The association between levels of samarium, hafnium, tungsten and rhenium in seminal plasma and the risk of idiopathic oligo-astheno-teratozoospermia in men of childbearing age.

Oligo-astheno-teratozoospermia (OAT) is a global public health problem, which affects 30% men of childbearing age. Meanwhile, with the rapid development of industry and economy, the contents of rare earth elements (REEs) in the environment are increasing. However, little is known about the associations between REEs levels and OAT risk. To evaluate the associations between the levels of four REEs (samarium (Sm), hafnium (Hf), tungsten (W), rhenium (Re)) in seminal plasma and OAT risk, from October 2021 to November 2022, semen samples from 924 men of childbearing age (460 controls and 464 cases) were collected from the reproductive center of the First Affiliated Hospital of Anhui Medical University. Inductively coupled plasma-mass spectrometry (ICP-MS) was used to measure the levels of Sm, Hf, Re and W in seminal plasma. Bayesian kernel machine regression (BKMR) was conducted to explore the joint effects of levels of four REEs in seminal plasma on the risk of OAT and select the one exerting a major role; generalized linear regression models (GLM) with log link function were employed to investigate the association of every REE level in seminal plasma and OAT risk; sankey diagram and linear regression models were utilized to describe the associations between the levels of four REEs and the indexes of sperm quality. The levels of four REEs in seminal plasma were higher in the case group than levels in the control group (pSm = 0.011, pHf = 0.040, pW = 0.062, pRe = 0.001, respectively). In BKMR analysis, the OAT risk increased when the overall levels of four REEs were higher than their 55th percentile compared to all of them at their 50th percentile, and Re level played a major role in the association. Additionally, Re level in seminal plasma was positively associated with  the OAT risk in the single element model after adjustment of covariates (medium vs. low: OR (95% CI) = 1.55 (1.10, 2.18); high vs. low: OR (95% CI) = 1.69 (1.18, 2.42)). Lastly, the sankey diagram and linear regression models revealed that Sm level was negatively associated with the PR%, total sperm count and total progressively motile sperm count; Hf level was negatively associated with the PR%; W and Re levels were negatively associated with the PR% and total motility, and Re level was positively associated with abnormal morphology rate. Men of childbearing age with OAT had higher levels of Sm, Hf and Re in seminal plasma than those in the control group. An increasing trend for the OAT risk was observed with an increase in mixture levels of Sm, Hf, W and Re, and Re exposure level played a major role in the association whether in BKMR model or single element model. Additionally, the levels of these four REEs were negatively associated with the indexes of sperm quality.

Ultrathin Hafnium Disulfide Atomic Crystals with ROS-Scavenging and Colon-Targeting Capabilities for Inflammatory Bowel Disease Treatment.

The exciting success of NBTXR3 in the clinic has triggered a tumult of activities in the design and development of hafnium-based nanoparticles. However, due to the concerns of nondegradation and limited functions, the biomedical applications of Hf-based nanoparticles mainly focus on tumors. Herein, tannic acid capped hafnium disulfide (HfS2@TA) nanosheets, a 2D atomic crystal of hafnium-based materials prepared by liquid-phase exfoliation, were explored as high-performance anti-inflammatory nanoagents for the targeted therapy of inflammatory bowel disease (IBD). Benefiting from the transformation of the S2-/S6+ valence state and huge specific surface area, the obtained HfS2@TA nanosheets were not only capable of effectively eliminating reactive oxygen species/reactive nitrogen species and downregulating pro-inflammatory factors but also could be excreted via kidney and hepatointestinal systems. Unexpectedly, HfS2@TA maintained excellent targeting capability to an inflamed colon even in the harsh digestive tract environment, mainly attributed to the electrostatic interactions between negatively charged tannic acid and positively charged inflamed epithelium. Encouragingly, upon oral or intravenous administration, HfS2@TA quickly inhibited inflammation and repaired the intestinal mucosa barrier in both dextran sodium sulfate and 2,4,6-trinitrobenzenesulfonic acid induced IBD models. This work demonstrated that ultrathin HfS2@TA atomic crystals with enhanced colon accumulation were promising for the targeted therapy of IBD.

