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Photo-induced activation of metal complexes in living cells for photodynamic therapy (PDT) and photo-activated chemotherapy (PACT)


Pierroz, Vanessa. Photo-induced activation of metal complexes in living cells for photodynamic therapy (PDT) and photo-activated chemotherapy (PACT). 2015, University of Zurich, Faculty of Science.

Abstract

Elaboration of new generations of more effective and safer metal-based anticancer agents, has been stimulated by the severe side effects encountered by patients undergoing chemotherapeutic treatments. In this search, ruthenium complexes have shown encouraging potential, demonstrating a wide antiproliferative profile against cancer cells. Seminal studies conducted in our labs have resulted in the development of ruthenium(II)-based new anticancer agents, which showed distinct cytotoxicity mechanisms.
First, a substitutionally-inert bis(dppz)-Ru(II) complex has been synthetized that impairs the mitochondrial membrane potential of cells leading to apoptosis. A follow- up structure-activity relationship analysis investigating the impact of lipophilicity, charge and size-based modification revealed the presence of carboxylic acid functionality as indispensable to confer cytotoxicity to the Ru(II) complex. This complex was successfully inactivated by protecting the carboxylate functionality with a photolabile protecting group. The anticancer activity could be regained by UV-A irradiation (2.58 J/cm2).
Second, a seemingly harmless ruthenium(II) complex was prepared. It targets the cell nucleus and causes significant damage to DNA, such as single-strand breaks (SSBs) and purines oxidation upon UV-A irradiation (1.29 J/cm2). After 24 h, double- strand breaks (DSBs) are also created that lead overall to cell death.
Collectively, these findings are an important progress towards developing a new class of metal-based anticancer agents, which have the potential to overcome the drawbacks of the current platinum-based drugs.

Abstract

Elaboration of new generations of more effective and safer metal-based anticancer agents, has been stimulated by the severe side effects encountered by patients undergoing chemotherapeutic treatments. In this search, ruthenium complexes have shown encouraging potential, demonstrating a wide antiproliferative profile against cancer cells. Seminal studies conducted in our labs have resulted in the development of ruthenium(II)-based new anticancer agents, which showed distinct cytotoxicity mechanisms.
First, a substitutionally-inert bis(dppz)-Ru(II) complex has been synthetized that impairs the mitochondrial membrane potential of cells leading to apoptosis. A follow- up structure-activity relationship analysis investigating the impact of lipophilicity, charge and size-based modification revealed the presence of carboxylic acid functionality as indispensable to confer cytotoxicity to the Ru(II) complex. This complex was successfully inactivated by protecting the carboxylate functionality with a photolabile protecting group. The anticancer activity could be regained by UV-A irradiation (2.58 J/cm2).
Second, a seemingly harmless ruthenium(II) complex was prepared. It targets the cell nucleus and causes significant damage to DNA, such as single-strand breaks (SSBs) and purines oxidation upon UV-A irradiation (1.29 J/cm2). After 24 h, double- strand breaks (DSBs) are also created that lead overall to cell death.
Collectively, these findings are an important progress towards developing a new class of metal-based anticancer agents, which have the potential to overcome the drawbacks of the current platinum-based drugs.

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Additional indexing

Item Type:Dissertation
Referees:Gasser Gilles, Ferrari Stefano, Lopes Massimo, Therrien Bruno
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2015
Deposited On:06 May 2015 07:27
Last Modified:05 Apr 2016 19:14

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