Advisor(s)

Vladimir Torchilin

Contributor(s)

Shashi Murthy, Heather Clark

Date of Award

2011

Date Accepted

11-2011

Degree Grantor

Northeastern University

Degree Level

M.S.

Degree Name

Master of Science

Department or Academic Unit

Bouvé College of Health Sciences, Department of Pharmaceutical Sciences

Keywords

pharmaceutical sciences, cancer therapy, Doxil, nanoparticles, survivin-siRNA

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

Over the last few decades, cancer chemotherapy has advanced by leaps and bounds and yet cancer has been incurable so far. Cancer, uncontrolled growth of cells, depends on several mechanisms for its proliferation and inhibition of cell death. These processes confer unique properties on the cancer. Even though several unique cytotoxic drugs are available and combination therapies are employed, tumor cells are able to survive in many cases. The tumors develop resistance to most of the therapies rendering the cytotoxic drugs ineffective. Moreover, the chemotherapy tends to cause serious side-effects. As a result, a drug delivery system needs to be developed which will target only the tumors as well as aim at reducing the resistance.

To reduce the resistance of cancer cell lines due to the presence of survivin gene and improve the sensitivity towards doxorubicin, a combinatorial therapy was developed involving the use of liposomes as nanocarriers for the drug and siRNA. Survivin-siRNA was used to induce RNA interference (RNAi) in the cells and reduce the sensitivity. Cationic liposomes were complexed with the siRNA and later coincubated with Doxil (doxorubicin in PEGylated liposomes) to develop the lipoplex-coincubated-liposomes which carried both survivin-siRNA and doxorubicin. These formulations were characterized by size, zeta potential and gel electrophoresis. They were tested for their in vitro cytotoxicity via a cell viability assay against resistant and sensitive cancer cell lines. Moreover, stability studies, cell-uptake studies and Transmission Electron Microscope (TEM studies) were performed. It was found that the combination therapy showed significant improvement in cytotoxicity only in few concentrations and in few cell lines and time periods of treatments. Also, the formulations were not found to be extremely stable over the period of study. Thus, a lack of robustness in the combination therapy and the formulations was observed through these studies.

Document Type

Master's Thesis

Rights Information

copyright 2011

Rights Holder

Bhushan Samir Pattni

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