使用全氟丁烷气体微泡载体进行反义寡核苷酸的系统性靶向递送可减少猪冠状动脉再狭窄模型中的新生内膜形成。

Systemic targeted delivery of antisense with perflourobutane gas microbubble carrier reduced neointimal formation in the porcine coronary restenosis model.

作者信息

Kipshidze Nicholas N, Porter Thomas R, Dangas George, Yazdi Hamid, Tio Fermin, Xie Feng, Hellinga David, Fournadjiev Jana, Wolfram Roswitha, Seabron Rufus, Waksman Ron, Abizaid Alexander, Roubin Gary, Iyer Sriram, Leon Martin B, Moses Jeffrey W, Iversen Patrick

机构信息

Lenox Hill Heart and Vascular Institute and Cardiovascular Research Foundation, 130 East 77th Street, Black Hall, 9th Floor, New York, NY 10021, USA.

出版信息

Cardiovasc Radiat Med. 2003 Jul-Sep;4(3):152-9. doi: 10.1016/S1522-1865(03)00184-7.

DOI:10.1016/S1522-1865(03)00184-7

PMID:14984716

Abstract

HYPOTHESIS

The antisense phosphorodiamidate morpholino oligomer (PMO), AVI-4126, has been effective in reducing neointimal formation in animal models following delivery by pluronic gels, local delivery catheters and coated stents. Greater flexibility of repeated-dosage regimens and reduced procedure complexity may be provided by systemic injection of AVI-4126 bound to perfluorobutane gas microbubble carriers. The purpose of this study was to investigate the effects of perfluorocarbon gas microbubble carrier (PGMC)-based systemic delivery of AVI-4126 on expression of the c-myc in vascular tissue and restenosis after stent implantation.

METHODS

Seven pigs underwent stent implantation (3 stents/animal). Five pigs received IV injection of PGMC and 2 mg of AVI-4126 (AVI BioPharma). Two served as control. Four hours postprocedure, 3 pigs were sacrificed and stented segments analyzed by high-performance liquid chromatography (HPLC) and Western blot. In chronic experiments, 4 pigs (12 stent sites) were sacrificed at 28 days.

RESULTS

HPLC analysis of plasma samples of treated animals showed minimal presence of AVI-4126. HPLC of the treated arteries demonstrated easily detected concentrations of AVI-4126. Western blot analysis of the stented vessels demonstrated modest inhibition of c-myc. Morphometry showed that the neointimal area was significantly reduced in the AVI-4126/PGMC group compared with control (2.63+/-1.99 vs. 4.77+/-.1.71 mm2, respectively, P<.05).

CONCLUSION

In the porcine coronary stent model, systemic targeted delivery of AVI-4126 using PGMC carrier significantly inhibited neointimal formation.

摘要

假设

反义磷酰二胺吗啉代寡聚物（PMO）AVI-4126在通过普朗尼克凝胶、局部给药导管和涂层支架给药后，已有效地减少了动物模型中的新生内膜形成。与全氟丁烷气体微泡载体结合的AVI-4126全身注射可能会提供更大的重复给药方案灵活性，并降低手术复杂性。本研究的目的是调查基于全氟碳气体微泡载体（PGMC）的AVI-4126全身给药对血管组织中c-myc表达及支架植入后再狭窄的影响。

方法

7头猪接受支架植入（每头动物植入3个支架）。5头猪静脉注射PGMC和2mg AVI-4126（AVI生物制药公司）。2头作为对照。术后4小时，处死3头猪，用高效液相色谱法（HPLC）和蛋白质免疫印迹法分析支架段。在慢性实验中，4头猪（12个支架部位）在28天时处死。

结果

对治疗动物血浆样本的HPLC分析显示AVI-4126的存在极少。对治疗动脉的HPLC显示很容易检测到AVI-4126的浓度。对支架血管的蛋白质免疫印迹分析显示c-myc有适度抑制。形态测量显示，与对照组相比，AVI-4126/PGMC组的新生内膜面积显著减少（分别为2.63±1.99和4.77±1.71mm2，P<0.05）。