Prospects of nanoparticle-based radioenhancement for radiotherapy

Radiotherapy is a key pillar of solid cancer treatment. Despite a high level of conformal dose deposition, radiotherapy is limited due to co-irradiation of organs at risk and subsequent normal tissue toxicities. Nanotechnology offers an attractive opportunity for increasing the efficacy and safety of cancer radiotherapy. Leveraging the freedom of design and the growing synthetic capabilities of the nanomaterial-community, a variety of engineered nanomaterials have been designed and investigated as radiosensitizers or radioenhancers. While research so far has been primarily focused on gold nanoparticles and other high atomic number materials to increase the absorption cross section of tumor tissue, recent studies are challenging the traditional concept of high-Z nanoparticle radioenhancers and highlight the importance of catalytic activity. This review provides a concise overview on the knowledge of nanoparticle radioenhancement mechanisms and their quantification. It critically discusses potential radioenhancer candidate materials and general design criteria for different radiation therapy modalities, and concludes with research priorities in order to advance the development of nanomaterials, to enhance the efficacy of radiotherapy and to increase at the same time the therapeutic window

Surgical Sealant with Integrated Shape‐Morphing Dual Modality Ultrasound and Computed Tomography Sensors for Gastric Leak Detection

Postoperative anastomotic leaks are the most feared complications after gastric surgery. For diagnostics clinicians mostly rely on clinical symptoms such as fever and tachycardia, often developing as a result of an already fully developed, i.e., symptomatic, surgical leak. A gastric fluid responsive, dual modality, electronic‐free, leak sensor system integrable into surgical adhesive suture support materials is introduced. Leak sensors contain high atomic number carbonates embedded in a polyacrylamide matrix, that upon exposure to gastric fluid convert into gaseous carbon dioxide (CO$_{2}$). CO$_{2}$ bubbles remain entrapped in the hydrogel matrix, leading to a distinctly increased echogenic contrast detectable by a low‐cost and portable ultrasound transducer, while the dissolution of the carbonate species and the resulting diffusion of the cation produces a markedly reduced contrast in computed tomography imaging. The sensing elements can be patterned into a variety of characteristic shapes and can be combined with nonreactive tantalum oxide reference elements, allowing the design of shape‐morphing sensing elements visible to the naked eye as well as artificial intelligence‐assisted automated detection. In summary, shape‐morphing dual modality sensors for the early and robust detection of postoperative complications at deep tissue sites, opening new routes for postoperative patient surveillance using existing hospital infrastructure is reported

Reversal of the ΔdegP Phenotypes by a Novel rpoE Allele of Escherichia coli

RseA sequesters RpoE (σE) to the inner membrane of Escherichia coli when envelope stress is low. Elevated envelope stress triggers RseA cleavage by the sequential action of two membrane proteases, DegS and RseP, releasing σE to activate an envelope stress reducing pathway. Revertants of a ΔdegP ΔbamB strain, which fails to grow at 37°C due to high envelope stress, harbored mutations in the rseA and rpoE genes. Null and missense rseA mutations constitutively hyper-activated the σE regulon and significantly reduced the major outer membrane protein (OMP) levels. In contrast, a novel rpoE allele, rpoE3, resulting from the partial duplication of the rpoE gene, increased σE levels greater than that seen in the rseA mutant background but did not reduce OMP levels. A σE-dependent RybB::LacZ construct showed only a weak activation of the σE pathway by rpoE3. Despite this, rpoE3 fully reversed the growth and envelope vesiculation phenotypes of ΔdegP. Interestingly, rpoE3 also brought down the modestly activated Cpx envelope stress pathway in the ΔdegP strain to the wild type level, showing the complementary nature of the σE and Cpx pathways. Through employing a labile mutant periplasmic protein, AcrAL222Q, it was determined that the rpoE3 mutation overcomes the ΔdegP phenotypes, in part, by activating a σE-dependent proteolytic pathway. Our data suggest that a reduction in the OMP levels is not intrinsic to the σE-mediated mechanism of lowering envelope stress. They also suggest that under extreme envelope stress, a tight homeostasis loop between RseA and σE may partly be responsible for cell death, and this loop can be broken by mutations that either lower RseA activity or increase σE levels

Catalytic activity imperative for nanoparticle dose enhancement in photon and proton therapy.

