Combination of ruthenium based photosensitizers and low level light therapy as upgrade purpose for photodynamic therapy application

• Grant number: 17/00418-6
• Support Opportunities: Scholarships abroad - Research
• Start date: March 01, 2017
• End date: February 28, 2018
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Roberto Santana da Silva
• Grantee: Roberto Santana da Silva
• Host Investigator: Michael R Hanblim
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Harvard University, Boston, United States

Abstract

The project submitted here untitled "Combination of metal based photosensitizers and low level light therapy as upgrade purpose of photodynamic therapy application" is part of the research line of Prof Roberto Santana da Silva (USP), and Michael R. Hamblin (Harvard School and Massachussets General Hospital). This involves the synergistic effect of low levels of visible or near-infrared (NIR) light combined with radicals produced by photosensitizers when submitted to light irradiation therapy. The use of low levels of visible or near-infrared (NIR) light therapy (LLLT) for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing tissue damage has been known for almost forty years since the invention of lasers. Originally thought to be a peculiar property of laser light (soft or cold lasers), the subject has now broadened to include photobiomodulation and photobiostimulation using non-coherent light. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, the biochemical mechanisms underlying the positive effects of LLLT in photodynamic therapy remains controversial. One observation of those studies involving the production of nitric oxide (NO) when LLLT is applying. NO seems to play an important role on light irradiation therapy and maybe could drive an upgrade on Photodynamic Therapy (PDT). The possibility to use ruthenium complex as a drug based on NO release character was first mooted for the team by Dr Silva`s group in 2001 suggesting stimulation of nitrosyl ruthenium complex could promote NO release. The pursuit of these species is of great interest since there is the possibility of creating a new clinical therapy against cancer, based on light irradiation, the technique known as PDT. NO promotes angiogenesis by activation of COX-2 which stimulates the production of proangiogenic factors and prostaglandins. NO also has an invasion stimulating effect which is mediated by upregulation of MMP-2 and MMP-9 (matrix metalloproteinases). However, considering the cytostatic and/or cytotoxic effects of NO, strategies should be developed to manipulate NO levels in the tumor environment for therapeutic gain. Alternative mechanisms for NO delivery would be the use of light induced NO releasing drugs. These are capable of causing sustained release of NO with a wide range of half-lives, and with predictable estimated doses. They can simultaneously exert a multitude of anticancer activities including enhancement of apoptotic stimuli, inhibition of metastasis, inhibition of angiogenesis, and inhibition of hypoxia, and may improve their therapeutic index. Despite all efforts to widen the clinical repertoire of PDT and possible combination with LLLT, there are still challenges to overcome: 1) Is the energy density and power density are key biological parameters for the effectiveness of laser therapy; 2) there is no efficient delivery of the drug-activating light to deep tissues; 3) classical non-targeted photosensitizers lack sufficient tumor selectivity and are also taken up by the neighboring normal tissues, resulting in undesirable toxic side-effects. To tackle these obstacles, approaches relying on active targeting towards tumor cells should be considered. The energy and fluency used in PDT should also be considered as important part to understand the biological mechanism involved in cell protection or death. Those results seem to be related to the combination of LLLT and PDT. In the proposed project understand combination of LLLT, NO and ruthenium phthalocianine will be crucial to improve the effectiveness of PDT.