Development of gemcitabine and clofazimine coloaded liposomal delivery system for osteosarcom treatment

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2016

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Çalışkan, Yağmur

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New strategies for more effective treatments need to be developed to cure osteosarcoma patients. Current study was designed to produce a dual drug delivery system with Gemcitabine (GEM) and Clofazimine (CLF) co-loaded liposomes against osteosarcoma diseases. GEM is a second line therapy for osteosarcoma and with combinational use of another regimen it could be much more effective. CLF, an antimycobacterial agent, has been recently recognized as effective on cancer treatment and it was suggested to act on osteosarcoma disease since Wnt signaling pathway is one of the pathway that CLF affects. To prevent the increased toxicities of both agents and control their biodistribution, they were encapsulated into PEGylated liposome. The liposomes were produced in sizes to be administered intravenously (D: 100-150 nm). With the small size of liposomes the tumor cells could be targeted passively by the liposomal system via enhanced permeation and retention effect. Liposomal formulations showed high GEM and CLF loading capacities (90.1±1.16 and 80.1±1.45) and very slow release of GEM and CLF was observed. The cytotoxicity of liposomal formulations were investigated by MTT test and toxicity improvement was observed for co-loaded liposomes compared with single agent loaded liposomes after 24 h incubation with Saos-2 cells. Free drugs treated groups showed higher cytotoxicities than the liposomal formulations. Flow cytometry results were similar; there were more cells in apoptotic stage in GEM/CLF combinational groups (both free and liposomal formulations) than single agent groups and toxicity of GEM/CLF co-loaded liposomal formulation was numerically lower than the free GEM/CLF group. Cell cycle analysis indicates accumulation of cell population at G0/G1 phase was high when treated with liposomes co-loaded with GEM and CLF. GEM and CLF had apoptotic effects on Saos-2 cells as mitochondrial membrane depolarized cells’ ratio increased. Caspase-3 positive cells and early apoptotic cells percentage was increased compared to untreated groups at 24 h. GEM showed a synergistic effect with CLF on Saos-2 cells. With these results, it can be suggested liposomal formulation co-loaded with GEM and CLF would have potential for treating osteosarcoma.

Subject Keywords

Osteosarcoma., Chemotherapy., Bones, Drug delivery systems.

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http://etd.lib.metu.edu.tr/upload/12620646/index.pdf
https://hdl.handle.net/11511/26194

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Graduate School of Natural and Applied Sciences, Thesis

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Citation Formats

Y. Çalışkan, “Development of gemcitabine and clofazimine coloaded liposomal delivery system for osteosarcom treatment,” M.S. - Master of Science, Middle East Technical University, 2016.