Figure 1. (A) TEM micrograph of an individual HfOR2R NP. Scale bar = 5 nm. (B) X-ray radiograph and (C) fluorescence of CY5-HfOR2R NPs in an Eppendorf tube. (D) Hydrodynamic diameter of HfOR2R NPs and CY5-HfOR2R NPs in water over 24 h. (E,F) Live/Dead assay confirmed >99% viability and (G,H) confocal microscopy confirmed cellular uptake of CY5-HfOR2R NPs in (E,G) HeLa and (F,H) THP-1 cells. Scale bars = 20 m
This work will be presented at MRS 2018 and at SFB 2018
Statement of Purpose: Hafnium oxide (HfO2) with a k-edge of 50 keV is being explored as a clinical X-ray contrast agent. HfO2 NPs are also in clinical trials as radiosensitizers that induce immune action against tumor sites. However, the unpredictable stability of commercially available HfO2 makes it hard to predict their pharmacokinetics and their size range of ((50-100 nm) results in zero clearance from an in vivo system. Therefore, in this study we have executed a modular approach for the design and scalable synthesis of novel, non-sintered, 4-8 nm metal oxide nanoparticles (e.g. Hafnium oxide, Gadolinium oxide) with 40-60 fold higher X-ray attenuation cross-sections than the NPs diameter. Contrast-enhanced computed tomography (CT) and spectral (color) X-ray CT with the aid of these new class of probes have the potential to enable targeted image guided therapeutics with CT as a lower cost and higher resolution alternative to PET and MRI.
Results: We achieved >95% efficient conversion of the amorphous seed NPs to crystalline orthorhombic-HfO2 NPs. HfO2 NPswere ~4-5 nm in diameter (Fig. 1A) and formed non-sintered flocculants, 220-290 nm in diameter. As-prepared CY5-HfO2 NPs exhibited simultaneous X-ray contrast and fluorescence in multispectral imaging (Fig. B,C). Both HfO2 and CY5-HfO2 NPs remained well-dispersed over 24 h (Fig. 1D). The measured zeta potential was -13 to -16 mV. Encapsulating the HfO2 NPs in a SiO2 shell reduced the hydrodynamic diameter to ~30 nm and inhibited the formation of flocculants. MTT and Live/Dead assays confirmed that the HfO2 NPs were neither cytotoxic nor pro-inflammatory (Fig. 1E,F). Confocal microscopy confirmed highly efficient uptake of Cy5-HfO2 NPs by HeLa cells and THP-1 cells (Fig. 1G,H).
Conclusion: HfO2 NPs were prepared using a novel templated synthesis resulting in crystalline NPs, ~4-5 nm in diameter, which flocculate into 220-290 nm clusters. Therefore, these NPs are anticipated to provide both long blood circulation and eventual renal clearance through phagocytic breakdown after delivery as radiographic imaging probe or radiosensitizer.
Acknowledgments: NSF DMR-1309587, DAAD PPP, Notre Dame GCI, Walther Cancer Foundation, NDnano.
Contributors: Prakash D. Nallathamby,1 Viktoriya Sokolova,2 Oleg Prymak,2 Matthias Epple2 and Ryan K. Roeder 1
1University of Notre Dame
2University of Duisburg-Essen
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