Nanoparticle-based radioenhancement is a promising strategy for extending the therapeutic ratio of radiotherapy. While (pre)clinical results are encouraging, sound mechanistic understanding of nanoparticle radioenhancement, especially the effects of nanomaterial selection and irradiation conditions, has yet to be achieved. Here, we investigate the radioenhancement mechanisms of selected metal oxide nanomaterials (including SiO2, TiO2, WO3 and HfO2), TiN and Au nanoparticles for radiotherapy utilizing photons (150 kVp and 6 MV) and 100 MeV protons. While Au nanoparticles show outstanding radioenhancement properties in kV irradiation settings, where the photoelectric effect is dominant, these properties are attenuated to baseline levels for clinically more relevant irradiation with MV photons and protons. In contrast, HfO2 nanoparticles retain some of their radioenhancement properties in MV photon and proton therapies. Interestingly, TiO2 nanoparticles, which have a comparatively low effective atomic number, show significant radioenhancement efficacies in all three irradiation settings, which can be attributed to the strong radiocatalytic activity of TiO2, leading to the formation of hydroxyl radicals, and nuclear interactions with protons. Taken together, our data enable the extraction of general design criteria for nanoparticle radioenhancers for different treatment modalities, paving the way to performance-optimized nanotherapeutics for precision radiotherapy

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

Mass, Light and Colour of the Cosmic Web in the Supercluster SCL2243-0935 (z=0.447)

Context: In 2.2m MPG-ESO/WFI data we discovered several mass peaks through weak lensing, forming a possible supercluster at redshift 0.45. Through multi-colour wide-field imaging with CFHT/Megaprime and INT/WFC we identify early-type galaxies and trace the supercluster network with them. Through EMMI/NTT multi-object spectroscopy we verify the initial shear-selected cluster candidates. Using weak lensing we obtain mass estimates for the supercluster centre and the filaments. Results: We identified the centre of the SCL2243-0935 supercluster, MACS J2243-0935, which was found independently by Ebeling et al. (2010). 13 more clusters or overdensities are embedded in a filamentary network, half of them are already spectroscopically confirmed. Three (5-15) Mpc filaments are detected, and we estimate the global size of SCL2243 to 45x15x50 Mpc, making it one of the largest superclusters known at intermediate redshifts. Weak lensing yields r_200=(2.06+/-0.13) Mpc and M_200=(1.54+/-0.29)x10^15 M_sun for MACS J2243 with M/L=428+/-82, very similar to results from size-richness cluster scaling relations. Integrating the weak lensing surface mass density over the supercluster network (defined by increased i-band luminosity or g-i colours), we find (1.53+/-1.01)x10^15 M_sun and M/L=305+/-201 for the three main filaments, consistant with theoretical predictions. The filaments' projected surface mass density is 0.007-0.012, corresponding to 10-100 times the critical density. The greatly varying density of the cosmic web is also reflected in the mean colour of galaxies. Conclusions: SCL2243 is significantly larger and much more richly structured than other known superclusters such as A901/902 or MS0302 studied with weak lensing before. It is a text-book supercluster with little contamination along the line of sight, making it a perfect sandbox for testing new techniques probing the cosmic web.Comment: 26 pages, 16 figures, accepted for publication Astronomy and Astrophysics. Minor corrections implemented as requested by the refere

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

A prosodically controlled word and nonword repetition task for 2- to 4- year-olds: Evidence from typically developing children

An association has been found between nonword repetition and language skills in school-aged children with both typical and atypical language development (Dollaghan & Campbell, 1998; Ellis Weismer et al., 2000; Gathercole & Baddeley, 1990; Montgomery, 2002). This raises the possibility that younger children’s repetition performance may be predictive of later language deficits. In order to investigate this possibility, it is important to establish that elicited repetition with very young children is both feasible and informative. To this end, a repetition task was designed and carried out with 66 children aged 2-4. The task consisted of 18 words and 18 matched nonwords that were systematically manipulated for length and prosodic structure. In addition, an assessment of receptive vocabulary was administered. The repetition task elicited high levels of response. Total scores as well as word and nonword scores were sensitive to age. Lexical status and item length affected performance regardless of age: words were repeated more accurately than nonwords, and one-syllable items were repeated more accurately than two-syllable items, which were in turn repeated more accurately than three-syllable items. The effect of prosodic structure was also significant. Whole syllable errors were almost exclusive to unstressed syllables, with those preceding stress being most vulnerable. Performance on the repetition task was significantly correlated with performance on the receptive vocabulary test. Since this repetition task was effective in eliciting responses from most of the 2 to 4-year-old participants, tapped developmental change in their repetition skills, and revealed patterns in their performance, it has the potential to identify deficits in very early repetition skills that may be indicative of wider language difficulties