TY - JOUR
T1 - PEGylated and functionalized aliphatic polycarbonate polyplex nanoparticles for intravenous administration of HDAC5 siRNA in cancer therapy
AU - Frère, Antoine
AU - Baroni, Alexandra
AU - Hendrick, Elodie
AU - Delvigne, Anne Sophie
AU - Orange, Francois
AU - Peulen, Olivier
AU - Dakwar, George R.
AU - Diricq, Jérome
AU - Dubois, Philippe
AU - Evrard, Brigitte
AU - Remaut, Katrien
AU - Braeckmans, Kevin
AU - De Smedt, Stefaan C.
AU - Laloy, Julie
AU - Dogné, Jean Michel
AU - Feller, Georges
AU - Mespouille, Laetitia
AU - Mottet, Denis
AU - Piel, Géraldine
PY - 2017/1/25
Y1 - 2017/1/25
N2 - 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 -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.
AB - 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 -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.
KW - Aliphatic polycarbonate
KW - Intravenous administration
KW - Polyethylene glycol
KW - Polyplex nanoparticles
KW - Protein corona
KW - siRNA
UR - http://www.scopus.com/inward/record.url?scp=85011043647&partnerID=8YFLogxK
U2 - 10.1021/acsami.6b15064
DO - 10.1021/acsami.6b15064
M3 - Article
AN - SCOPUS:85011043647
SN - 1944-8244
VL - 9
SP - 2181
EP - 2195
JO - ACS Applied Materials and Interfaces
JF - ACS Applied Materials and Interfaces
IS - 3
ER -