Assessment of stability, toxicity and immunogenicity of new polymeric nanoreactors for use in enzyme replacement therapy of MNGIE.

TitleAssessment of stability, toxicity and immunogenicity of new polymeric nanoreactors for use in enzyme replacement therapy of MNGIE.
Publication TypeJournal Article
Year of Publication2009
AuthorsDe Vocht, C., A. Ranquin, R. Willaert, J. A. Van Ginderachter, T. Vanhaecke, V. Rogiers, W. Versées, P. Van Gelder, and J. Steyaert
JournalJ Control Release
Date Published2009 Aug 04
KeywordsAnimals, Bacterial Outer Membrane Proteins, Cell Survival, Cells, Cultured, Escherichia coli, Escherichia coli Proteins, Hepatocytes, L-Lactate Dehydrogenase, Macrophages, Male, Mice, Mice, Inbred C57BL, Nanoparticles, Oxazoles, Particle Size, Polymers, Rats, Rats, Sprague-Dawley, Receptors, Virus, Thymidine Phosphorylase

The lack of a crucial metabolic enzyme can lead to accumulating substrate concentrations in the bloodstream and severe human enzyme deficiency diseases. Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is such a fatal genetic disorder, caused by a thymidine phosphorylase deficiency. Enzyme replacement therapy is a strategy where the deficient enzyme is administered intravenously in order to decrease the toxic substrate concentrations. Such a therapy is however not very efficient due to the fast elimination of the native enzyme from the circulation. In this study we evaluate the potential of using polymeric enzyme-loaded nanoparticles to improve the delivery of therapeutic enzymes. We constructed new 200-nanometer PMOXA-PDMS-PMOXA polymeric nanoparticles that encapsulate the enzyme thymidine phosphorylase. These particles are permeabilised for substrates and products by the reconstitution of the nucleoside-specific porin Tsx in their polymeric wall. We show that the obtained 'nanoreactors' are enzymatically active and stable in blood serum at 37 degrees C. Moreover, they do not provoke cytotoxicity when incubated with hepatocytes for 4 days, nor do they induce a macrophage-mediated inflammatory response ex vivo and in vivo. All data highlight the potential of such nanoreactors for their application in enzyme replacement therapy of MNGIE.

Alternate JournalJ Control Release
PubMed ID19371766
Research group: