AL-Shakarchi, Wejdan (2018) The co-administration of anticancer and pro-apoptotic agents as a novel approach in liver cancer therapy. Doctoral thesis, Keele University.

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Hepatocellular carcinoma accounts for 85% of primary liver cancer that are usually characterised by defective or ineffective apoptosis which is considered to be the main cause of cancer progression. In this study, Cytochrome-C which is a pro-apoptotic protein is combined with hybrid (iron oxide-gold) nanoparticles and triggers mitochondrial downstream apoptosis pathway in the tumour cells. The nanoparticle complex enables delivery of this difficult protein through the cell membrane. In this research, five different anticancer drugs (doxorubicin, oxaliplatin, paclitaxel, vincristine and vinblastine) were used against liver cancer and U937 cell lines to assess their IC50 values alone and to check their toxicity after their co-administration with cytochrome C hybrid formulation. These combinations resulted in an increase in the cytotoxicity of the used chemotherapeutic drugs and remarkable decrease in the amount needed to kill hepatic cancer cells. For that reason, Iron-gold hybrid nanoparticles offer a promising tool for cytochrome-c delivery into tumour cells and enhance the specific targeting of therapeutic particles to their site of action.

The preliminary results reflected the increasing killing abilities of chemotherapeutic therapies when co-administered with cytochrome C hybrid formulation by targeting the natural killing mechanism inside the cells and activating its pathways. Subsequent to these results, further work was done in formulation of one platform therapeutic device with Polymeric amphiphiles hydrophilic poly(allylamine) polymer (PAA) grafting with 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-thiol(oxadiazole, Ox). Paclitaxel (PTX) was selected as a hydrophobic drug model to check its water solubility behaviour after loading into PAA-HNP-C platform. These new devices showed a significant increase in drug uptake level and increase in PTX cytotoxicity against liver cancer cell lines. The data from this work showed a significant increase in the apoptosis activities of combining treatment anticancer agents (doxorubicin, paclitaxel, oxaliplatin, vinblastine and vincristine) and the hybrid formulation of the cytochrome-C within the liver cell lines, which leads to cellular death. Therefore, this combined method may give promise step for the future of liver cancer treatment regimes. In addition to, formulating the HNP-CYT-C and PTX into as active single platform for increasing the PTX cytotoxicity. More laboratory investigation is needed to check the activity of this formulation as a preparing step to further in vivo studies.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy
Contributors: Hoskins, C (Thesis advisor)
Curtis, Anthony (Thesis advisor)
Depositing User: Lisa Bailey
Date Deposited: 30 Jul 2018 11:24
Last Modified: 08 Oct 2020 13:33

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