Fucoidan-coated nanoparticles target radiation-induced P-selectin to enhance chemoradiotherapy in murine colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related death for both men and women, highlighting the need for new treatment strategies. Advanced disease is often treated with a combination of radiation and cytotoxic agents, such as DNA damage repair inhibitors and DNA damaging agents. To optimize the therapeutic window of these multimodal therapies, advanced nanomaterials have been investigated to deliver sensitizing agents or enhance local radiation dose deposition. In this study, we demonstrate the feasibility of employing an inflammation targeting nanoscale metal-organic framework (nMOF) platform to enhance CRC treatment. This novel formulation incorporates a fucoidan surface coating to preferentially target P-selectin, which is over-expressed or translocated in irradiated tumors. Using this radiation stimulated delivery strategy, a combination PARP inhibitor (talazoparib) and chemotherapeutic (temozolomide) drug-loaded hafnium and 1,4-dicarboxybenzene (Hf-BDC) nMOF was evaluated both in vitro and in vivo. Significantly, these drug-loaded P-selectin targeted nMOFs (TT@Hf-BDC-Fuco) show improved tumoral accumulation over multiple controls and subsequently enhanced therapeutic effects. The integrated radiation and nanoformulation treatment demonstrated improved tumor control (reduced volume, density, and growth rate) and increased survival in a syngeneic CRC mouse model. Overall, the data from this study support the continued investigation of radiation-priming for targeted drug delivery and further consideration of nanomedicine strategies in the clinical management of advanced CRC.

Radiotherapy-Activated Hafnium Oxide Nanoparticles Produce Abscopal Effect in a Mouse Colorectal Cancer Model.

PURPOSE: Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumor-specific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare. METHODS: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model. RESULTS: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells. CONCLUSION: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy.

DNA damage enhancement by radiotherapy-activated hafnium oxide nanoparticles improves cGAS-STING pathway activation in human colorectal cancer cells.

The cGAS-STING pathway can be activated by radiation induced DNA damage and because of its important role in anti-cancer immunity activation, methods to increase its activation in cancer cells could provide significant therapeutic benefits for patients. We explored the impact of hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy on cell death, DNA damage, and activation of the cGAS-STING pathway. We demonstrate that NBTXR3 activated by radiotherapy enhances cell destruction, DNA double strand breaks, micronuclei formation and cGAS-STING pathway activation in a human colorectal cancer model, compared to radiotherapy alone.

Lanthanide-Doped Hafnia Nanoparticles for Multimodal Theranostics: Tailoring the Physicochemical Properties and Interactions with Biological Entities.

High-Z metal oxide nanoparticles hold promise as imaging probes and radio-enhancers. Hafnium dioxide nanoparticles have recently entered clinical evaluation. Despite promising early clinical findings, the potential of HfO2 as a matrix for multimodal theranostics is yet to be developed. Here, we investigate the physicochemical properties and the potential of HfO2-based nanoparticles for multimodal theranostic imaging. Undoped and lanthanide (Eu3+, Tb3+, and Gd3+)-doped HfO2 nanoparticles were synthesized and functionalized with various moieties including poly(vinylpyrrolidone) (PVP), (3-aminopropyl)triethoxysilane (APTES), and folic acid (FA). We show that different synthesis routes, including direct precipitation, microwave-assisted synthesis, and sol-gel chemistry, allow preparation of hafnium dioxide particles with distinct physicochemical properties. Sol-gel based synthesis allows preparation of uniform nanoparticles with dopant incorporation efficiencies superior to the other two methods. Both luminescence and contrast properties can be tweaked by lanthanide doping. We show that MRI contrast can be unified with radio-enhancement by incorporating lanthanide dopants in the HfO2 matrix. Importantly, ion leaching from the HfO2 host matrix in lysosomal-like conditions was minimal. For Gd:HfO2 nanoparticles, leaching was reduced >10× compared to Gd2O3, and no relevant cytotoxic effects have been observed in monocyte-derived macrophages for nanoparticle concentrations up to 250 µg/mL. Chemical surface modification allows further tailoring of the cyto- and hemocompatibility and enables functionalization with molecular targeting entities, which lead to enhanced cellular uptake. Taken together, the present study illustrates the manifold properties of HfO2-based nanomaterials with prospective clinical utility beyond radio-enhancement.

Anodic formation and biomedical properties of hafnium-oxide nanofilms.

