Utilizing targeted gene therapy with nanoparticles binding alpha v beta 3 for imaging and treating choroidal neovascularization.
Utilizing targeted gene therapy with nanoparticles binding alpha v beta 3 for imaging and treating choroidal neovascularization.
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DOI：
10.1371/journal.pone.0018864
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发表时间：
2011-04-29
期刊：
影响因子：
3.7
通讯作者：
Miller JW
中科院分区：
文献类型：
--
作者：
Salehi-Had H;Roh MI;Giani A;Hisatomi T;Nakao S;Kim IK;Gragoudas ES;Vavvas D;Guccione S;Miller JW
整合素αvβ3在新生血管内皮细胞上差异表达。我们研究了一种新型的静脉注射αvβ3整合素-配体偶联纳米颗粒（NP）是否可以靶向脉络膜新生血管膜（CNV）进行成像和靶向基因治疗。采用激光光凝法诱导大鼠CNV病变。通过将NP与绿色荧光蛋白质质粒（NP-GFP g）偶联来评价NP用于体内成像和基因递送的效用。罗丹明标记（Rd-NP）用于定位NP在脉络膜的flatmount。在第1、2或3周静脉内注射Rd-NP-GFP g颗粒。在治疗组中，大鼠在第1、3和5天接受含有显性负性Raf突变基因（NP-ATPμ-Raf）的NP。对CNV大小和渗漏的变化以及TUNEL阳性细胞进行定量。在注射Rd-NP-GFPg后长达3天的体内观察到GFP质粒表达。脉络膜标本证实了NP的定位和GFP质粒在CNV中的表达。用NP-ATPμ-Raf处理CNV，CNV体积减小42%（P<0.001）。OCT分析显示CNV大小在第5天开始减小，到第7天达到统计学显著性。血管造影分级显示治疗后CNV渗漏明显减少（P<0.001）。有显着更多的凋亡（TUNEL阳性）细胞核在治疗的CNV。全身应用αvβ3靶向的NP可用于标记CNV的异常血管进行成像。使用NP-ATPμ-Raf进行靶向基因递送，通过诱导CNV中的细胞凋亡，导致CNV的尺寸减小和渗漏。
The integrin αvβ3 is differentially expressed on neovascular endothelial cells. We investigated whether a novel intravenously injectable αvβ3 integrin-ligand coupled nanoparticle (NP) can target choroidal neovascular membranes (CNV) for imaging and targeted gene therapy. CNV lesions were induced in rats using laser photocoagulation. The utility of NP for in vivo imaging and gene delivery was evaluated by coupling the NP with a green fluorescing protein plasmid (NP-GFPg). Rhodamine labeling (Rd-NP) was used to localize NP in choroidal flatmounts. Rd-NP-GFPg particles were injected intravenously on weeks 1, 2, or 3. In the treatment arm, rats received NP containing a dominant negative Raf mutant gene (NP-ATPμ-Raf) on days 1, 3, and 5. The change in CNV size and leakage, and TUNEL positive cells were quantified. GFP plasmid expression was seen in vivo up to 3 days after injection of Rd-NP-GFPg. Choroidal flatmounts confirmed the localization of the NP and the expression of GFP plasmid in the CNV. Treating the CNV with NP-ATPμ-Raf decreased the CNV size by 42% (P<0.001). OCT analysis revealed that the reduction of CNV size started on day 5 and reached statistical significance by day 7. Fluorescein angiography grading showed significantly less leakage in the treated CNV (P<0.001). There were significantly more apoptotic (TUNEL-positive) nuclei in the treated CNV. Systemic administration of αvβ3 targeted NP can be used to label the abnormal blood vessels of CNV for imaging. Targeted gene delivery with NP-ATPμ-Raf leads to a reduction in size and leakage of the CNV by induction of apoptosis in the CNV.
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影响因子：
4.4
作者：
Gaudreault, J;Fei, D;Shiu, V
通讯作者：
Shiu, V
影响因子：
5.3
作者：
HEIDECKER, G;HULEIHEL, M;RAPP, UR
通讯作者：
RAPP, UR
影响因子：
64.5
作者：
BROOKS, PC;MONTGOMERY, AMP;CHERESH, DA
通讯作者：
CHERESH, DA
DOI：
10.1073/pnas.93.18.9764
发表时间：
1996-09-03
影响因子：
11.1
作者：
Friedlander, M;Theesfeld, CL;Cheresh, DA
通讯作者：
Cheresh, DA
影响因子：
56.9
作者：
BROOKS, PC;CLARK, RAF;CHERESH, DA
通讯作者：
CHERESH, DA