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

Biochemical transformations of inorganic nanomedicines in buffers, cell cultures and organisms

The field of nanomedicine is rapidly evolving, with new materials and formulations being reported almost daily. In this respect, inorganic and inorganic-organic composite nanomaterials have gained significant attention. However, the use of new materials in clinical trials and their final approval as drugs has been hampered by several challenges, one of which is the complex and difficult to control nanomaterial chemistry that takes place within the body. Several reviews have summarized investigations on inorganic nanomaterial stability in model body fluids, cell cultures, and organisms, focusing on their degradation as well as the influence of corona formation. However, in addition to these aspects, various chemical reactions of nanomaterials, including phase transformation and/or the formation of new/secondary nanomaterials, have been reported. In this review, we discuss recent advances in our understanding of biochemical transformations of medically relevant inorganic (composite) nanomaterials in environments related to their applications. We provide a refined terminology for the primary reaction mechanisms involved to bridge the gaps between different disciplines involved in this research. Furthermore, we highlight suitable analytical techniques that can be harnessed to explore the described reactions. Finally, we highlight opportunities to utilize them for diagnostic and therapeutic purposes and discuss current challenges and research priorities.ISSN:2040-3364ISSN:2040-337

Uptake, distribution and radio-enhancement effects of gold nanoparticles in tumor microtissues

Radiotherapy is an integral and highly effective part of cancer therapy, applicable in over 50% of patients affected by cancer. Due to the low specificity of the X-ray irradiation, the maximal radiation dose is greatly limited in order to avoid damage to surrounding healthy tissue. The limitations in applicable dose oftentimes result in the survival of a subpopulation of radio-resistant cells that then cause cancer reoccurence. Approaches based on tumor-targeted high atomic number inorganic nanoparticles have been proposed to locally increase the photoelectric absorption cross-section of tumors relative to healthy tissue. However, the complex interplay between the nanoparticle radio-enhancers and the tumor tissue has led to poor translation of in vitro findings to (pre)clinics. Here, we report the development of a tumor microtissue model along with analytical imaging for the quantitative assessment of nanoparticle-based radio-enhancement as a function of nanoparticle size, uptake and intratissural distribution. The advanced in vitro model exhibits key features of cancerous tissues, including diminished susceptibility to drugs and attenuated response to nanoparticle treatment compared to corresponding conventional 2D cell cultures. Whereas radio-enhancement effects between 2D and 3D cell cultures were comparable for 5 nm gold particles, the limited penetration of 50 nm gold nanoparticles into 3D microtissues led to a significantly reduced radio-enhancement effect in 3D compared to 2D. Taken together, tumor microtissues, which in stark contrast to 2D cell culture exhibit tissue-like features, may provide a valuable high-throughput intermediate pre-selection step in the preclinical translation of nanoparticle-based radio-enhancement therapy designs.ISSN:2516-023

Chemically Stable, Strongly Adhesive Sealant Patch for Intestinal Anastomotic Leakage Prevention

Intestinal anastomotic leaking, which involves the discharge of chemically aggressive, non‐sterile fluids into the abdomen, remains one of the most dreaded postoperative complications of abdominal surgery. Depending on the site and the patient condition, incidence ranging between 4% and 21% and mortality rates up to 27% are reported. Currently available surgical sealants only poorly address the issue, especially since most commonly used fibrin glues fail due to insufficient adhesion and chemical instability. Here, a chemically highly resistive, leak‐tight, and mucoadhesive hydrogel sealant, which is grafted on the surface of the intestinal wall using a mutually interpenetrating network that traverses hydrogel and tissue is presented. In contrast to clinically used fibrin‐based sealants (including Tachosil), the developed adhesive poly(acrylamide‐methyl acrylate‐acrylic acid) patch does not degrade and exhibits strong tissue adhesion even when exposed to intestinal fluid. The biocompatible hydrogel patch effectively seals anastomotic leaks in ex vivo intestinal models, greatly surpassing commercial sealants (time to patch‐failure >24 h compared to 5 min for commonly used Tachosil). Importantly, the developed adhesive patch paves the way for the application of both mechanically and chemically robust sealants suitable for the treatment and prevention of intestinal leaks. © 2021 Wiley‐VCH GmbH.ISSN:1616-3028ISSN:1616-301

