am6b15064_si_001.pdf (910.83 kB)
PEGylated and Functionalized Aliphatic Polycarbonate Polyplex Nanoparticles for Intravenous Administration of HDAC5 siRNA in Cancer Therapy
journal contribution
posted on 2016-12-28, 00:00 authored by Antoine Frère, Alexandra Baroni, Elodie Hendrick, Anne-Sophie Delvigne, François Orange, Olivier Peulen, George R. Dakwar, Jérôme Diricq, Philippe Dubois, Brigitte Evrard, Katrien Remaut, Kevin Braeckmans, Stefaan C. De Smedt, Julie Laloy, Jean-Michel Dogné, Georges Feller, Laetitia Mespouille, Denis Mottet, Géraldine PielGuanidine
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.
History
Usage metrics
Categories
Keywords
biocompatible polyplex nanoparticlesPEGylated nanoparticles decreasesFBSpolyethylene glycol chainssiRNA complexationcancer cellsFunctionalized Aliphatic Polycarbonate Polyplex Nanoparticlesnon-PEGylatedHDAC 5 siRNApolyplexehistone deacetylase 5vivoCancer Therapy Guanidinemorpholine functionalized aliphatic polycarbonate polymers
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC