X-ray radio-enhancement by Ti3_{3}C2_{2}Tx_{x} MXenes in soft tissue sarcoma

Radiotherapy is a cornerstone of cancer treatment. However, due to the low tissue specificity of ionizing radiation, damage to the surrounding healthy tissue of the tumor remains a significant challenge. In recent years, radio-enhancers based on inorganic nanomaterials have gained considerable interest. Beyond the widely explored metal and metal oxide nanoparticles, 2D materials, such as MXenes, could present potential benefits because of their inherently large specific surface area. In this study, we highlight the promising radio-enhancement properties of Ti$_{3}$C$_{2}$T$_{x}$ MXenes. We demonstrate that atomically thin layers of titanium carbides (Ti$_{3}$C$_{2}$T$_{x}$ MXenes) are efficiently internalized and well-tolerated by mammalian cells. Contrary to MXenes suspended in aqueous buffers, which fully oxidize within days, yielding rice-grain shaped rutile nanoparticles, the MXenes internalized by cells oxidize at a slower rate. This is consistent with cell-free experiments that have shown slower oxidation rates in cell media and lysosomal buffers compared to dispersants without antioxidants. Importantly, the MXenes exhibit robust radio-enhancement properties, with dose enhancement factors reaching up to 2.5 in human soft tissue sarcoma cells, while showing no toxicity to healthy human fibroblasts. When compared to oxidized MXenes and commercial titanium dioxide nanoparticles, the intact 2D titanium carbide flakes display superior radio-enhancement properties. In summary, our findings offer evidence for the potent radio-enhancement capabilities of Ti$_{3}$C$_{2}$T$_{x}$ MXenes, marking them as a promising candidate for enhancing radiotherapy

Protein Aggregation on Metal Oxides Governs Catalytic Activity and Cellular Uptake.

Engineering of catalytically active inorganic nanomaterials holds promising prospects for biomedicine. Catalytically active metal oxides show applications in enhancing wound healing but have also been employed to induce cell death in photodynamic or radiation therapy. Upon introduction into a biological system, nanomaterials are exposed to complex fluids, causing interaction and adsorption of ions and proteins. While protein corona formation on nanomaterials is acknowledged, its modulation of nanomaterial catalytic efficacy is less understood. In this study, proteomic analyses and nano-analytic methodologies quantify and characterize adsorbed proteins, correlating this protein layer with metal oxide catalytic activity in vitro and in vivo. The protein corona comprises up to 280 different proteins, constituting up to 38% by weight. Enhanced complement factors and other opsonins on nanocatalyst surfaces lead to their uptake into macrophages when applied topically, localizing >99% of the nanomaterials in tissue-resident macrophages. Initially, the formation of the protein corona significantly reduces the nanocatalysts' activity, but this activity can be partially recovered in endosomal conditions due to the proteolytic degradation of the corona. Overall, the research reveals the complex relationship between physisorbed proteins and the catalytic characteristics of specific metal oxide nanoparticles, providing design parameters for optimizing nanocatalysts in complex biological environments

Intraplate seismicity and releated mantle hydration at the Nicaraguan trench outer rise

We examine micro-earthquake records from a dense temporary array of ocean bottom seismometers (OBS) and hydrophones that has been installed from September to November 2005 at the trench outer rise offshore Nicaragua. Approximately 1.5 locatable earthquakes per day within the array of 110 × 120 km show the high seismic activity in this region. Seismicity is restricted to the upper ∼15 km of the mantle and hence where temperatures reach 350–400 °C, which is smaller than values observed for large mantle intraplate events (650 °C). Determination of moment tensor solutions suggest a change of the stress region from tensional in the upper layers of the oceanic plate to compressional beneath. The neutral plane between both regimes is located at ∼6–9 km beneath Moho and thus very shallow. Fluids, which are thought to travel through the tensional fault system into the upper mantle, may not be able to penetrate any deeper. The earthquake catalogue, which seems to be complete for magnitudes above Mw = 1.6–1.8, suggests a strong change of the lithospheric rheology when approaching the trench. And b-factors, that is the ratio between small and large earthquakes increase significantly in the closest 20 km to the trench axis, implying that the crust and upper mantle is massively weakened and hence ruptures more frequently but under less release of stress. We explain this with a partly serpentinized upper mantle

Extreme disorder in an ultrahigh-affinity protein complex

Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes

Metal–Organic Framework Mediated Radio-Enhancement Assessed in High-Throughput-Compatible 3D Tumor Spheroid Co-Cultures

Inorganic nanomaterials have gained increasing attention in radiation oncology, owing to their radiation therapy enhancing properties. To accelerate candidate material selection and overcome the disconnect between conventional 2D cell culture and in vivo findings, screening platforms unifying high-throughput with physiologically relevant endpoint analysis based on 3D in vitro models are promising. Here, a 3D tumor spheroid co-culture model based on cancerous and healthy human cells is presented for the concurrent assessment of radio-enhancement efficacy, toxicity, and intratissural biodistribution with full ultrastructural context of radioenhancer candidate materials. Its potential for rapid candidate materials screening is showcased based on the example of nano-sized metal–organic frameworks (nMOFs) and direct benchmarking against gold nanoparticles (the current “gold standard”). Dose enhancement factors (DEFs) ranging between 1.4 and 1.8 are measured for Hf-, Ti-, TiZr-, and Au-based materials in 3D tissues and are overall lower than in 2D cell cultures, where DEF values exceeding 2 are found. In summary, the presented co-cultured tumor spheroid—healthy fibroblast model with tissue-like characteristics may serve as high-throughput platform enabling rapid, cell line-specific endpoint analysis for therapeutic efficacy and toxicity assessment, as well as accelerated radio-enhancer candidate screening.ISSN:2701-019

Nanoanalytical Insights into the Stability, Intracellular Fate, and Biotransformation of Metal-Organic Frameworks

Metal-organic frameworks (MOFs) have found increasingapplicationsin the biomedical field due to their unique properties and high modularity.Although the limited stability of MOFs in biological environmentsis increasingly recognized, analytical techniques have not yet beenharnessed to their full potential to assess the biological fate ofMOFs. Here, we investigate the environment-dependent biochemical transformationsof widely researched nanosized MOFs (nMOFs) under conditions relevantto their medical application. We assess the chemical stability ofantimicrobial zinc-based drug delivery nMOFs (Zn-ZIF-8 and Zn-ZIF-8:Ce)and radio-enhancer candidate nMOFs (Hf-DBA, Ti-MIL-125, and TiZr-PCN-415)containing biologically nonessential group IV metal ions. We revealthat even a moderate decrease in pH to values encountered in lysosomes(pH 4.5-5) leads to significant dissolution of ZIF-8 and partialdissolution of Ti-MIL-125, whereas no substantial dissolution wasobserved for TiZr-PCN-415 and Hf-DBA nMOFs. Exposure to phosphate-richbuffers led to phosphate incorporation in all nMOFs, resulting inamorphization and morphological changes. Interestingly, long-termcell culture studies revealed that nMOF (bio)transformations of, e.g.,Ti-MIL-125 were cellular compartment-dependent and that the phosphatecontent in the nMOF varied significantly between nMOFs localized inlysosomes and those in the cytoplasm. These results illustrate thedelicate nature and environment-dependent properties of nMOFs acrossall stages of their life cycle, including storage, formulation, andapplication, and the need for in-depth analyses of biotransformationsfor an improved understanding of structure-function relationships.The findings encourage the considerate choice of suspension buffersfor MOFs because these media may lead to significant material alterationsprior to application.ISSN:1944-8244ISSN:1944-825

