E. Fattal et al., BIODEGRADABLE POLYALKYLCYANOACRYLATE NANOPARTICLES FOR THE DELIVERY OF OLIGONUCLEOTIDES, Journal of controlled release, 53(1-3), 1998, pp. 137-143
Antisense oligonucleotides with base sequences complementary to a spec
ific RNA can, after binding to intracellular mRNA, selectively modulat
e the expression of a gene. However, these molecules are poorly stable
in biological fluids and are characterized by a low intracellular pen
etration. In view of using oligonucleotides as active molecules, the d
evelopment of polymeric particulate carriers was considered. Oligonucl
eotides were associated with biodegradable polyalkylcyanoacrylate nano
particles through the formation of ion pairs between the negatively ch
arged oligonucleotides and hydrophobic cations. Oligonucleotides bound
to these nanoparticles were found to be protected from nuclease attac
k 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 intraven
ous administration to mice and the stability of these molecules has be
en evaluated by original methodology based on the use of polyacrylamid
e gel electrophoresis (PAGE) followed by multichannel radioactivity co
unting. Stability in vivo in the plasma and in the liver was shown to
be improved when the oligonucleotides were adsorbed onto the nanoparti
cles. These results obtained both in vitro and in vivo open exciting p
erspectives 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). (C) 1998 Elsevier Science B.V.