High-effective reactive oxygen species inducer based on Mn-tetraphenylporphyrin loaded PLGA nanoparticles in binary catalyst therapy

Abstract

The mechanisms of binary catalyst therapy (BCT) and photodynamic therapy (PDT) are based on the formation of reactive oxygen species (ROS). This ROS formation results from specific chemical reactions. In BCT, light exposure does not necessarily initiate ROS formation and BCT application is not limited to regions of tissues that are accessible to illumination like photodynamic therapy (PDT). The principle of BCT is electron transition, resulting in the interaction of a transition metal complex (catalyst) and substrate molecule. MnIII- tetraphenylporphyrin chloride (MnClTPP) in combination with an ascorbic acid (AA) has been proposed as an appropriate candidate for cancer treatment regarding the active agents in BCT. The goal of this study was to determine whether MnClTPP in combination with AA would be a promising agent for BCT. The problem of used MnClTPP's, low solubility in water, was solved by MnClTPP loading into PLGA matrix. H2O2 produced during AA decomposition oxidized MnClTPP to high-reactive oxo-MnV species. MnClTPP in presence AA leads to the production of excessive ROS levels in vitro. ROS are mainly substrates of catalase and superoxide dismutase (H2O2 and O2●-). SOD1 and catalase were identified as the key players of the MnClTPP ROS-induced cell defense system. The cytotoxicity of MnClTPP-loaded nanoparticles (NPs) was greatly increased in the presence of specific catalase inhibitor (3-amino-1,2,4-triazole (3AT)) and superoxide dismutase 1 (SOD1) inhibitor (diethyldithiocarbamate (DDC)). Cell death resulted from the combined activation of caspase-dependent (caspase 3/9 system) and independent pathways, namely the AIF translocation to nuclei. Preliminary acute toxicity and in vivo anticancer studies have been revealed the safe and potent anticancer effect of PLGA-entrapped MnClTPP in combination with AA. The findings indicate that MnClTPP-loaded PLGA NPs are promising agents for BCT.