Gold nanoparticles as high-resolution X-ray imaging contrast agents for the analysis of tumor-related micro-vasculature

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Angiogenesis is widely investigated in conjunction with cancer development, in particular because of the possibility of early stage detection and of new therapeutic strategies. However, such studies are negatively affected by the limitations of imaging techniques in the detection of microscopic blood vessels (diameter 3-5 μm) grown under angiogenic stress. We report that synchrotron-based X-ray imaging techniques with very high spatial resolution can overcome this obstacle, provided that suitable contrast agents are used. Results We tested different contrast agents based on gold nanoparticles (AuNPs) for the detection of cancer-related angiogenesis by synchrotron microradiology, microtomography and high resolution X-ray microscopy. Among them only bare-AuNPs in conjunction with heparin injection provided sufficient contrast to allow in vivo detection of small capillary species (the smallest measured lumen diameters were 3-5 μm). The detected vessel density was 3-7 times higher than with other nanoparticles. We also found that bare-AuNPs with heparin allows detecting symptoms of local extravascular nanoparticle diffusion in tumor areas where capillary leakage appeared. Conclusions Although high-Z AuNPs are natural candidates as radiology contrast agents, their success is not guaranteed, in particular when targeting very small blood vessels in tumor-related angiography. We found that AuNPs injected with heparin produced the contrast level needed to reveal--for the first time by X-ray imaging--tumor microvessels with 3-5 μm diameter as well as extravascular diffusion due to basal membrane defenestration. These results open the interesting possibility of functional imaging of the tumor microvasculature, of its development and organization, as well as of the effects of anti-angiogenic drugs.

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Publié le 01 janvier 2012
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Langue English
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Chienet al.Journal of Nanobiotechnology2012,10:10 http://www.jnanobiotechnology.com/content/10/1/10
R E S E A R C HOpen Access Gold nanoparticles as highresolution Xray imaging contrast agents for the analysis of tumorrelated microvasculature 1,2 11 31 1,2,4* ChiaChi Chien, HsiangHsin Chen , ShengFeng Lai , KangChao Wu , Xiaoqing Cai , Yeukuang Hwu, 5 67* Cyril Petibois , Yong Chuand Giorgio Margaritondo
Abstract Background:Angiogenesis is widely investigated in conjunction with cancer development, in particular because of the possibility of early stage detection and of new therapeutic strategies. However, such studies are negatively affected by the limitations of imaging techniques in the detection of microscopic blood vessels (diameter 35μm) grown under angiogenic stress. We report that synchrotronbased Xray imaging techniques with very high spatial resolution can overcome this obstacle, provided that suitable contrast agents are used. Results:We tested different contrast agents based on gold nanoparticles (AuNPs) for the detection of cancer related angiogenesis by synchrotron microradiology, microtomography and high resolution Xray microscopy. Among them only bareAuNPs in conjunction with heparin injection provided sufficient contrast to allowin vivo detection of small capillary species (the smallest measured lumen diameters were 35μm). The detected vessel density was 37 times higher than with other nanoparticles. We also found that bareAuNPs with heparin allows detecting symptoms of local extravascular nanoparticle diffusion in tumor areas where capillary leakage appeared. Conclusions:Although highZ AuNPs are natural candidates as radiology contrast agents, their success is not guaranteed, in particular when targeting very small blood vessels in tumorrelated angiography. We found that AuNPs injected with heparin produced the contrast level needed to revealfor the first time by Xray imagingtumor microvessels with 35μm diameter as well as extravascular diffusion due to basal membrane defenestration. These results open the interesting possibility of functional imaging of the tumor microvasculature, of its development and organization, as well as of the effects of antiangiogenic drugs. Keywords:Synchrotron, Xrays, Angiography, Angiogenesis, Contrast, Au Nanoparticles, Heparin
Background Limited contrast has been a crucial problem in radiology since the discovery of Xrays [1]. The problem is parti cularly acute in the imaging of small blood vessels [2], in particular in the detection of vascular angiogenesis, critical for the early diagnosis of cancer [3], notably for tumors becoming malignant after vascularization. This is a relevant issue: angiogenesis is widely investi gated in conjunction with cancer development [48], and could lead to early detection and new therapeutic
* Correspondence: phhwu@sinica.edu.tw; Giorgio.margaritondo@epfl.ch 1 Institute of Physics, Academia Sinica, Nankang, Taipei 115, Taiwan 7 Ecole Polytechnique Fédérale de Lausanne (EPFL), CH1015 Lausanne, Switzerland Full list of author information is available at the end of the article
strategies [9,10]. However, such studies are negatively impacted by the limitations of established imaging tech niques in the detection of microvessels. New approaches, synchrotronbased Xray microradiology and microtomography, were recently tested for angio graphy studies [2,3,1113]. Effective contrast agents are highly desirable for these techniques. Finding such agents is therefore a prime objective, in particular for nanotechnology. Nanoparticles and other nanosystems are indeed increasingly investigated as con trast agents for radiology. However, the effectiveness of different types of nanoparticles in angiogenesis studies was not yet satisfactorily tested. Extensive tests are
© 2012 Chien et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.