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

Scalable Synthesis of Ultrasmall Metal Oxide Radio-Enhancers Outperforming Gold

Nanoparticle-based radio-enhancement has the potential to improve cancer cell eradication by augmenting the photoelectric cross-section of targeted cancer cells relative to the healthy surroundings. Encouraging results have been reported for various nanomaterials, including gold and hafnia. However, the lack of scalable synthesis methods and comparative studies is prohibitive to rationalized material design and hampers translation of this promising cancer management strategy. Here, we present a scalable (>100 g day–1) and sterile alternative to conventional batch synthesis of group IV metal oxides (TiO2, ZrO2, and HfO2), which yields near-monodisperse ultrasmall metal oxide nanoparticles with radio-enhancement properties. Access to group IV oxide nanoparticles, which solely differ in atomic number but otherwise exhibit comparable morphologies, sizes, and surface chemistries, enables the direct comparison of their radio-enhancement properties to rationally guide material selection for optimal radio-enhancement performance. We show that the metal oxide nanoparticles exhibit atomic-number-dependent radio-enhancement in cancer cells (HT1080 and HeLa), which is attenuated to baseline levels in normal fibroblasts (normal human dermal fibroblasts). The observed radio-enhancement effects show excellent agreement with physical dose enhancement and nanoparticle dosimetry calculations. Direct benchmarking against gold nanoparticles, the current gold standard in the field, rationalizes the use of hafnia nanoparticles based on their radio-enhancement performance, which is superior to equi-sized gold nanoparticles. Taken together, the competitive radio-enhancement properties for near-monodisperse nanoparticles produced by scalable and sterile flame spray synthesis offer a route to overcoming key roadblocks in the translation of nanoparticle-based radio-enhancers.ISSN:0897-475

Scalable Synthesis of Ultrasmall Metal Oxide Radio-Enhancers Outperforming Gold

Nanoparticle-based radio-enhancement has the potential to improve cancer cell eradication by augmenting the photoelectric cross-section of targeted cancer cells relative to the healthy surroundings. Encouraging results have been reported for various nanomaterials, including gold and hafnia. However, the lack of scalable synthesis methods and comparative studies is prohibitive to rationalized material design and hampers translation of this promising cancer management strategy. Here, we present a scalable (>100 g day–1) and sterile alternative to conventional batch synthesis of group IV metal oxides (TiO2, ZrO2, and HfO2), which yields near-monodisperse ultrasmall metal oxide nanoparticles with radio-enhancement properties. Access to group IV oxide nanoparticles, which solely differ in atomic number but otherwise exhibit comparable morphologies, sizes, and surface chemistries, enables the direct comparison of their radio-enhancement properties to rationally guide material selection for optimal radio-enhancement performance. We show that the metal oxide nanoparticles exhibit atomic-number-dependent radio-enhancement in cancer cells (HT1080 and HeLa), which is attenuated to baseline levels in normal fibroblasts (normal human dermal fibroblasts). The observed radio-enhancement effects show excellent agreement with physical dose enhancement and nanoparticle dosimetry calculations. Direct benchmarking against gold nanoparticles, the current gold standard in the field, rationalizes the use of hafnia nanoparticles based on their radio-enhancement performance, which is superior to equi-sized gold nanoparticles. Taken together, the competitive radio-enhancement properties for near-monodisperse nanoparticles produced by scalable and sterile flame spray synthesis offer a route to overcoming key roadblocks in the translation of nanoparticle-based radio-enhancers.ISSN:0897-475

Smart sealants for prevention and monitoring of gastrointestinal anastomotic leaks using portable smartphone-controlled ultrasound transducers

Millions of patients every year undergo gastrointestinal surgery. While often lifesaving, sutured and stapled reconnections leak in around 10% of the cases. Penetration of digestive fluids into the peritoneal cavity may lead to dreadful complications, including sepsis and premature death. Modern suture supports and tissue adhesives only insufficiently address the issue. Due to the scarcity of alternatives, surgeons rely on monitoring surrogate markers and clinical symptoms, which oftentimes lack sensitivity and specificity, hence only offering late-stage detection of already fully developed leaks. Here, a first-of-its-kind, modular, intelligent suture support patch capable of sealing and monitoring leaks under harsh gastrointestinal conditions is presented. The smart adhesive layered hydrogel patch provides, in addition to unprecedented tissue sealing under most demanding conditions, unique leak-detection capabilities based on pH and/or enzyme-responsive sensing elements, which can be read out by non-invasive point-of-need ultrasound imaging. Reliable detection of the breaching of sutures in as little as 3 hours in intestinal leak and 15 minutes in gastric leak conditions, and before an actual leak develops, is demonstrated. This technology paves the way for next-generation suture support materials that offer disambiguation in cases of anastomotic leaks based on point-of-need monitoring, without reliance on complex electronics or bulky (bio)electronic implantables

Modular stimuli-responsive hydrogel sealants for early gastrointestinal leak detection and containment

Millions of patients every year undergo gastrointestinal surgery. While often lifesaving, sutured and stapled reconnections leak in around 10% of cases. Currently, surgeons rely on the monitoring of surrogate markers and clinical symptoms, which often lack sensitivity and specificity, hence only offering late-stage detection of fully developed leaks. Here, we present a holistic solution in the form of a modular, intelligent suture support sealant patch capable of containing and detecting leaks early. The pH and/or enzyme-responsive triggerable sensing elements can be read out by point-of-need ultrasound imaging. We demonstrate reliable detection of the breaching of sutures, in as little as 3 hours in intestinal leak scenarios and 15 minutes in gastric leak conditions. This technology paves the way for next-generation suture support materials that seal and offer disambiguation in cases of anastomotic leaks based on point-of-need monitoring, without reliance on complex electronics or bulky (bio)electronic implantables.ISSN:2041-172