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Well-dispersed gold nanoparticles (NP) coated with tiopronin were synthesized by X-ray irradiation without reducing agents. High-resolution transmission electron microscopy shows that the average core diameters of the NPs can be systematically controlled by adjusting the tiopronin to Au mole ratio in the reaction. Three methods were used to study the NP uptake by cells: quantitative measurements by inductively coupled plasma mass spectrometry, direct imaging with high lateral resolution transmission electron microscopy and transmission X-ray microscopy. The results confirmed that the NP internalization mostly occurred via endocytosis and concerned the cytoplasm. The particles, in spite of their small sizes, were not found to arrive inside the cell nuclei. The synthesis without reducing agents and solvents increased the biocompatibility as required for potential applications in analysis and biomedicine in general.

We report the analysis of a reducing-agent-free synthetic method based on intense X-ray irradiation in the presence of 11-mercaptoundecanoic acid (MUA) and their application in biomedical imaging. The method is very effective in controlling the size and size distribution of Au nanoparticles in colloidal solutions: gold nanoparticles (AuNPs) as small as similar to 1.2 +/- 0.25 nm are synthesized in a one-pot irradiation procedure without reducing agents. We found two coexisting properties of these small AuNPs: a strong visible fluorescence and very high accumulation in cells, which enabled a new type of multimodality imaging using X-ray and visible light microscopies. These properties come as a direct consequence of the precise size control; specifically, they exist only when the particle size is smaller than similar to 1.4 nm. We found that this process critically depends on several parameters including the solution pH, the solution temperature and the irradiation time. Most important is the fact that the increase of the irradiation time is not necessarily beneficial, since an optimum value exists to obtain small particles with a narrow size distribution. The 1.4 nm AuNPs are not toxic and significantly accumulate in tumor tissues in animal tests, as confirmed by X-ray imaging and fluorescence microscopy. This biodistribution could open the way for the use of these nanoparticles in X-ray imaging.

We describe a simple and effective method to obtain colloidal surface-functionalized Au nanoparticles. The method is primarily based on irradiation of a gold solution with high-flux X-rays from a synchrotron source in the presence of 11-mercaptoundecanoic acid (MUA). Extensive tests of the products demonstrated high colloidal density as well as excellent stability, shelf life, and biocompatibility. Specific tests with X-ray diffraction, UV-visible spectrometry, visible microscopy, Fourier transform infrared spectroscopy, dark-field visible-light scattering microscopy, and transmission electron microscopy demonstrated that MUA, being an effective surfactant, not only allows tunable size control of the nanoparticles, but also facilitates functionalization. The nanoparticle sizes were 6.45 ± 1.58, 1.83 ± 1.21, 1.52 ± 0.37 and 1.18 ± 0.26 nm with no MUA and with MUA-to-Au ratios of 1:2, 1:1, and 3:1. The MUA additionally enabled functionalization with l-glycine. We thus demonstrated flexibility in controlling the nanoparticle size over a large range with narrow size distribution. Refereed/Peer-reviewed

Well-dispersed gold nanoparticles (NP) coated with tiopronin were synthesized by X-ray irradiation without reducing agents. High-resolution transmission electron microscopy shows that the average core diameters of the NPs can be systematically controlled by adjusting the tiopronin to Au mole ratio in the reaction. Three methods were used to study the NP uptake by cells: quantitative measurements by inductively coupled plasma mass spectrometry, direct imaging with high lateral resolution transmission electron microscopy and transmission X-ray microscopy. The results confirmed that the NP internalization mostly occurred via endocytosis and concerned the cytoplasm. The particles, in spite of their small sizes, were not found to arrive inside the cell nuclei. The synthesis without reducing agents and solvents increased the biocompatibility as required for potential applications in analysis and biomedicine in general Refereed/Peer-reviewed

Background Nanoparticles can be used for targeted drug delivery, in particular for brain cancer therapy. However, this requires a detailed analysis of nanoparticles from the associated microvasculature to the tumor, not easy because of the required high spatial resolution. The objective of this study is to demonstrate an experimental solution of this problem, based in vivo and post-mortem whole organ imaging plus nanoscale 3-dimensional (3D) X-ray microscopy. Results The use of gold nanoparticles (AuNPs) as contrast agents paved the way to a detailed high-resolution three dimensional (3D) X-ray and fluorescence imaging analysis of the relation between xenografted glioma cells and the tumor-induced angiogenic microvasculature. The images of the angiogenic microvessels revealed nanoparticle leakage. Complementary tests showed that after endocytotic internalization fluorescent AuNPs allow the visible-light detection of cells. Conclusions AuNP-loading of cells could be extended from the case presented here to other imaging techniques. In our study, they enabled us to (1) identify primary glioma cells at inoculation sites in mice brains; (2) follow the subsequent development of gliomas. (3) Detect the full details of the tumor-related microvasculature; (4) Finding leakage of AuNPs from the tumor-related vasculature, in contrast to no leakage from normal vasculature. Electronic supplementary material The online version of this article (doi:10.1186/s12951-015-0140-2) contains supplementary material, which is available to authorized users.

Background Quantitative analysis of nanoparticle uptake at the cellular level is critical to nanomedicine procedures. In particular, it is required for a realistic evaluation of their effects. Unfortunately, quantitative measurements of nanoparticle uptake still pose a formidable technical challenge. We present here a method to tackle this problem and analyze the number of metal nanoparticles present in different types of cells. The method relies on high-lateral-resolution (better than 30 nm) transmission x-ray microimages with both absorption contrast and phase contrast -- including two-dimensional (2D) projection images and three-dimensional (3D) tomographic reconstructions that directly show the nanoparticles. Results Practical tests were successfully conducted on bare and polyethylene glycol (PEG) coated gold nanoparticles obtained by x-ray irradiation. Using two different cell lines, EMT and HeLa, we obtained the number of nanoparticle clusters uptaken by each cell and the cluster size. Furthermore, the analysis revealed interesting differences between 2D and 3D cultured cells as well as between 2D and 3D data for the same 3D specimen. Conclusions We demonstrated the feasibility and effectiveness of our method, proving that it is accurate enough to measure the nanoparticle uptake differences between cells as well as the sizes of the formed nanoparticle clusters. The differences between 2D and 3D cultures and 2D and 3D images stress the importance of the 3D analysis which is made possible by our approach.