Phd Degree / Doktora
Permanent URI for this collectionhttps://hdl.handle.net/11147/2869
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Doctoral Thesis Synthesis, Characterization and Investigation of Cytotoxic Effects of Drug Loaded Zif-8 Metal-Organic Frameworks(01. Izmir Institute of Technology, 2021) Mete, Derya; Şanlı Mohamed, GülşahThe biocompatible ZIF-8 intelligent material, a member of the metal-organic framework family, has a biodegradable property in an acidic environment due to its poor coordination bonds. Because cancerous cells are more acidic than healthy cells, our studies aim to ensure that doxorubicin, sorafenib, and apalutamide, encapsulated in ZIF-8, target cancer cells responsive to pH, thereby reducing damage to healthy cells. In addition, ZIF-8 was selected not only as a carrier system but also as a therapeutic effect. Because ZIF-8 material is biodegradable, it is divided into zinc and 2-methylimidazole components in cancer cells. Research shows that the decrease in the amount of zinc is essential in the formation of cancer cells. Zinc is reported to be in lower intracellular concentrations in HCC and prostate cell lines instead of healthy variants. It aims to create dual cytotoxic effects on cancer cells by combining the effects of zinc-drug on a single platform.Doctoral Thesis Pre-Clinical Trial Treatment of Hepatocellular Carcinoma on Cirrhosis in a Rat Model(İzmir Institute of Technology, 2017) Zeybek Kuyucu, Ayça; Şanlı Mohamed, GülşahHepatocellular carcinoma (HCC) is the second most common cause of cancer related mortality worldwide. AKT pathway has been found activated in 50% of HCC cases, making it promising target. Therefore we assess efficacy of the allosteric AKT inhibitor or the combination of Sorafenib with AKT inhibitor compared to untreated control and to standard treatment, Sorafenib, in vitro and in vivo. AKT inhibitor blocked phosphorylation of AKT in vitro and strongly inhibited cell growth and migration with significantly higher potency than Sorafenib. Similarly, apoptotic cell was strongly increased by AKT inhibitor in vitro. To mimic human advanced HCC, we used diethylnitrosamine-induced cirrhotic rat model with fully developed HCC. MRI analyses showed that AKT inhibitor significantly reduced overall tumor size. Furthermore, number of tumors was decreased by AKT inhibitor, which was associated with increased apoptosis and decreased proliferation. Tumor contrast enhancement was significantly decreased in the AKT inhibitor group. Moreover, on tumor tissue sections, we observed a vascular normalization and a significant decrease in fibrosis in surrounding liver of animals treated with AKT inhibitor. Finally, pAKT/AKT levels in AKT inhibitor treated tumors were reduced, followed by down regulation of actors of AKT downstream signaling pathway: pmTOR, pPRAS40, pPLCγ1 and pS6K1. In conclusion, we demonstrated that AKT inhibitor blocks AKT phosphorylation in vitro and in vivo. In HCC-rat model, AKT inhibitor was well tolerated, showed anti-fibrotic effect and had stronger antitumor effect than Sorafenib. Our results confirm the importance of targeting AKT in HCC.