Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dr. Aaron Mohs

Abstract

Cancer is the leading cause of death in the United States and its high mortality rate can be attributed towards poor diagnosis methods and less effective therapeutic treatments. Many nanotechnology-based diagnostics and therapeutics are being developed to improve cancer patient outcomes. In this work, we have studied nanoparticles for diagnostic and therapeutic applications in cancer treatment.

In the first work, novel fluorescent NPs loaded with indocyanine green (ICG) were developed for bioimaging applications of pancreatic cancer. Targeted fluorescent nanoparticles (NPs) are being developed to image a range of cancer types with the goal to improve patient outcomes by utilizing in applications like fluorescence-guided surgery. Hyaluronic acid (HA) is a natural ligand for CD44 which is overexpressed in various cancers including pancreatic cancer and hence was used as a targeting moiety. In this study, fluorescent NPs were synthesized by conjugating HA to various hydrophobic aromatic amino acid derivatives to form amphiphilic NPs to which ICG was physically loaded to form self-assembled fluorescent NPs. The NPs were characterized for their physicochemical and spectral properties. In vitro characterization was performed in pancreatic cancer cell lines to study NP toxicity, uptake and bioimaging. Preliminary in vivo study was performed to evaluate the potential of NPs as contrast agents for fluorescence image guided surgery. Overall, the results are promising to use the fluorescent NPs for various in vitro and in vivo imaging applications targeting CD44 overexpressed cancers.

In the second work, we have focused on oncolytic viruses (OVs) used as therapeutics for cancer treatment and have developed methods to label OVs to better understand them. OVs are a new class of therapeutic agents used for cancer treatment and hence, we have to find ways to gain insights into the intracellular transport and mechanisms of OV. Novel labeling and imaging techniques can offer new opportunities to study the virus. In this study, we developed methods for labeling OVs using methods which were mild, specific and efficient. Due to the unique properties of biotin and AF647, viral proteins were conjugated to either of the label and the resulting labeled OVs were characterized for their infectious and genomic activity as well as particle size distribution analysis. The labeling was confirmed by various immunoassays as well as cellular imaging studies. To evaluate the impact of labeling on OV, the pharmacokinetic and biodistribution profiles of labeled and unlabeled OVs were studied. Labeled OVs can be used for longer imaging studies thus providing detailed information regarding the OV and can also be utilized to investigate the dynamic functions of OV. The methods developed to label OV provide a powerful tool to study the OV.

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