Oxygen Nanobubbles for Ultrasound-guided Targeting of Cancer Hypoxia
Abstract
The effective targeting of hypoxia remains one of the most important and unsolved problems in cancer therapy. Hypoxia has been shown to correlate with significant unfavorable prognosis in several types of cancer. Hypoxia-adaptive pathways effect cellular and epigenetic changes in the tumor. Here, oxygen nanobubbles (ONBs) were designed to target the hypoxic tumor regions. Through in vitro and in vivo studies, we established the potential of ONBs in enhancing ultrasound imaging contrast, perturbing the microenvironment and epigenetic status of the hypoxic cell, and acting as in vitro and ex vivo hyperspectral imaging agents. The first part of my thesis focuses on the development of ONBs to help regulate the epigenetic state and hypoxia-adaptive pathways of the tumor cell. Our technique enables us to significantly halt tumor progression and monitor the tumor using ultrasound and fluorescence imaging in vivo. Next, ONBs were utilized in increasing the efficacy of conventional methylating chemotherapeutic, temozolomide, for enhanced bladder cancer therapy. In the third chapter of this dissertation, ONBs were precisely delivered to orthotopic bladder cancer tumors in mice using Doppler ultrasound. It was found that ONB uptake in tumors can be significantly enhanced using ultrasound guiding. Further, reoxygenation because of ONBs led to enhanced efficacy of a conventional chemotherapeutic, mitomycin-C, in mice models. The fourth chapter of this dissertation focuses on the application of ONBs in dark-field microscopy to enable quantitative imaging and dynamic detection of the nanoparticles, in vitro and ex vivo. Finally, parameters are established to scale-up ONBs for evaluation in pet dogs with naturally-occuring urothelial carcinoma.
Degree
Ph.D.
Advisors
Irudayaraj, Purdue University.
Subject Area
Biomedical engineering|Medicine|Nanotechnology
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