Graduate Thesis Or Dissertation
 

1) Improving the Uptake and Retention of Gadolinium in Tumors for Potential Gadolinium-Neutron Capture Therapy. 2) Integration of Gemcitabine or Localized Irradiation into dsRNA Therapy Significantly Enhanced the Resultant Anti-tumor Activity

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  • Cancer is one of the leading causes of death in the U.S., and new approaches to control cancer are constantly sought. This dissertation is comprised of two parts: (i) improving the uptake and retention of gadolinium in tumors for potential gadoliniumneutron capture therapy (Gd-NCT) and (ii) integration of gemcitabine or localized irradiation into dsRNA therapy significantly enhanced the resultant anti-tumor activity. One of the key factors for a successful Gd-NCT is to deliver and maintain a sufficient amount of Gd in tumor tissues (50-200 μg of Gd/g of wet tumor) during neutron irradiation, which has proven to be challenging to achieve. A gadolinium-encapsulated liposome (Gd-liposome) formulation was designed to address this need. The formulation was prepared by complexing diethylenetriaminepentaacetic acid (Gd- DTPA) with poly-L-lysine and then encapsulating the Gd-DTPA complexes intopegylated liposomes. The Gd-liposome formulation delivered as high as 159 μg of pure Gd per g of wet tumor tissue into model tumors in mice. A liposome-in-thermosensitive gel system that significantly extended the retention of the Gd in model tumors in mice was also designed. These Gd delivery systems may be used to deliver Gd into solid tumors for NCT and tumor imaging. Despite of the potent tumoricidal activity of polyinosine-cytosine (e.g. poly(I:C)), a synthetic dsRNA, in culture, its in vivo anti-tumor activity has proven to be limited. Gemcitabine, a chemotherapy agent, or localized x-ray radiation was successfully integrated into poly(I:C) therapy to improve the resultant anti-tumor activity in murine tumor models. Combining gemcitabine with poly(I:C) synergistically inhibited the growth of model tumors in mice and also generated a strong and durable tumorspecific immune response. Alternatively, integrating localized x-ray radiation into poly(I:C) therapy significantly delayed the tumor growth, but the combined activity was synergistic only in mice with highly immunogenic tumors, indicating that the T cell-mediated immunity was responsible for the synergy. The type I interferons (IFN- α/β) induced by poly(I:C) played a critical role in the resultant anti-tumor activity. These combination therapies may represent a promising approach to improve the clinical outcomes of poly(I:C) therapy.
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