Biodegradable polyalkylcyanoacrylate nanoparticles for the delivery of oligonucleotides.
Antisense oligonucleotides with base sequences complementary to a specific RNA can, after binding to intracellular mRNA, selectively modulate the expression of a gene. However, these molecules are poorly stable in biological fluids and are characterized by a low intracellular penetration. In view of using oligonucleotides as active molecules, the development of polymeric particulate carriers was considered. Oligonucleotides were associated with biodegradable polyalkylcyanoacrylate nanoparticles through the formation of ion pairs between the negatively charged oligonucleotides and hydrophobic cations. Oligonucleotides bound to these nanoparticles were found to be protected from nuclease attack in cell culture media and their cellular uptake was increased as the result of the capture of nanoparticles by an endocytotic/phagocytotic pathway. The in vivo pharmacokinetic profile of oligonucleotides free or associated with nanoparticles has been investigated after intravenous administration to mice and the stability of these molecules has been evaluated by original methodology based on the use of polyacrylamide gel electrophoresis (PAGE) followed by multichannel radioactivity counting. Stability in vivo in the plasma and in the liver was shown to be improved when the oligonucleotides were adsorbed onto the nanoparticles. These results obtained both in vitro and in vivo open exciting perspectives for the specific delivery of oligonucleotides to the liver, thus considering this approach for the treatment of liver diseases (e.g. liver metastasis or hepatitis).
Fattal
E
E
Laboratoire de Physico-chimie-Pharmacotechnie-Biopharmacie, URA CNRS 1218, Université Paris-Sud, Faculté de Pharmacie, Chatenay-Malabry, France.
Vauthier
C
C
Aynie
I
I
Nakada
Y
Y
Lambert
G
G
Malvy
C
C
Couvreur
P
P
D000818:Animals; D002478:Cells, Cultured; D003487:Cyanoacrylates; D004337:Drug Carriers; D006207:Half-Life; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008863:Microspheres; D010316:Particle Size; D013873:Thionucleotides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D014018:Tissue Distribution
D003487:Cyanoacrylates; D004337:Drug Carriers; D013873:Thionucleotides