Strategies for Overcoming Shortcomings of Thermal Ablations: A Comprehensive Study of Nanoparticle Transport During Photothermal Chemotherapy Treatments, and High Frequency Irreversible Electroporation
Dewitt, Matthew Ryan
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Cancer continues to be a leading cause of death worldwide despite the increasing research advances into novel treatments. Thermal ablation of tumors is a relatively established method for the destruction of many tumor types, despite inherent shortcomings including incomplete tumor treatment and non-specific treatment. Novel therapies are currently studied including nanoparticle-based therapies to overcome these limitations. One field of research is focused on utilizing non-lethal hyperthermia to enhance carried chemotherapeutic drugs. Additionally a novel field of non-thermal ablations termed Irreversible Electroporation has recently been developed to treat tumors by irreversibly destroying cell membrane function through short electrical pulses. The goal of the present study is to research two novel potential treatments for cancer that do not require thermal destruction of tissue. Firstly, we developed and tested novel ways to load the antineoplastic agent Cisplatin into SWNHs to test the ability to thermally enhance carried drugs with non-lethal, mild hyperthermia. We attached the imaging agent Quantum Dots (QDs) to the particles to understand how hyperthermia affects cellular uptake, minimizing thermal enhancement. Results of this study highlight the need for better biomimetic in vitro models of the tumors to study how hyperthermia affects tissue level transport of nanoparticles. In the second aim we utilized a perfusable 3D collagen in vitro model of the tumor microenvironment, previously developed by our group to study tumor angiogenesis, to study nanoparticle transport. We demonstrated the ability of this model to study key mass transport obstacles nanoparticles face in the tumor including extravasation from a leaky, pro-angiogenic vasculature, diffusion in the extracellular matrix, and cellular uptake in a 3D environment. This model was then utilized in the third aim to study how mild hyperthermia affects transport of SWNHs. Results from this aim were valuable in showing the utility of the 3D in vitro model to controllably test the effects of external stimuli on transport of particles and shows how mild hyperthermia can selectively allow increased permeability of SWNHs in the tumor, increasing selectivity of nanoparticle transport to the targeted tissue. Lastly, we tested the non-thermal ablation, high-frequency irreversible electroporation (H-FIRE) in a 3D tumor platform and in an in vivo swine model to better understand the ability of H-FIRE to produce repeatable destruction of hepatocellular carcinoma, a disease state growing in incidence rate. We then used H-FIRE in an outpatient treatment for infiltrative skin tumors in equines, showcasing the ability to deliver high voltage, short duration pulses in a clinical setting without muscle contractions. Ultimately, the results of this study the engineering studies that must occur to optimize novel treatments utilizing non-lethal hyperthermia, or non-thermal death mechanism to treat cancer. The studies show the usefulness of more complex 3D in vitro models of tumors for early development of novel therapies and the utility of in vivo models to validate studies.
- Doctoral Dissertations