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"Nanoparticles of Gallium Prussian Blue Analog for Theranostic Use"

We have developed nanoparticles (NPs) derived from the gallium analog of Prussian blue (GaPB; Fig.1) as a novel structural platform to explore the concurrent diagnostic and therapeutic applications of the Ga(III) ion in a single structure.1-5  Our preliminary results show that GaPB NPs are hydrolytically stable at physiological pH and nontoxic to cells.  Furthermore, GaPB NPs can penetrate the cell membrane and undergo highly selective ion exchange towards iron and copper to release gallium, paving the road for their potential applications in biomedical imaging and therapy.6  For example, use of such GaPB structural platform allowed for a simple one-step1 Ga-labeling method to be developed for preparing a single-phase nanoparticle bimodal PET/MRI imaging agent, as demonstrated in one of our recent publications.7  We will continue to explore the ability of GaPB NPs to disrupt the homeostasis of iron in cancer cells and pathogenic microbes.

The goals for the REU students who work on this project will be:

1. to develop the skills in the synthesis and characterization of GaPB NPs with different sizes and surface modifications
2. to obtain hands-on experience in evaluating cellular uptake of GaPB NPs in cancer cells and pathogenic microbes in order to investigate the intracellular ion exchange between Ga3+ and Fe3+ to inhibit the activity of ribonucleotide reductase (RR) that is essential for NDA synthesis in these cells; and
3. to learn the data processing techniques in the evaluation of the effect of GaPB NPs on cell proliferation, migration, and tubule formation during angiogenesis via intracellular copper depletion using such NPs as a novel strategy for inhibiting angiogenesis in an in vitro 3D model of tubule-formation from endothelia cells.

References

1. Weiner, R. E.; Avis, I.; Neumann, R. D.; Mulshine, J. L., "Transferrin Dependence of Ga(NO3)3 Inhibition of Growth in Human-Derived Small Cell Lung Cancer Cells." J. Cell. Biochem., 1996, 63 (S24), 276-287.

2. Larson, S. M.; Rasey, J. S.; Allen, D. R.; Nelson, N. J.; Grunbaum, Z.; Harp, G. D.; Williams, D. L., "Common Pathway for Tumor-Cell Uptake of Ga-67 and Fe-59 Via a Transferrin Receptor." Journal of the National Cancer Institute, 1980, 64 (1), 41-53.

3. Chitambar, C. R.; Zivkovic, Z., "Uptake of Ga-67 by Human-Leukemic Cells - Demonstration of Transferrin Receptor-Dependent and Transferrin-Independent Mechanisms." Cancer Research, 1987, 47 (15), 3929-3934.

4. Warrell Jr, R. P., "Gallium for Treatment of Bone Diseases." Handbook of Metal-Ligand Interactions in Biological Fluids: Bioinorganic Medicine, 1995, 2, 1253-1265.

5. Warrell, R. P.; Alcock, N. W.; Bockman, R. S., "Gallium Nitrate Inhibits Accelerated Bone Turnover in Patients with Bone Metastases." Journal of Clinical Oncology, 1987, 5 (2), 292-298

6. Murthi, K. S.; Valley, B; Yang, L. D.; Fry, A.; Woodward, P.; Huang, S. D., "Gallium Analogue of Soluble Prussian Blue KGa[Fe(CN)6]·nH2O: Synthesis, Characterization and Potential Biomedical Applications."  Inorg. Chem., 2013, 52, 2790-2792.

7. Kandanapitiye, M.; Gott, M. D.; Sharits, A.; Jurisson, S. S.; Woodward, P. M.; Huang, S. D., "Incorporation of Gallium-68 Into the Crystal Structure of Prussian Blue to Form K68GaxFe1-x[Fe(CN)6] Nanoparticles: Toward a Novel Bimodal PET/MRI Imaging Agent."  Dalton Trans., 2016, 45, 9174-81.