Advisor(s)

Mansoor M. Amiji

Contributor(s)

Heather Clark, Shashi Mehta

Date of Award

2011

Date Accepted

8-2011

Degree Grantor

Northeastern University

Degree Level

M.S.

Degree Name

Master of Science

Department or Academic Unit

Bouve College of Health Sciences, Department of Pharmaceutical Sciences

Keywords

pharmaceutical sciences, oncology, molecular biology, hyperoxia therapy, breast cancer, nanoemulsion delivery systems

Subject Categories

Chemotherapy, Cancer - Treatment

Disciplines

Pharmacology, Toxicology and Environmental Health

Abstract

Despite significant advances in new drug discoveries and treatment combinations, the mortality rate due to cancer has not changed significantly over the last fifty years in the United States and many parts of the world. The inability to detect cancer in its early stage accounts for the lethality, which is then associated with poor prognosis as a result of dissemination to other
organs. In breast cancer, for instance, current therapeutic strategies fail to remove root cause of the diseased. This is largely because of the insufficient accumulation of chemotherapeutic agents into the tumor site upon systemic administration and micro environmental selection pressures leading to development of multidrug resistance. As such, there is a critical need to develop more effective therapeutic strategies for breast cancer that lead to enhanced clinical benefits of anticancer therapeutics without the associated systemic toxicity.

Upon initiation of angiogenesis and recruitment of neovasculature, there are regions of solid tumor that lack blood supply. These regions are characterized by the hypoxia, which has been implicated to provide a selective niche for alteration of tumor cell phenotype leading to resistance. Hypoxia induces the expression of hypoxia inducible factor (HIF), which acts as the transcriptional activator of other genes important in disease aggressiveness and metastasis. These include genes that regulate cell proliferation, angiogenesis, glucose transport and metabolism, and cellular invasion from primary tumor.

Based on the need to develop strategies that can alter tumor hypoxia-induced changes, the objective of this study is to evaluate the reversal through hyperoxia treatment in combination with a drug delivery system that can increase tumor drug concentrations, residence, and intracellular delivery. This study evaluated the role of oil-in-water nanoemulsionformulation encapsulating a hydrophobic derivative of doxorubicin, an anthracycline anticancer agent, on cytotoxicity and apoptotic enhancement of tumor cells treated under different oxygen conditions.

Nanoemulsion formulations using fish oil, which is rich in omega-3 polyunsaturated fatty acids, as the internal hydrophobic phase, show rapid intracellular accumulation of doxorubicin stearate (DOX stearate) in the endosomes which acts as a reservoir for the release of free DOX over period of time. Increased levels of the reactive oxygen species were detected in the cells treated with 40 and 60% hyperoxia which aid in the cell killing efficiency of DOX stearate. Also, the cytotoxicity and apoptotic activity of doxorubicin stearate was evaluated when administered in nanoemulsion formulations to cells incubated under different oxygen conditions. The data showed enhanced cell killing efficiency of the drug at lower drug concentration. Using MDAMB- 231 triple negative human breast adenocarcinoma cells, we evaluated the changes in expression profile of gene and protein levels of HIF-1α upon treatment with hypoxia, normoxia, nd hyperoxia conditions. Western blot analysis did show degradation of HIF-1α at increase oxygen level but needs to be proved in a better way. Lastly, the results of this study provided important guidance on the clinical utility of hyperoxia therapy in breast cancer patients.

Document Type

Master's Thesis

Rights Information

copyright 2011

Rights Holder

Hardip Gopani


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