Hafnium dioxide (HfO2) is attracting attention for bio-related applications due to its good cytocompatibility, high density, and resistance to corrosion and mechanical damage. Here we synthesize two types of hafnium-oxide thin films on substrates via self-organized electrochemical anodization: (1) an array of hierarchically structured nanorods anchored to a thin oxide layer and (2) a microscopically flat oxide film. The nanostructured film is composed of a unique mixture of HfO2, suboxide Hf2O3, and oxide-hydroxide compound HfO2·nH2O whereas the flat film is mainly HfO2. In vitro interaction of the two films with MG-63 osteoblast-like cells and Gram-negative E. coli bacteria is studied for the first time to assess the potential of the films for biomedical application. Both films reveal good cytocompatibility and affinity for proteins, represented by fibronectin and especially albumin, which is absorbed in a nine times larger amount. The morphology and specific surface chemistry of the nanostructured film cause a two-fold enhanced antibacterial effect, better cell attachment, significantly improved proliferation of cells, five-fold rise in the cellular Young's modulus, slightly stronger production of reactive oxygen species, and formation of cell clusters. Compared with the flat film, the nanostructured one features the weakening of AFM-measured adhesion force at the cell/surface interface, probably caused by partially lifting the nanorods from the substrate due to the strong contact with cells. The present findings deepen the understanding of biological processes at the living cell/metal-oxide interface, underlying the role of surface chemistry and the impact of nanostructuring at the nanoscale.

Highly Effective Radioisotope Cancer Therapy with a Non-Therapeutic Isotope Delivered and Sensitized by Nanoscale Coordination Polymers.

Nuclear medicine with radioisotopes is extremely useful for clinical cancer diagnosis, prognosis, and treatment. Herein, polyethylene glycol (PEG)-modified nanoscale coordination polymers (NCPs) composed of hafnium (Hf4+) and tetrakis (4-carboxyphenyl) porphyrin (TCPP) are prepared via a one-pot reaction. By chelation with the porphyrin structure of TCPP, such Hf-TCPP-PEG NCPs could be easily labeled with 99mTc4+, an imaging radioisotope widely used for single-photon emission computed tomography (SPECT) in a clinical environment. Interestingly, Hf, as a high- Z element in such 99mTc-Hf-TCPP-PEG NCPs, could endow nontherapeutic 99mTc with the therapeutic function of killing cancer cells, likely owing to the interaction of Hf with γ rays emitted from 99mTc to produce charged particles for radiosensitization. With efficient tumor retention, as revealed by SPECT imaging, our 99mTc-Hf-TCPP-PEG NCPs offer exceptional therapeutic results in eliminating tumors with moderate doses of 99mTc after either local or systemic administration. Importantly, those biodegradable NCPs could be rapidly excreted without much long-term body retention. Our work, showing the success of applying NCPs for radioisotope therapy (RIT), presents a potential concept for the realization of highly effective cancer treatment with 99mTc, a short-half-life (6.0 h) diagnostic radioisotope, which is promising for cancer RIT with enhanced efficacy and reduced side effects.

A novel approach to low-temperature synthesis of cubic HfO2 nanostructures and their cytotoxicity.

The development of a strategy to stabilise the cubic phase of HfO2 at lower temperatures is necessary for the emergence of unique properties that are not realised in the thermodynamically stable monoclinic phase. A very high temperature (>2600 °C) is required to produce the cubic phase of HfO2, whereas the monoclinic phase is stable at low temperature. Here, a novel rapid synthesis strategy was designed to develop highly crystalline, pure cubic-phase HfO2 nanoparticles (size <10 nm) using microwave irradiation. Furthermore, the as-prepared nanoparticles were converted to different morphologies (spherical nanoparticles and nanoplates) without compromising the cubic phase by employing a post-hydrothermal treatment in the presence of surface modifiers. The cytotoxicities and proliferative profiles of the synthesised cubic HfO2 nanostructures were investigated over the MCF-7 breast cancer cell line, along with caspase-3/7 activities. The low-temperature phase stabilisation was significantly attributed to surface imperfections (defects and deformations) induced in the crystal lattice by the desirable presence of Na2S·xH2O and NaOH. Our work provides unprecedented insight into the stabilisation of nanoscale cubic-phase HfO2 in ambient environments; the method could be extended to other challenging phases of nanomaterials.

Impact of degradable nanowires on long-term brain tissue responses.

