, Fuchs’s dystrophy, corneal ulceration, traumatic injury, abrasions or scarring, inflammation, and infection. Corneal transplant surgery could involve replacing the entire cornea (penetrating keratoplasty) or selective replacement of the corneal layers (e.g. Descemet’s membrane endothelial keratoplasty and deep anterior lamellar keratoplasty). Immunologic graft rejection is one of the main causes of graft failure in these corneal transplantations. The 2-year rejection rate …

Electrospraying Extracellular Matrix To Form Nanoparticles, Patrick Link

Theses and Dissertations

Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of death worldwide. Alveolar wall destruction is a significant contributor to COPD. Inflammatory macrophages are a major source of the Extracellular Matrix (ECM) proteolysis. ECM breakdown causes air to get trapped in the alveoli, obstructing airflow. One step in curing COPD may be to convert inflammatory to pro-regenerative macrophages. Recently, decellularized ECM scaffolds have shown the ability to induce a pro-regenerative phenotype.

Yet these scaffolds are incapable for reaching the alveolar region of the lungs. To reach the alveolar region particles need a diameter of 1-5 μm or smaller than 300 …

Radioprotective Cerium Oxide Nanoparticles: Molecular Imaging Investigations Of Conps’ Pharmacokinetics, Efficacy, And Mechanisms Of Action, Philip R. Mcdonagh Iii

Theses and Dissertations

Cerium oxide nanoparticles (CONPs) are being investigated for several anti-oxidant applications in medicine. One of their most promising applications is as a radioprotective drug, an area of research in need due to the severe side effects from radiation therapy. In this work, the potential of CONPs as a radioprotective drug is examined using four criteria: favorable biodistribution/pharmacokinetics, low toxicity, ability to protect normal tissue from radiation damage, and lack of protection of tumor. The mechanisms of action of CONPs are also studied. Biodistribution was determined in radiolabeled CONPs with surface coatings including citrate, dextran T10-amine (DT10-NH₂), dextran T10-polyethylene …

Creation Of An Annotated Library On Fda Approved Nanomedicines, Marley R. Hodson, Tanin Izadi, Nastassja Lewinski Ph.D, Bridget T. Mcinnes Ph.D

UROP Posters

Nanomedicine is a type of nanotechnology used in the medical field to limit the dosage amount and target drug delivery to specific cells. Nanomedicines that are approved and used tend to be extremely successful; however despite over a decade of research, only a limited number of nanomedicines have advanced for clinical use. A possible reason for the numerous nanomedicine failures is lack of easily accessible information and research on previous nanomedicines. In this project, we have compiled nanomedicine labeling information from the Drugs@FDA website. We have extracted phrases/sentences from labels relating to keywords on nanomaterial properties and drug profile characteristics. …

Synthesis, Surface Functionalization, And Biological Testing Of Iron Oxide Nanoparticles For Development As A Cancer Therapeutic, Stanley E. Gilliland Iii

Theses and Dissertations

Iron oxide nanoparticles are highly researched for their use in biomedical applications such as drug delivery, diagnosis, and therapy. The inherent biodegradable and biocompatible nanoparticle properties make them highly advantageous in nanomedicine. The magnetic properties of iron oxide nanoparticles make them promising candidates for magnetic fluid hyperthermia applications. Designing an efficient iron oxide nanoparticle for hyperthermia requires synthetic, surface functionalization, stability, and biological investigations. This research focused on the following three areas: optimizing synthesis conditions for maximum radiofrequency induced magnetic hyperthermia, designing a simple and modifiable surface functionalization method for specific or broad biological stability, and in vitro and in …

Modified Seed Growth Of Iron Oxide Nanoparticles In Benzyl Alcohol: Magnetic Nanoparticles For Radio Frequency Hyperthermia Treatment Of Cancer, Stanley E. Gilliland Iii

Theses and Dissertations

Iron oxide nanoparticles have received sustained interest for biomedical applications as synthetic approaches are continually developed for precise control of nanoparticle properties. This thesis presents an investigation of parameters in the benzyl alcohol synthesis of iron oxide nanoparticles. A modified seed growth method was designed for obtaining optimal nanoparticle properties for magnetic fluid hyperthermia. With a one or two addition process, iron oxide nanoparticles were produced with crystallite sizes ranging from 5-20 nm using only benzyl alcohol and iron precursor. The effects of reaction environment, temperature, concentration, and modified seed growth parameters were investigated to obtain precise control over properties …