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Mechanism evaluation of antitumoral action of phthalocyanine ruthenium complexes as nitric oxide and singlet oxygen producers by light irradiation. photochemical, photophysical and in vitro and in vivo cytotoxicity measurements

Grant number: 12/25241-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2013
Effective date (End): May 31, 2016
Field of knowledge:Interdisciplinary Subjects
Principal Investigator:Roberto Santana da Silva
Grantee:Juliana Alves Uzuelli
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Nitric oxide (NO) is a biological messenger that has vital importance in many physiological processes, such as cardiovascular control, neural signaling and defense against microorganisms and tumors. In addition, NO is also anticancerigeneo which would enable the use of NO donors compounds in clinical treatments, for example in Photodynamic Therapy (PDT). Based on the chemical and biological characteristics of the molecule NO is vital that becomes the search of systems capable of releasing NO in a controlled way in biological systems. One possibility involves imminent nitrosyl ruthenium complexes whose strategy would be to use compounds that would be thermodynamically stable, but photochemically active.Compounds that absorb in the region of therapeutic window and are likely to propitiate photoinduced electron transfer may, in the presence of ruthenium nitrosyl complexes, produce NO. Based on that the goal of this project is the study of energy transfer and photoinduced electron in complex trans-[RuNO (cp-R) (NO2)] (cp-R is modified phthalocyanine with loads ranging from -3 to -7) as agents producing reactive oxygen species (ROS) and nitrogen (ERONs) by light irradiation in the region of 500 nm to 700 nm. Measurements of NO, singlet oxygen and its derivatives are determined for different oxygen concentrations and potential cytotoxicity in cell lines cancerigeneas evaluated. Photochemical studies by light irradiation in the visible region will be realized both deaerated means as a function of oxygen concentration. Quantification of NO using selective electrode and monitoring will be carried out spectrophotometric (UV-visible and infravelho) developed. Photophysical and kinetic methods will be conducted in order to describe the electron transfer process and photoinduced energy, observed in the species under study.Some biochemical processes related to interaction ruthenium complex-cell are evaluated for ruthenium interaction with cell surface proteoglycans by labeling with fluorophores; phosphorylation of Akt and mitogen-activated protein kinase (MAPK) Assessment of AMPK (AMP-activated protein kinase ), JNK (c-jun terminal kinase-N) and ATF3 (factor 3 transcriptional activation) in response to treatment with the ruthenium complex in the aforementioned cell lines.Later we will evaluate the cytotoxic potential of species which produce both nitric oxide (NO) and singlet oxygen (1O2) in photodynamic therapy of cancers. Parallel studies are also performed photochemical and photophysical quantizing to ROS and ERONs in aqueous medium and conveyed in the presence of liposomal delivery systems.