Labeling and Tracking Stem Cells By X-Ray Imaging Using a Hybrid Bismuth/Carbon Nanotube Contrast Agent
Authors: Hernández-Rivera Mayra , Kumar Ish , Cho Stephen Younglae , Whitmire Kenton H. , da Graça Cabreira-Hansen Maria , Wilson Lon J. 
Published: February 2020

Great interest in using carbon nanostructures for a plethora of biomedical applications, including cellular-based therapies, has emerged as a new interdisciplinary field. The hydrophobic nature of these materials allow them to cross the cell membrane without the need of transfection agents (which tend to be cytotoxic), making carbon nanomaterials suitable to transport associated materials into the inner space of cells for therapy, imaging, or combined applications. In regenerative medicine, the poor retention and survival of stem cells represent two major problems for the effectiveness of these therapies. Therefore, it is essential to be able to track stem cells in vivoto better understand the outcome of stem cell therapies.

 Here we described the successful synthesis of a carbon-based contrast agent (CA) for X-ray computed tomography (CT) imaging. The CA consists of a hybrid material containing ultra-short single-walled carbon nanotubes (20-80 nm, US-tubes) and a Bi(III) oxo-salicylate cluster which has been previously described.1 Bismuth was chosen over iodine, which is the conventional element used for X-ray contrast, due to its higher atomic number and its extremely low toxicity.2,3The Bi(III) oxo-salicylate cluster@US-tubes contains 20% by weight of bismuth with no detectable release of bismuth after a 48 hour exposure to various biological challenges, suggesting the presence of a strong supramolecular interaction between the two materials.

This promising new X-ray CA material has been studied as an intracellular CA to label porcine bone marrow-derived mesenchymal stem cells (MSCs), with no cytotoxicity being observed. The free Bi(III)-oxo-salicylate cluster is not able to translocate into stem cells by itself, thus, the US-tube platform serves as a nano-carrier to deliver bismuth into MSCs. The potential use of the Bi(III) oxo-salicylate cluster@US-tubes as an X-ray CA has been assessed and shown to significantly increase X-ray attenuation when internalized into MSCs. These findings offer a new technology for stem cell biodistribution and tracking studies after transplantation.

Acknowledgments:

We gratefully acknowledge The Welch Foundation for supporting this work as well as the Department of Chemistry and the Smalley-Curl Institute at Rice University.  Also special thanks to the Stem Cell Center at the Texas Heart Institute.

References:

1.           Boyd, T. D., Kumar, I., Wagner, E. E. & Whitmire, K. H. Synthesis and structural studies of the simplest bismuth(III) oxo-salicylate complex: [Bi4(μ3-O)2(HO-2-C6H4CO2)8]·2Solv (Solv = MeCN or MeNO2). Chem. Commun.
50,3556–3559 (2014).

2.           Gordon, M. F., Abrams, R. I., Rubin, D. B., Barr, W. B. & Correa, D. D. Bismuth subsalicylate toxicity as a cause of prolonged encephalopathy with myoclonus. Mov. Disord.
10,220–222 (1995).

3.           Reynolds, P. T., Abalos, K. C., Hopp, J. & Williams, M. E. Bismuth Toxicity: A Rare Cause of Neurologic Dysfunction. Int. J. Clin. Med.
03, 46–48 (2012).