Novel PDGFβR antisense encapsulated in polymeric nanospheres for the treatment of restenosis

被引:48
作者
Cohen-Sacks, H
Najajreh, Y
Tchaikovski, V
Gao, G
Elazer, V
Dahan, R
Gati, I
Kanaan, M
Waltenberger, J [1 ]
Golomb, G
机构
[1] Univ Ulm, Dept Internal Med 2, Med Ctr, Robert Koch Str 8, D-89081 Ulm, Germany
[2] Hebrew Univ Jerusalem, Fac Med, Dept Pharmaceut, Sch Pharm, IL-91905 Jerusalem, Israel
[3] Bethlehem Univ, Dept Life Sci, Div Mol Genet, Bethlehem, Palestine
关键词
restenosis; gene therapy; antisense oligonucleotides; smooth muscle cells; slow-release formulation; local drug delivery;
D O I
10.1038/sj.gt.3301830
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (similar to300 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.
引用
收藏
页码:1607 / 1616
页数:10
相关论文
共 37 条
[31]   The experimental use of antisense oligonucleotides: a guide for the perplexed [J].
Stein, CA .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 108 (05) :641-644
[32]   EFFECTS OF ANTISENSE C-MYB OLIGONUCLEOTIDES ON VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION AND RESPONSE TO VESSEL WALL INJURY [J].
VILLA, AE ;
GUZMAN, LA ;
POPTIC, EJ ;
LABHASETWAR, V ;
DSOUZA, S ;
FARRELL, CL ;
PLOW, EF ;
LEVY, RJ ;
DICORLETO, PE ;
TOPOL, EJ .
CIRCULATION RESEARCH, 1995, 76 (04) :505-513
[33]  
Waltenberger J, 1997, CIRCULATION, V96, P4083
[34]   Ischemia-induced transplant arteriosclerosis in the rat - Induction of peptide growth factor expression [J].
Waltenberger, J ;
Akyurek, ML ;
Aurivillius, M ;
Wanders, A ;
Larsson, E ;
Fellstrom, B ;
Funa, K .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1996, 16 (12) :1516-1523
[35]  
Waltenberger J, 1999, CIRC RES, V85, P12
[36]  
WEINSTEIN R, 1982, GROWTH CELLS HORMONA, P145
[37]  
YAMADA KM, 1982, GROWTH CELLS HORMONA, P131