Winter Patrick M, Caruthers Shelton D, Zhang Huiying, Williams Todd A, Wickline Samuel A, Lanza Gregory M
Washington University, St. Louis, Missouri 63108, USA.
JACC Cardiovasc Imaging. 2008 Sep;1(5):624-34. doi: 10.1016/j.jcmg.2008.06.003.
Studies were performed to develop a prolonged antiangiogenesis therapy regimen based on theranostic alpha(nu)beta(3)-targeted nanoparticles.
Antiangiogenesis therapy may normalize atherosclerotic plaque vasculature and promote plaque stabilization. alpha(nu)beta(3)-targeted paramagnetic nanoparticles can quantify atherosclerotic angiogenesis and incorporate fumagillin to elicit acute antiangiogenic effects.
In the first experiment, hyperlipidemic rabbits received alpha(nu)beta(3)-targeted fumagillin nanoparticles (0, 30, or 90 microg/kg) with either a continued high fat diet or conversion to standard chow. The antiangiogenic response was followed for 4 weeks by cardiac magnetic resonance (CMR) molecular imaging with alpha(nu)beta(3)-targeted paramagnetic nanoparticles. In a second 8-week study, atherosclerotic rabbits received atorvastatin (0 or 44 mg/kg diet) alone or with alpha(nu)beta(3)-targeted fumagillin nanoparticles (only week 0 vs. weeks 0 and 4), and angiogenesis was monitored with CMR molecular imaging. Histology was performed to determine the location of bound nanoparticles and to correlate the level of CMR enhancement with the density of angiogenic vessels.
The alpha(nu)beta(3)-targeted fumagillin nanoparticles reduced the neovascular signal by 50% to 75% at 1 week and maintained this effect for 3 weeks regardless of diet and drug dose. In the second study, atherosclerotic rabbits receiving statin alone had no antineovascular benefit over 8 weeks. The alpha(nu)beta(3)-targeted fumagillin nanoparticles decreased aortic angiogenesis for 3 weeks as in study 1, and readministration on week 4 reproduced the 3-week antineovascular response with no carry-over benefit. However, atorvastatin and 2 doses of alpha(nu)beta(3)-targeted fumagillin nanoparticles (0 and 4 weeks) achieved marked and sustainable antiangiogenesis. Microscopic studies corroborated the high correlation between CMR signal and neovessel counts and confirmed that the alpha(nu)beta(3)-targeted nanoparticles were constrained to the vasculature of the aortic adventia.
The CMR molecular imaging with alpha(nu)beta(3)-targeted paramagnetic nanoparticles demonstrated that the acute antiangiogenic effects of alpha(nu)beta(3)-targeted fumagillin nanoparticles could be prolonged when combined with atorvastatin, representing a potential strategy to evaluate antiangiogenic treatment and plaque stability.
开展研究以开发一种基于诊疗用α（nu）β（3）靶向纳米颗粒的延长抗血管生成治疗方案。
抗血管生成治疗可使动脉粥样硬化斑块血管系统正常化并促进斑块稳定。α（nu）β（3）靶向顺磁性纳米颗粒可对动脉粥样硬化血管生成进行定量，并结合烟曲霉素以引发急性抗血管生成作用。
在第一个实验中，高脂血症兔接受α（nu）β（3）靶向烟曲霉素纳米颗粒（0、30或90微克/千克），同时持续给予高脂饮食或改为标准饲料。通过使用α（nu）β（3）靶向顺磁性纳米颗粒的心脏磁共振（CMR）分子成像对4周内的抗血管生成反应进行跟踪。在第二项为期8周的研究中，动脉粥样硬化兔单独接受阿托伐他汀（0或44毫克/千克饮食）或与α（nu）β（3）靶向烟曲霉素纳米颗粒联合使用（仅在第0周与第0周和第4周使用），并通过CMR分子成像监测血管生成。进行组织学检查以确定结合纳米颗粒的位置，并将CMR增强水平与血管生成血管的密度相关联。
α（nu）β（3）靶向烟曲霉素纳米颗粒在1周时使新生血管信号降低50%至75%，且无论饮食和药物剂量如何，该效果可维持3周。在第二项研究中，单独接受他汀类药物的动脉粥样硬化兔在8周内没有抗新生血管的益处。与研究1中一样，α（nu）β（3）靶向烟曲霉素纳米颗粒使主动脉血管生成减少3周，在第4周重新给药可再现3周的抗新生血管反应，且无残留益处。然而，阿托伐他汀和2剂α（nu）β（3）靶向烟曲霉素纳米颗粒（第0周和第4周）实现了显著且可持续的抗血管生成作用。显微镜研究证实了CMR信号与新生血管计数之间的高度相关性，并确认α（nu）β（3）靶向纳米颗粒局限于主动脉外膜的脉管系统。
使用α（nu）β（3）靶向顺磁性纳米颗粒的CMR分子成像表明，α（nu）β（3）靶向烟曲霉素纳米颗粒与阿托伐他汀联合使用时，其急性抗血管生成作用可延长，这代表了一种评估抗血管生成治疗和斑块稳定性的潜在策略。
