Novel PDGFbetaR antisense encapsulated in polymeric nanospheres for the treatment of restenosis.
Nanospheres composed of the biocompatible and biodegradable polymer, poly-DL-lactide/glycolide and containing platelet-derived growth factor beta-receptor antisense (PDGFbetaR-AS) have been formulated and examined in vitro and in vivo in balloon-injured rat restenosis model. The nanospheres (approximately 300 nm) of homogenous size distribution exhibited high encapsulation efficiency (81%), and a sustained release of PDGFbetaR-AS (phosphorothioated). Cell internalization was visualized, and the inhibitory effect on SMC was observed. Partially phosphorothioated antisense sequences were found to be more specific than the fully phosphorothioated analogs. A significant antirestenotic effect of the naked AS sequence and the AS-NP (nanoparticles) was observed in the rat carotid in vivo model. The extent of mean neointimal formation 14 days after injection of AS-NP, measured as a percentage of luminal stenosis, was 32.21 +/- 4.75% in comparison to 54.89 +/- 8.84 and 53.84 +/- 5.58% in the blank-NP and SC-NP groups, respectively. It is concluded that PLGA nanospheres containing phosphorothioated oligodeoxynucleotide antisense could serve as an effective gene delivery systems for the treatment of restenosis.
Cohen-Sacks
H
H
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Najajreh
Y
Y
Tchaikovski
V
V
Gao
G
G
Elazer
V
V
Dahan
R
R
Gati
I
I
Kanaan
M
M
Waltenberger
J
J
Golomb
G
G
D000818:Animals; D001672:Biocompatible Materials; D016893:Carotid Stenosis / Q000473:pathology / Q000628:therapy*; D002404:Catheterization; D018929:Cell Culture Techniques; D002455:Cell Division / Q000235:genetics; D003692:Delayed-Action Preparations; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D018613:Microscopy, Confocal; D008863:Microspheres; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*; D012008:Recurrence; D017539:Tunica Intima / Q000473:pathology
D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D016376:Oligonucleotides, Antisense; D020797:Receptor, Platelet-Derived Growth Factor beta