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Access Type

WSU Access

Date of Award

January 2018

Degree Type

Thesis

Degree Name

M.S.

Department

Pharmaceutical Sciences

First Advisor

Arun K. Iyer

Abstract

Tumor hypoxia is an oxygen deprived condition that is generally localized at the central core of the (necrotic) tumors. The necrotic core is surrounded by rapidly proliferating tumor epithelial cells, angiogenic blood vessel and tumor stromal components. Accumulated literature data indicate that tumor hypoxia has important roles in inducing drug resistance and maintaining cancer stemness (supporting a sub-population of virulent cancer stem cells, CSCs) that negatively impact therapeutic outcome as well as promote tumor relapse and metastasis. Thus, there is an urgent unmet need to target tumor hypoxic and CSCs for achieving better therapeutic response to drug treatment. It has been found that cell surface enzymes such as carbonic anhydrases (CA) that catalyze the reversible conversion of CO2 to bicarbonate are upregulated in various types of hypoxic tumors such as Colorectal Cancer. Thus, targeting CA and it responsive protein, such as Hypoxia Inducing Factor-1α (HIF-1α) is an important strategy for selective cancer therapy. Further, it is believed that developing a dual targeting delivery system that acts on the CSCs such as CD44 is a more effective strategy of tumor therapy. Towards this end, several studies are ongoing to develop CA-specific small molecule, peptide, and antibody based inhibitors that can be utilized in combination with Hyaluronic acid for tumor hypoxia targeting as well as CSCs targeting. Along these lines, we propose to develop biocompatible polymeric micelles decorated with CA-inhibitors for therapeutic warhead delivery to Colorectal Cancer. Using this hypothesis, we intend to establish the proof-of-concept to show that targeting hypoxia can be a potent strategy for the treatment of highly aggressive and resistant cancers.

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