Advisor(s)

Robert Campbell

Contributor(s)

Samuel J. Gatley, Rebecca L. Carrier

Date of Award

2008

Date Accepted

4-2008

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

Health sciences, Pharmacy, Lewis Lung

Subject Categories

Cancer--Treatment

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

The role of antitubulin drugs as vascular disrupting agents against cancer has been widely recognized. These agents bring about tumor ischemia and necrosis caused by microtubule disruption, alterations in cytoskeleton function of endothelial cells lining microvasculature, change in cell structure and in blood flow dynamics resulting in complete vascular shutdown in solid tumors. The drug colchicine (an alkaloid) is currently used to treat gouty arthritis but was initially shown to exhibit significant tumor vascular disrupting effects. Colchicine acts by depolymerizing microtubules but despite its impressive therapeutic profile as a vascular disrupting agent, it is too toxic to administer to cancer patients by IV route. We therefore developed PEGylated cationic liposomes (PCLs) loaded with colchicine to enhance tumor vascular-specific uptake of the drug and therefore reduce unwanted side-effects. LLC-Lewis lung Carcinoma, MS1-VEGF- endothelial cell lines were used as in vitro models. Colchicine-PCL preparations varied from 3 to 10 mole% drug and their like particle size and zeta potential were determined using a Zeta Particle Size Analyzer. The incorporation of colchicine in PCLs was evaluated by UV microplate reader and reverse phase HPLC analysis. The cytotoxicity profile was established by Sulforhodamine B (SRB) assay using a fluorescence microplate reader. Qualitative and quantitative analysis of the cytoskeleton was performed on each cell line using FITC-labeled β-tubulin antibody and the mean area of cytoskeleton and nucleus per cell was determined with free colchicine and colchicine-loaded PCLs using a fluorescence microscope. The extent of cytoskeletal disruption in each case was quantified using BIOQUANT software.

Document Type

Master's Thesis

Rights Holder

Shifalika Tangutoori


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