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Date of Award
Doctor of Philosophy (PhD)
Enormous progress has been made to treat cancer, and yet the mortality rate of cancer remains unacceptably high. High clinical resistance to molecularly targeted therapeutics has pushed interest again towards inhibiting universal biochemical hallmarks of cancer. Recent evidence suggests that malignant tumors acidify the local extracellular environment to activate proteases for degrading the tumor matrix, which facilitates metastasis, and explains why more aggressive tumors are more acidic. Current therapies have only focused on using the low pH for enhancing drug release in tumors, thereby still relying on the traditional paradigm of intracellular inhibition of pathways, a method that continues to have mixed results.
In this dissertation we explore the development of a novel platform that can be made to monitor and modify the critical tumor extracellular environment. The platform enables a shift in the paradigm of current cancer therapy from a predominantly intracellular approach to an extracellular synergistic method of targeting cancer. In the process, we demonstrate the synthesis of a novel type of CaCO3 nanoparticle, its stabilization, the increase of pH in vivo, a mathematical justification and simulation, and the subsequent inhibition of tumor growth and metastasis. By neutralizing the tumor extracellular microenvironment, the platform aims to prevent tumor progression and metastasis as well as minimize the traditional intracellular based pathways of resistance. Because of the broad universal aspect of low extracellular pH in cancer, particularly in the more malignant tumors, we expect this platform will also have wide applicability, with particular potency on the most aggressive of cancers.
Samuel Achilefu, Lihong Wang, Srikanth Singamaneni, Shelly Sakiyama-Elbert,
Available for download on Saturday, January 19, 2019