BACKGROUND: A promising approach to improve the performance of neural implants consists of adding nanomaterials, such as nanowires, to the surface of the implant. Nanostructured interfaces could improve the integration and communication stability, partly through the reduction of the cell-to-electrode distance. However, the safety issues of implanted nanowires in the brain need to be evaluated and understood before nanowires can be used on the surface of implants for long periods of time. To this end we here investigate whether implanted degradable nanowires offer any advantage over non-degradable nanowires in a long-term in vivo study (1 year) with respect to brain tissue responses. RESULTS: The tissue response after injection of degradable silicon oxide (SiOx)-coated gallium phosphide nanowires and biostable hafnium oxide-coated GaP nanowires into the rat striatum was compared. One year after nanowire injection, no significant difference in microglial or astrocytic response, as measured by staining for ED1 and glial fibrillary acidic protein, respectively, or in neuronal density, as measured by staining for NeuN, was found between degradable and biostable nanowires. Of the cells investigated, only microglia cells had engulfed the nanowires. The SiOx-coated nanowire residues were primarily seen in aggregated hypertrophic ED1-positive cells, possibly microglial cells that have fused to create multinucleated giant cells. Occasionally, degradable nanowires with an apparently intact shape were found inside single, small ED1-positive cells. The biostable nanowires were found intact in microglia cells of both phenotypes described. CONCLUSION: The present study shows that the degradable nanowires remain at least partly in the brain over long time periods, i.e. 1 year; however, no obvious bio-safety issues for this degradable nanomaterial could be detected.

Hafnium-doped hydroxyapatite nanoparticles with ionizing radiation for lung cancer treatment.

UNLABELLED: Recently, photodynamic therapy (PDT) is one of the new clinical options by generating cytotoxic reactive oxygen species (ROS) to kill cancer cells. However, the optical approach of PDT is limited by tissue penetration depth of visible light. In this study, we propose that a ROS-enhanced nanoparticle, hafnium-doped hydroxyapatite (Hf:HAp), which is a material to yield large quantities of ROS inside the cells when the nanoparticles are bombarded with high penetrating power of ionizing radiation. Hf:HAp nanoparticles are generated by wet chemical precipitation with total doping concentration of 15mol% Hf(4+) relative to Ca(2+) in HAp host material. The results show that the HAp particles could be successfully doped with Hf ions, resulted in the formation of nano-sized rod-like shape and with pH-dependent solubility. The impact of ionizing radiation on Hf:HAp nanoparticles is assessed by using in-vitro and in-vivo model using A549 cell line. The 2',7'-dichlorofluorescein diacetate (DCFH-DA) results reveal that after being exposed to gamma rays, Hf:HAp could significantly lead to the formation of ROS in cells. Both cell viability (WST-1) and cytotoxicity (LDH) assay show the consistent results that A549 lung cancer cell lines are damaged with changes in the cells' ROS level. The in-vivo studies further demonstrate that the tumor growth is inhibited owing to the cells apoptosis when Hf:HAp nanoparticles are bombarded with ionizing radiation. This finding offer a new therapeutic method of interacting with ionizing radiation and demonstrate the potential of Hf:HAp nanoparticles in tumor treatment, such as being used in a palliative treatment after lung surgical procedure. STATEMENT OF SIGNIFICANCE: Photodynamic therapy (PDT) is one of the new clinical options by generating cytotoxic reactive oxygen species (ROS) to kill cancer cells. Unfortunately, the approach of PDT is usually limited to the treatment of systemic disease and deeper tumor, due to the limited tissue penetration depth of visible light (620-690nm). Here we report a ROS-enhanced nanoparticle, hafnium-doped hydroxyapatite (Hf:HAp), which can trigger ROS when particles are irradiated with high penetrating power of ionizing radiation. The present study provides quantitative data relating ROS generation and the therapeutic effect of Hf:HAp nanoparticles in lung cancer cells. As such, this material has opened an innovative window for deeper tumor and systemic disease treatment.

Tuning Mesenchymal Stem Cell Response onto Titanium-Niobium-Hafnium Alloy by Recombinant Fibronectin Fragments.

