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ACS Appl Mater Interfaces. 2017 Jan 25;9(3):2181-2195. doi: 10.1021/acsami.6b15064. Epub 2017 Jan 11.

PEGylated and Functionalized Aliphatic Polycarbonate Polyplex Nanoparticles for Intravenous Administration of HDAC5 siRNA in Cancer Therapy.

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Laboratory of Pharmaceutical Technology and Biopharmacy (LTPB) - Center for Interdisciplinary Research on Medicines (CIRM), University of Liege , Avenue Hippocrate 15, 4000 Liege, Belgium.
Protein Signalisation and Interaction (PSI) - GIGA, University of Liege , Avenue de l'Hopital 11, 4000 Liege, Belgium.
Laboratory of Polymeric and Composite Materials, Center of Innovation and Research in Materials and Polymers (CIRMAP), Research Institute for Health Sciences and Technology, University of Mons , Place du Parc 20, 7000 Mons, Belgium.
Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), Department of Pharmacy, University of Namur , Rue de Bruxelles 61, 5000 Namur, Belgium.
Centre Commun de Microscopie Appliquée, University of Nice-Sophia Antipolis , Parc Valrose, 06108 Nice, France.
Metastasis Research Laboratory (MRL) - GIGA, University of Liege , Avenue Hippocrate 15, 4000 Liege, Belgium.
Laboratory for General Biochemistry and Physical Pharmacy, Ghent Research Group on Nanomedicines, Faculty of Pharmacy, Ghent University , Ottergemsesteenweg 460, 9000 Ghent, Belgium.
Laboratory of Biochemistry, Centre for Protein Engineering (CIP), University of Liège , Allée du 6 Août 13, 4000 Liège, Belgium.


Guanidine and morpholine functionalized aliphatic polycarbonate polymers are able to deliver efficiently histone deacetylase 5 (HDAC5) siRNA into the cytoplasm of cancer cells in vitro leading to a decrease of cell proliferation were previously developed. To allow these biodegradable and biocompatible polyplex nanoparticles to overcome the extracellular barriers and be effective in vivo after an intravenous injection, polyethylene glycol chains (PEG750 or PEG2000) were grafted on the polymer structure. These nanoparticles showed an average size of about 150 nm and a slightly positive ζ-potential with complete siRNA complexation. Behavior of PEGylated and non-PEGylated polyplexes were investigated in the presence of serum, in terms of siRNA complexation (fluorescence correlation spectroscopy), size (dynamic light scattering and single-particle tracking), interaction with proteins (isothermal titration calorimetry) and cellular uptake. Surprisingly, both PEGylated and non-PEGylated formulations presented relatively good behavior in the presence of fetal bovine serum (FBS). Hemocompatibility tests showed no effect of these polyplexes on hemolysis and coagulation. In vivo biodistribution in mice was performed and showed a better siRNA accumulation at the tumor site for PEGylated polyplexes. However, cellular uptake in protein-rich conditions showed that PEGylated polyplex lost their ability to interact with biological membranes and enter into cells, showing the importance to perform in vitro investigations in physiological conditions closed to in vivo situation. In vitro, the efficiency of PEGylated nanoparticles decreases compared to non-PEGylated particles, leading to the loss of the antiproliferative effect on cancer cells.


aliphatic polycarbonate; intravenous administration; polyethylene glycol; polyplex nanoparticles; protein corona; siRNA

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