Robert B. Campbell (Ph.D.)
Samuel Gatley, Mansoor M. Amiji, Akio Ohta, Kevin Foley
Date of Award
Doctor of Philosophy
Department or Academic Unit
Bouve Graduate School of Health Sciences. School of Pharmacy.
Colchicine, Lung Carcinoma, Pegylated cationic Liposomes, Tubulin targeting in cancer, Vascular disrupting agents, Vascular
Nonsteroidal anti-inflammatory agents--Analysis, Intravenous therapy, Injections (Intravenous)--Analysis, Cancer--Treatment--Technological innovations
Pharmacy and Pharmaceutical Sciences
Background: 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 blood vessels, change in cell structure and in blood flow dynamics resulting in complete vascular shutdown in solid tumors. The drug colchicine (an alkaloid), 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 intravenous route of administration.
Methods: In phase I, three lung cancer cell lines (LLC, MCA-205, and Chago-k- 1) and endothelial cell lines (MS1-VEGF, HMEC-1) were used. The incorporation efficiency in variety of PCLs was evaluated by reverse phase HPLC analysis. The cytotoxicity profile was established by Sulforhodamine B assay using a fluorescence microplate reader. Qualitative and quantitative analysis of the cytoskeleton and nuclear areas were performed on each cell line using FITC- labeled β-tubulin antibody; the mean area of cytoskeleton and nucleus per cell was determined by fluorescence microscopy. The extent of cytoskeletal disruption in each case was quantified using BIOQUANT software. For phase II studies, we developed an orthotopic mouse model of lung carcinoma to evaluate the therapeutic efficacy of PCL-colchicine. The distribution of the PCLs in C57Bl/6 mice was determined by the measuring the drug accumulated in various tissues using dual labeled PCL-colchicine, 111In radioisotope, tracking the PCLs and 3H, isotope tracking the colchicine itself. The therapeutic efficacy of the formulation was determined by monitoring relative extent of animal survival times.
Results: The loading efficiency of DOTAP-colchicine in PCLs was 78±8%. MS1- VEGF and HMEC-1 displayed both qualitative and quantitative cytoskeleton effects. The disruption of microtubules was most evident when colchicine was loaded in PCLs. Here we report a ~2 fold increase in the accumulation of PCL- colchicine in tumor bearing lung when compared to the normal lung, resulting in inhibition of tumor growth reflected by significantly extended survival times.
Conclusions: Our findings suggest a potential therapeutic benefit of using colchicine-loaded PCLs for the treatment of vascular-associated diseases such as cancer compared to free colchicine alone.
Tangutoori, Shifalika, "An evaluation of colchicine-loaded polyethyleneglycol (PEG)- modified cationic liposomes using in vitro and in vivo models of lung carcinoma" (2010). Pharmaceutical Science Dissertations. Paper 6. http://hdl.handle.net/2047/d20000034
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