Since metallic biomaterials used for bone replacement possess low bioactivity, the use of cell adhesive moieties is a common strategy to improve cellular response onto these surfaces. In recent years, the use of recombinant proteins has emerged as an alternative to native proteins and short peptides owing to the fact that they retain the biological potency of native proteins, while improving their stability. In the present study, we investigated the biological effect of two different recombinant fragments of fibronectin, spanning the 8-10th and 12-14th type III repeats, covalently attached to a new TiNbHf alloy using APTES silanization. The fragments were studied separately and mixed at different concentrations and compared to a linear RGD, a cyclic RGD and the full-length fibronectin protein. Cell culture studies using rat mesenchymal stem cells demonstrated that low to medium concentrations (30% and 50%) of type III 8-10th fragment mixed with type III 12-14th fragment stimulated cell spreading and proliferation compared to RGD peptides and the fragments separately. On the other hand, type III 12-14th fragment alone or mixed at low volume percentages ≤50% with type III 8-10th fragment increased alkaline phosphatase levels compared to the other molecules. These results are significant for the understanding of the role of fibronectin recombinant fragments in cell responses and thus to design bioactive coatings for biomedical applications.

Hafnium oxide nanoparticles: toward an in vitro predictive biological effect?

BACKGROUND: Hafnium oxide, NBTXR3 nanoparticles were designed for high dose energy deposition within cancer cells when exposed to ionizing radiation. The purpose of this study was to assess the possibility of predicting in vitro the biological effect of NBTXR3 nanoparticles when exposed to ionizing radiation. METHODS: Cellular uptake of NBTXR3 nanoparticles was assessed in a panel of human cancer cell lines (radioresistant and radiosensitive) by transmission electron microscopy. The radioenhancement of NBTXR3 nanoparticles was measured by the clonogenic survival assay. RESULTS: NBTXR3 nanoparticles were taken up by cells in a concentration dependent manner, forming clusters in the cytoplasm. Differential nanoparticle uptake was observed between epithelial and mesenchymal or glioblastoma cell lines. The dose enhancement factor increased with increase NBTXR3 nanoparticle concentration and radiation dose. Beyond a minimum number of clusters per cell, the radioenhancement of NBTXR3 nanoparticles could be estimated from the radiation dose delivered and the radiosensitivity of the cancer cell lines. CONCLUSIONS: Our preliminary results suggest a predictable in vitro biological effect of NBTXR3 nanoparticles exposed to ionizing radiation.

[Bactericidal and biologically stable coatings for medical implants and instruments]. / Bakteritsidnye i biologicheski stoikie pokrytiia dlia meditsinskikh implantov i instrumentov.

The experimental research showed the fine-film coating based on hafnium nitride to inhibit the pathogenic microflora and to exert the bactericidal effect by far less versus that of antibiotics; at the same time, the concentration of hafnium ions in the solution is just within the sensitivity limit detectable by the most recent registration methods--it amounts to less than 10(-10) mol/l. Therefore, according to the research results, the use of such coatings based on hafnium nitride is promising in manufacturing the surgical metal implants and medical instruments.

Antitumor activity of 1.3-diketonato zirconium (IV) and hafnium (IV) complexes.

Ten six-coordinate dihalogenobis (1.3-diketonato)zirconium (IV) and hafnium (IV) complexes as well as seven halogenotris(1.3-diketonato) zirconium(IV) and hafnium(IV) species were prepared and characterized by their elemental analysis, IR- and NMR-spectra. Their antitumor activity was tested using the intraperitoneally transplanted Sarcoma 180 tumor system in mice. Cisplatin was used in several doses as positive control compound. Seven complexes were highly active. The ratio of median survival time of treated to untreated control animals ranged up to 3 (T/C = 300%; the experiment was interrupted after that time) for these compounds. Significance according to Kruskal-Wallis test, long-time survivors, and animals which are dead on day 5 and day 30 are given. The possible mechanism of action compared to cisplatin is discussed.

In vitro cell growth inhibition by metallocene dichlorides.

The in vitro growth-inhibiting potencies of titanocene dichloride (TDC), zirconocene dichloride (ZDC), hafnocene dichloride (HDC), vanadocene dichloride (VDC), and molybdocene dichloride (MDC) against Ehrlich ascites tumor (EAT) cells cultured in viro as permanently growing suspension cultures were determined. The most striking growth-suppression activity was detected for VDC. A VDC concentration as low as 5. 10(-6) mol/l effects a highly significant diminution of cell proliferation. TDC and MDC inhibit cellular growth only concentration of 5 . 10(-4) or 10(-3) mol/l, respectively, whereas ZDC and HDC, which are ineffective against EAT cells in vivo, require higher concentration levels. The growth inhibition is caused by a cytotoxic action of the metallocene dichlorides, as is demonstrated in the case of VDC and TDC by differentiation of live and dead EAT cells by means of the dye lissamine green.