TY - JOUR
T1 - Topical and intravitreous administration of cationic nanoemulsions to deliver antisense oligonucleotides directed towards VEGF KDR receptors to the eye
AU - Hagigit, Tal
AU - Abdulrazik, Muhammad
AU - Orucov, Faik
AU - Valamanesh, Faty
AU - Lambert, Martin
AU - Lambert, Gregory
AU - Behar-Cohen, Francine
AU - Benita, Simon
PY - 2010/8
Y1 - 2010/8
N2 - Antisense oligonucleotides (ODNs) specific for VEGFR-2-(17 MER) and inhibiting HUVEC proliferation . in-vitro were screened. One efficient sequence was selected and incorporated in different types of nanoemulsions the potential toxicity of which was evaluated on HUVEC and ARPE19 cells. Our results showed that below 10 μl/ml, a 2.5% mid-chain triglycerides cationic DOTAP nanoemulsion was non-toxic on HUVEC and retinal cells. This formulation was therefore chosen for further experiments. . In-vitro transfection of FITC ODNs in ARPE cells using DOTAP nanoemulsions showed that nanodroplets do penetrate into the cells. Furthermore, ODNs are released from the nanoemulsion after 48. h and accumulate into the cell nuclei. In both . ex-vivo and . in-vivo ODN stability experiments in rabbit vitreous, it was noted that the nanoemulsion protected at least partially the ODN from degradation over 72. h. The kinetic results of fluorescent ODN (Hex) distribution in DOTAP nanoemulsion following intravitreal injection in the rat showed that the nanoemulsion penetrates all retinal cells. Pharmacokinetic and ocular tissue distribution of radioactive ODN following intravitreal injection in rabbits showed that the DOTAP nanoemulsion apparently enhanced the intraretinal penetration of the ODNs up to the inner nuclear layer (INL) and might yield potential therapeutic levels of ODN in the retina over 72 h post injection.
AB - Antisense oligonucleotides (ODNs) specific for VEGFR-2-(17 MER) and inhibiting HUVEC proliferation . in-vitro were screened. One efficient sequence was selected and incorporated in different types of nanoemulsions the potential toxicity of which was evaluated on HUVEC and ARPE19 cells. Our results showed that below 10 μl/ml, a 2.5% mid-chain triglycerides cationic DOTAP nanoemulsion was non-toxic on HUVEC and retinal cells. This formulation was therefore chosen for further experiments. . In-vitro transfection of FITC ODNs in ARPE cells using DOTAP nanoemulsions showed that nanodroplets do penetrate into the cells. Furthermore, ODNs are released from the nanoemulsion after 48. h and accumulate into the cell nuclei. In both . ex-vivo and . in-vivo ODN stability experiments in rabbit vitreous, it was noted that the nanoemulsion protected at least partially the ODN from degradation over 72. h. The kinetic results of fluorescent ODN (Hex) distribution in DOTAP nanoemulsion following intravitreal injection in the rat showed that the nanoemulsion penetrates all retinal cells. Pharmacokinetic and ocular tissue distribution of radioactive ODN following intravitreal injection in rabbits showed that the DOTAP nanoemulsion apparently enhanced the intraretinal penetration of the ODNs up to the inner nuclear layer (INL) and might yield potential therapeutic levels of ODN in the retina over 72 h post injection.
KW - AMD
KW - Cationic
KW - DOTAP
KW - Nanoemulsion
KW - Oligonucleotide
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=77954314021&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2010.04.013
DO - 10.1016/j.jconrel.2010.04.013
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 20420865
AN - SCOPUS:77954314021
SN - 0168-3659
VL - 145
SP - 297
EP - 305
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 3
ER -