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

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

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

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

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

Prospects of Nanoparticle-based Radioenhancement for Radiotherapy

Radiotherapy is a key pillar of solid cancer treatment. Despite 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 fundamental 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

Abstract 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 (CO2). CO2 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