X-ray radio-enhancement by Ti₃C₂Tₓ MXenes in soft tissue sarcoma

Radiotherapy is a cornerstone of cancer treatment. However, due to the low tissue specificity of ionizing radiation, damage to the surrounding healthy tissue of the tumor remains a significant challenge. In recent years, radio-enhancers based on inorganic nanomaterials have gained considerable interest. Beyond the widely explored metal and metal oxide nanoparticles, 2D materials, such as MXenes, could present potential benefits because of their inherently large specific surface area. In this study, we highlight the promising radio-enhancement properties of Ti₃C₂Tₓ MXenes. We demonstrate that atomically thin layers of titanium carbides (Ti₃C₂Tₓ MXenes) are efficiently internalized and well-tolerated by mammalian cells. Contrary to MXenes suspended in aqueous buffers, which fully oxidize within days, yielding rice-grain shaped rutile nanoparticles, the MXenes internalized by cells oxidize at a slower rate. This is consistent with cell-free experiments that have shown slower oxidation rates in cell media and lysosomal buffers compared to dispersants without antioxidants. Importantly, the MXenes exhibit robust radio-enhancement properties, with dose enhancement factors reaching up to 2.5 in human soft tissue sarcoma cells, while showing no toxicity to healthy human fibroblasts. When compared to oxidized MXenes and commercial titanium dioxide nanoparticles, the intact 2D titanium carbide flakes display superior radio-enhancement properties. In summary, our findings offer evidence for the potent radio-enhancement capabilities of Ti₃C₂Tₓ MXenes, marking them as a promising candidate for enhancing radiotherapy.ISSN:2047-4830ISSN:2047-484

Radiotherapy Enhancement by Ti3C2Tx MXenes

Radiotherapy is an integral part of cancer therapy. Due to the low tissue specificity of radiation, damage to tumor-surrounding healthy tissue remains a major concern. Radio-enhancers based on inorganic nanomaterials have attracted considerable attention in recent years. In addition to widely exploited metal and metal oxides nanoparticles, 2D materials may offer potential advantages due to their intrinsically high specific surface area. Here, we report on the promising radio-enhancement properties of Ti3C2Tx MXenes. We show that Ti3C2Tx MXenes are readily internalized and well-tolerated by mammalian cells. In contrast to MXenes suspended in aqueous buffers which fully oxidize within days (yielding rice-grain shaped rutile nanoparticles), MXenes internalized by cells display slower oxidation rates, in line with cell-free experiments showing slower oxidation in cell media and lysosomal buffers compared to antioxidant-devoid dispersants. The MXenes show potent radio-enhancement properties with dose enhancement factors of up to 2.5 in human soft tissue sarcoma cells and no toxicity towards healthy human fibroblasts. Benchmarking against oxidized MXenes and commercial titanium dioxide nanoparticles indicates superior radio-enhancement properties of the intact 2D titanium carbide flakes. Taken together, this work provides direct evidence for the potent radio-enhancement properties of Ti3C2Tx MXenes rendering them a promising candidate material for radiotherapy enhancement.ISSN:2573-229

Radiotherapy Enhancement by Ti3C2Tx MXenes

Radiotherapy is an integral part of cancer therapy. Due to the low tissue specificity of radiation, damage to tumor-surrounding healthy tissue remains a major concern. Radio-enhancers based on inorganic nanomaterials have attracted considerable attention in recent years. In addition to widely exploited metal and metal oxides nanoparticles, 2D materials may offer potential advantages due to their intrinsically high specific surface area. Here, we report on the promising radio-enhancement properties of Ti3C2Tx MXenes. We show that Ti3C2Tx MXenes are readily internalized and well-tolerated by mammalian cells. In contrast to MXenes suspended in aqueous buffers which fully oxidize within days (yielding rice-grain shaped rutile nanoparticles), MXenes internalized by cells display slower oxidation rates, in line with cell-free experiments showing slower oxidation in cell media and lysosomal buffers compared to antioxidant-devoid dispersants. The MXenes show potent radio-enhancement properties with dose enhancement factors of up to 2.5 in human soft tissue sarcoma cells and no toxicity towards healthy human fibroblasts. Benchmarking against oxidized MXenes and commercial titanium dioxide nanoparticles indicates superior radio-enhancement properties of the intact 2D titanium carbide flakes. Taken together, this work provides direct evidence for the potent radio-enhancement properties of Ti3C2Tx MXenes rendering them a promising candidate material for radiotherapy enhancement