Rational design of organic and organometallic thermoresponsive or tumor-selective anticancer drugs and their in vitro and in vivo biological evaluation

Clavel, Catherine (Clavel, Catherine Marie Amélie)
Advisor: Dyson, Paul Joseph

Conventional chemotherapy leads to severe side-effects such as nephrotoxicity, nausea and vomiting and fatigue along with drug resistance. Alkylating agents used to treat cancer were even shown to provoke second cancers, often years after the end of chemotherapy treatment. Innovative treatments in the clinic are being explored, using hyperthermia in conjunction with chemotherapy to enhance the cytotoxicity of anticancer drugs in tumor cells or as a drug delivery system along with liposomal formulations. In this dissertation, a new duotherapy with regional hyperthermia and chemotherapy concept is described including low molecular weight thermoactive chlorambucil- and ruthenium(II)-based drugs with fluorous chains that are selectively triggered by mild hyperthermia, i.e. essentially inactive at 37¿°C and active under mild hyperthermia. These new compounds were prepared, characterized, and evaluated for their in vitro cytotoxicity against a panel of human cancer cell lines and non-cancerous immortalized cells. The compounds show considerable chemothermal selectivity towards cancer cells for compounds with the longest fluorous chain. The presence of fluorine was found to be critical for thermoresponsive behavior. Furthermore, in vitro assays such as cell motility, cell uptake and cell cycle arrest and in vivo studies on the CAM for assessing antiangiogenic and antitumor effects were performed to gain insights into their mechanism of action. In parallel, a ruthenium(II)¿arene complex with a cleavable perfluoroalkyl-ligand was found to display remarkable selectivity toward cancer cells. IC50 values on several cancer cell lines are in the range of 25 ¿ 45 ¿M, with no cytotoxic effect observed on nontumorigenic (HEK-293) cells. Consequently, this complex was used as the basis for the development of a number of related derivatives, which were screened in cancerous and noncancerous cell lines. Promising derivatives and the lead compound were further studied in vitro and also evaluated in vivo for antiangiogenic activity in the CAM model and in a xenografted ovarian carcinoma tumor (A2780) grown on the CAM. A 90% reduction in the tumor growth was observed for the lead compound. Lastly, thermoresponsive compounds and the tumor-selective lead complex were evaluated in an in vivo xenografted mouse model, validating the thermoresponsive concept in this preclinical model. Indeed, duotherapy with hyperthermia and chemotherapy showed a synergistic tumor growth reduction of 78.7 and 89.9% for thermoresponsive compounds, while the tumor-selective compound led to a tumor reduction of 89.6%, with no toxicity observed relative to body weight of the mice. Biodistribution was additionally assessed for ruthenium-based complexes by ICP-MS measurements.


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