Periodicity in tumor vasculature targeting kinetics of ligand-functionalized nanoparticles studied by dynamic contrast enhanced magnetic resonance imaging and intravital microscopy.
Periodicity in tumor vasculature targeting kinetics of ligand-functionalized nanoparticles studied by dynamic contrast enhanced magnetic resonance imaging and intravital microscopy.
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DOI：
10.1007/s10456-013-9380-7
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发表时间：
2014-01
期刊：
影响因子：
9.8
通讯作者：
Haraldseth, Olav
中科院分区：
文献类型：
--
作者：
Hak, Sjoerd;Cebulla, Jana;Huuse, Else Marie;Davies, Catharina de L.;Mulder, Willem J. M.;Larsson, Henrik B. W.;Haraldseth, Olav
在过去的二十年中，靶向纳米颗粒的发展促进了它们作为分子显像剂和靶向药物递送载体的应用。纳米颗粒增强的血管生成肿瘤血管系统分子成像已经引起了特别的兴趣。这不仅是因为血管生成在各种疾病中起着重要作用，而且还因为内皮细胞表面受体可以直接接触到相对较大的循环纳米颗粒。通常，通过分析给药前和给药后设定时间点获得的肿瘤图像的对比度分布，研究靶向这些受体的纳米颗粒。尽管一些令人兴奋的概念验证研究证明了相对靶标浓度和分布的定性评估，但这些研究并没有提供纳米颗粒靶向动力学的定量信息。这些动力学不仅取决于纳米颗粒的特性，还取决于受体的结合和再循环。在这项研究中，我们利用活体显微镜和动态对比增强磁共振成像技术监测αvβ3-整合素特异性纳米颗粒的体内靶向动力学，并利用隔室模型来量化纳米颗粒的靶向率。因此，这种方法可以促进靶向纳米颗粒设计的优化，并有望提供更多体内受体水平的定量信息。有趣的是，我们还观察到αvβ3-整合素靶向纳米颗粒的积累动力学具有周期性，并假设这种周期性是由受体结合、内化和循环动力学引起的。综上所述，这表明我们的实验方法为体内纳米颗粒靶向提供了新的见解，这可能对一般的血管靶向有用。
In the past two decades advances in the development of targeted nanoparticles have facilitated their application as molecular imaging agents and targeted drug delivery vehicles. Nanoparticle-enhanced molecular imaging of the angiogenic tumor vasculature has been of particular interest. Not only because angiogenesis plays an important role in various pathologies, but also since endothelial cell surface receptors are directly accessible for relatively large circulating nanoparticles. Typically, nanoparticle targeting towards these receptors is studied by analyzing the contrast distribution on tumor images acquired before and at set time points after administration. Although several exciting proof-of-concept studies demonstrated qualitative assessment of relative target concentration and distribution, these studies did not provide quantitative information on the nanoparticle targeting kinetics. These kinetics will not only depend on nanoparticle characteristics, but also on receptor binding and recycling. In this study, we monitored the in vivo targeting kinetics of αvβ3-integrin specific nanoparticles with intravital microscopy and dynamic contrast enhanced magnetic resonance imaging, and using compartment modeling we were able to quantify nanoparticle targeting rates. As such, this approach can facilitate optimization of targeted nanoparticle design and it holds promise for providing more quantitative information on in vivo receptor levels. Interestingly, we also observed a periodicity in the accumulation kinetics of αvβ3-integrin targeted nanoparticles and hypothesize that this periodicity is caused by receptor binding, internalization and recycling dynamics. Taken together, this demonstrates that our experimental approach provides new insights in in vivo nanoparticle targeting, which may proof useful for vascular targeting in general.
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