Improved oligonucleotide uptake and stability by a new drug carrier, the SupraMolecular Bio Vector (SMBV).
Antisense oligodeoxynucleotides are potential therapeutic agents, but their development is still limited by both a poor cellular uptake and a high degradation rate in biological media. The strategy that we propose to face these problems is to use small synthetic carriers, around 30 nm diameter, the SupraMolecular Bio Vectors (SMBV). We used positively charged SMBV and settled the ionic incorporation of negatively charged oligonucleotides into these carriers. A minimal leakage of 10% of total incorporated oligonucleotides was then measured during two months. Both protection and uptake of oligonucleotides were then analyzed. On the one hand, we showed that the incorporation of oligonucleotides into the selected SMBV allows to significantly increase, 8 times, their half-life, in cell growth medium. On the other hand, the internalization of the SMBV, into cells, by an endosomal pathway has been characterized. The essential point is that the SMBV uptake elicits the simultaneous oligonucleotide uptake. The oligonucleotide amount that goes through cells within 5 h can be up to 30 times higher than for free oligonucleotides and the fraction of oligonucleotides that is present in the cytosol is increased up to 10 fold after incorporation into the SMBV. This study demonstrates the ability of SMBV to improve oligonucleotide cellular behaviour.
Berton
M
M
EA/UPRES 2048, Laboratoire d'Oncologie Cellulaire et Moléculaire, Faculté des Sciences Pharmaceutiques and Centre Claudius Regaud, Toulouse, France.
Sixou
S
S
Kravtzoff
R
R
Dartigues
C
C
Imbertie
L
L
Allal
C
C
Favre
G
G
D000818:Animals; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D003470:Culture Media; D003600:Cytosol / Q000378:metabolism; D004337:Drug Carriers; D004705:Endocytosis; D011992:Endosomes / Q000502:physiology; D006207:Half-Life; D008051:Lipid Bilayers; D018613:Microscopy, Confocal; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011134:Polysaccharides
D003470:Culture Media; D004337:Drug Carriers; D008051:Lipid Bilayers; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D011134:Polysaccharides; D002738:Chloroquine