Date of Award
7-18-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Cancer remains a leading cause of morbidity and mortality worldwide, with millions of new cases diagnosed each year and a significant number of deaths attributed to the disease. Traditional cancer treatments like surgery, chemotherapy, and radiation therapy often face limitations, including non-specific targeting, significant side effects, and the potential for drug resistance. Advances in nanotechnology have opened new avenues for cancer diagnosis and treatment. However, the prospect of clinical translation of current cancer nanomedicine is hampered by many challenges, such as off-targeting toxicity of nanoparticles, poor tumor accumulation, size, aggregation-imposed vascular confinement, and complex designs for combining imaging and therapeutic agents. To address these issues, this dissertation explores the design, synthesis, characterization, and applications of multifunctional hybrid theranostic nanoplatforms, integrating imaging and therapeutic capabilities into a single nanoparticle system. The hybrid nanoparticles combine the stability and multifunctionality of inorganic materials with the biocompatibility and degradability of organic components, creating a versatile tool for precision medicine. We first designed tannic acid-based bimetallic nanoplatforms. Gadolinium and titanium were incorporated via coordination bonds with tannic acid to generate contrast for magnetic resonance imaging (MRI) and reactive oxygen species (ROS) for radionuclide-stimulated dynamic therapy (RaST). Fluorescent dyes were incorporated to synergize with MRI and enable both shallow and deep tissue imaging. This innovative approach allows targeted tumor imaging with dual imaging modalities and potential RaST application using a single nanoparticle platform. We also developed monodispersed calcium carbonate (CaCO3) nanoparticles as a multifunctional pH-responsive nanoplatform. LS301, a tumor-targeting near-infrared fluorescent dye-peptide conjugate, and doxorubicin were loaded for fluorescence imaging and chemotherapeutic effects, respectively. The formulated nanoplatform showed pH-controlled drug release, with doxorubicin potentiating cancer inhibition when released from CaCO3 nanoparticles into a less acidic tumor environment. Furthermore, we developed new near-infrared fluorescent gold nanoclusters (AuNCs) with a small protein-level size of 2 nm. We discovered that AuNCs display a neuron maturation-dependent internalization pattern, showing stronger signals in mature neurons than in early-stage neurogenesis cells. The high selectivity for neurons over glial cells underscores their potential as specific neuro-imaging agents. Intravenous injection of AuNCs into mice and subsequent imaging revealed that these protein-sized nanoparticles crossed the blood-brain barrier and were distributed in multiple brain regions. These findings highlight the potential of using AuNCs for brain imaging and targeted interventions in neurological disorders. Together, this work lays a strong foundation for multifunctional hybrid theranostic nanoplatforms engineered to enhance imaging modalities such as optical imaging and MRI while enabling targeted drug delivery and inducible therapeutics with improved efficiency, paving the way for innovative and effective cancer theranostics and integrated image-guided interventions.
Language
English (en)
Chair
Samuel Achilefu
Committee Members
Srikanth Singamaneni