Zhu, LiangLeBrun, Alexander Mark2019-10-112019-10-112015-01-0111378http://hdl.handle.net/11603/15717Magnetic nanoparticles have gained prominence in the last two decades for use in clinical applications such as drug delivery, medical imaging, and recently hyperthermia therapies. In magnetic nanoparticle hyperthermia, an external alternating magnetic field is applied to the nanoparticles to generate localized heating to targeted tissue region. Once the nanoparticles are delivered to the targeted area, their spatial distribution dominates the spatial temperature elevation in the tissue. The challenge is that nanoparticle deposition is often non-uniform and uncontrollable. The focus of this dissertations research is to design heating protocols for tumors with unique geometries and nanoparticle distributions based on microCT scans of tumors with nanoparticle deposition. Our proposed method is tested and evaluated in animal experiments in the treatment of prostatic cancer tumors implanted in mice. In vivo animal experiments are performed on xenograft prostatic cancer (PC3) tumors in immunodeficient mice to investigate how the infusion rate affects the distribution of magnetic nanoparticles in the tumor tissue. The nanoparticle distribution volume obtained from the microCT scan is used to evaluate spreading of the nanoparticles from the injection site in tumors. Heating experiments are performed to quantify relationships among microCT Hounsfield Unit (HU) values, local nanoparticle concentrations in tumors, and the specific absorption rate (SAR) induced when nanoparticles are subject to an alternating magnetic field. An infusion rate of 3 µL/min is identified to result in the most repeatable nanoparticle distribution in PC3 tumors. Linear relationships have been obtained to first convert microCT gray scale values to HU values, then to local nanoparticle concentrations, and finally to nanoparticle-induced SAR values. The total energy deposition rate in tumors is calculated and the observed similar total energy deposition rates in all three infusion rate groups suggest improvement in minimizing nanoparticle leakage from the tumors. The tumor geometry and SAR distribution in the PC3 tumors are then imported into finite element software for heating protocol design. The heat transfer process is modeled using the transient Pennes bioheat equation that is coupled with a first-order chemical reaction equation to estimate the time when complete thermal damage to tumor cells occurs. The goal is to completely damage the tumor tissue while preserving the surrounding healthy tissue. When the infusion rate is 3 µL/min, the average time for complete thermal damage to the tumor is approximately 25 minutes while collateral thermal damage to surrounding healthy tissue is below our criterion. As the infusion rate increases, the time required for complete thermal damage to the tumor increases by up to 90%, in the meantime, the amount of collateral thermal damage to the healthy tissue increases drastically, exceeding the criterion. The results of this part of the study identify a designed heating protocol to be tested in further experimental settings. To validate the designed heating protocols, we perform in vivo animal experiment on PC3 tumors with similar size, shape, and injection strategy as in the previous parts of the study. The mice are injected at a low infusion rate of 3 µL/min so that the nanoparticles are confined to the injection region. The mice are then placed inside of an alternating magnetic field for the designed heating time of 25 minutes to induce tumor damage. The tumor shrinkage/growth following the heating is recorded over an 8 week period to verify treatment efficacy of the heating protocol. The implemented thermal dosage following the design shows complete disappearance of the tumors after only one week and the disappearance is maintained for 8 weeks. On the other hand, inadequate thermal dosages showed tumor recurrence despite an initial tumor shrinkage. The untreated tumors triple its size over the 8 week observation period. Histological analysis is also performed to quantitatively determine the extent of thermal damage. The control and sham groups show normal healthy PC3 with small necrotic regions due to poor blood supply, while the treated tumor showed necrotic tissue and severe cellular morphological changes as well as damage to the surrounding muscle.This item may be protected under Title 17 of the U.S. Copyright Law. It is made available by UMBC for non-commercial research and education. For permission to publish or reproduce, please see http://aok.lib.umbc.edu/specoll/repro.php or contact Special Collections at speccoll(at)umbc.eduCancerHyperthermiaImageMagneticMicroCTNanoparticleText