Introduction

Hafnium oxide (HfO₂,Figure 1) exhibits remarkable chemical inertness, a high dielectric constant, elevated melting point, density, refraction index, and visible light transparency. These properties, coupled with its minimal reactivity in biological systems, position hafnium-based nanomaterials (Hf-NMs) as promising candidates for roles as radiosensitizers and X-ray contrast agents.[1]

For biomedical applications, hafnium oxide nanoparticles (NPs) are difficult to cause redox reactions or electron transfers and have certain chemical inertness in biological media. These characteristics indicated that hafnium oxide NPs have low toxicity, consequently reducing their potential biological security concerns. [2,3] NBTXR3, mainly composed of hafnium oxide modified by negatively charged polymer comprising phosphate groups, provided by NANOBIOTIX Company, has entered the clinical trial II/III phase for many kinds of tumor therapy, [4,5] and the achievement of European market approval (CE marking) for NBTXR3 (brand-name: Hensify) in the treatment of locally advanced soft tissue sarcoma was concluded in 2019. Currently, clinical studies on synergistic CHT and IT based on hafnium oxide-mediated radiosensitization effects are also underway. [6-8]

Synthesis of hafnium oxide Nanomaterials[8]

Sol-gel method is the most frequently used method for preparing various nano-sized metal-oxides. The regular sol-gel method contains four steps: hydrolysis and poly-condensation, gelation, drying, and high-temperature treatment. [9]  Tirosh and Markovich used the same procedure but with 1-octadecene as an organic solvent in the presence of oleylamine as a capping agent to control the defect concentration and obtained HfO₂ nanorods with ferromagnetic property.[10] Besides, Ramos-González et al. reported a comparison between polymerized complexand polymer precursor (PP) derived sol-gel methods for the synthesis of HfO₂ nanoparticles.  The precursor gels prepared by these two methods required heat treatment at 500–800 °C. By increasing the HfCl₄ concentration, mixed cubic and monoclinic phases of HfO₂ nanoparticles were observed by the PC method. However, the hafnium oxide NPs prepared in the presence of PP only exhibited a monoclinic phase. 

The hydrothermal method is a chemical reaction carried out in an aqueous solution, which is an essential dissolution recrystallization process. In 2007, with the assistance of microwave and ultrasound, Meskin et al. prepared hafnium oxide NPs with amorphous HfO(OH)₂·nH₂O as a precursor through hydrothermal, hydrothermal/ultrasound and hydrothermal/microwave methods at 250 °C. Their results showed that the HfO₂ nanoparticles have fast crystallization behavior and better crystallinity with the help of ultrasound/microwave. Sahraneshin et al. prepared water-dispersed hafnium oxide with a size of 4 nm in a high alkaline media through the surfactantassisted hydrothermal synthesis at 350 °C, 16 MPa water within a short reaction time of 10 min. In addition, HfO₂ preferred to form needle-shaped structures at low KOH condition. With the increasing KOH concentration, the particle dimensions reduced from needle to oval to nanosphere, and finally resulting in dense flower-like nanostructures. Similarly, Wan et al. successfully synthesized tetragonal phase (t-HfO₂) and monoclinic phase (m-HfO₂) of hafnium oxide through the hydrothermal route by adjusting the pH value of the HfCl₄ precursor, reaction temperature, aging time and seeding procedure. They found that the t-HfO₂ product was produced during the initial process of forming m-HfO₂, and thus reducing the reaction time could produce high-purity t-HfO_2. Moreover, lower concentration of NaOH, higher temperature, longer reaction time and addition of m-HfO₂ seeds were more conducive for the formation of m-HfO₂.

Solvothermal method is developed on the basis of hydrothermal method by using organic solvent instead of water as the reaction medium. Besides, solvothermal method has unique advantages such as avoiding amorphous precipitates and even the use of various surfactants, easy control of the morphology and size of products. Niederberger et al. took this approach involving the reaction of Hf ethoxide with benzyl alcohol at relatively low temperature (250 °C) to synthesize HfO₂ NPs. The final product has high purity and the yield can reach the gram quantities. Similar to hydrothermal method, the solvothermal process can be accelerated by the use of a microwave heating approach. The nonaqueous method without the assist of surfactants still causes the agglomeration of NPs, and they found that the addition of amines such as oleylamine could improve the monodispersity of NPs since oleylamine provided the basic environment in which carboxylic acids could dissociate and replace chloride to control the crystal growth. Furthermore, the additionally added amines could also be easily purified, leaving a suitable surface of hafnium oxide for further applications.[8]

Some other synthetic methods such as co-precipitation and single-step autoigniting combustion technique have also been studied to fabricate hafnium oxide NPs. Researcher can choose the most suitable method according to different application fields. [8]

Conclusions and Perspectives

Hafnium oxide NPs showed signiffcant radio-sensitization effects across a large panel of human cancer models. The NBTXR3 has been approved in European marketing for RT to soft tissue sarcoma. Most reported clinically used hafnium oxide NPs are intratumorally injected, which limits the application value of different cancer treatments. Li et al. developed an intravenously injectable PEGmodiffed hafnium oxide nanoassemblies (NAs) to overcome the limitation. In vivo biodistribution demonstrated that a large proportion of the administrated hafnium oxide NAs had been eliminated after 90 days due to its degradability in the physiological environment, Subsequently, no apparent body weight variation and slice lesions of the major organ was observed compared to the control group after systemic administration the hafnium oxide NAs (30 mg/mL, 200 μL) for 3 months. The results indicated that HfO₂ hafnium oxide NAs were a radioactive sensitizer with better biological safety, whether focusing on short-term or long-term biological toxicity.[11] Therefore, rational design and surface engineering methods can greatly improve hafnium oxide values in practical applications and pave the way for clinical applications.

References

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[2] Field James A, Luna Velasco Antonia, Boitano Scott A, et al. Chemosphere. 2011,84,(10):1401.

[3] Jayaraman V, Bhavesh G, Chinnathambi S, et al., Materials Express.2014, 4:375.

[4] Bonvalot S, Rutkowski PL, Thariat J, et al. Lancet Oncol. 2019, 20(8):1148.

[5] Chajon Rodriguez E , Pracht M , De Baere T ,et al., Int J Radiat Oncol. 2018, 102(3):51.

[6] Galon J, Lae M, Thariat JO,et al., Int. J. Radiat. Oncol., Biol., Phys. 2018, 102, S204.

[7] Hu Y, Welsh J, Paris S, etal., J ImmunoTher Cancer 2020, 8, A117.

[8] Ding S, Chen L, Liao J, et al., Small. 2023;19(32):2300341.

[9] Aurobind SV, Amirthalingam KP, Gomathi H. Adv Colloid Interface Sci, 2006, 121(1-3):1.

[10] Tirosh E, Markovich G. Adv. Mater. 2007, 19, 2608.

[11] Li Y, Qi Y, Zhang H.et al., Biomaterials 2020, 226, 119538.