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

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.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.Limited contrast has been a crucial problem in radiology since the discovery of X-rays [1]. The problem is particularly 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 investigated in conjunction with cancer development [4-8], and could lead to early detection and new therapeutic strategies [9,10]. However, such studies are negatively impacted by the limitations of established imaging techniques in the detection of micro-vessels. New approaches, synchrotron-based X-ray micro-radiology and micro-tomography, were