Nonalcoholic fatty liver disease (NAFLD) is a prevalent disease, in which the pathophysiological mechanisms are not fully understood yet, but among others are associated with increased oxidative stress (ROS) in liver tissue. ROS can be removed by artificial organelles, which equip their host cells with supporting enzyme function. Artificial organelles need to be placed in the cytosol for efficient activity i.e., their lysosomal escape is required. Their long-term activity is often limited by degradation of natural enzymes, the typical biocatalytically active entity in artificial organelles. Therefore, our assemblies contain an encapsulated small organic molecule, the salen-manganese complex EUK, as a catalase mimic. Different EUKs were synthesized and compared for their activity and long-term stability. Encapsulation of the lead candidate in polymeric micelles equipped the enzyme-mimic with the ability for a lysosomal escape and a higher stability in solution. The polymeric shell of the artificial organelle consists of either poly(cholesteryl methacrylate) or poly(2-carboxyethyl acrylate). Both these hydrophilic polymers exhibit lysosomal escape abilities. The assembled artificial organelles were evaluated in cell culture in terms of cytotoxicity and uptake as well as lysosomal escape efficacy. Inducing oxidative stress via paraquat in cells equipped with the EUK-loaded micelles improved their survival rate compared to untreated cells, illustrating intracellular biocatalytic activity.<br/>Taken together, the assembled artificial organelles including the enzyme mimic and the ability to escape the lysosome offer the opportunity as an antioxidant in NAFLD.

Polymeric artificial organelles containing an enzyme mimic

2019 Fall National Meeting

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