Differential reinforcement of cGAS-STING pathway-involved immunotherapy by biomineralized bacterial outer membrane-sensitized EBRT and RNT.

Radiotherapy (RT), including external beam radiation therapy (EBRT) and radionuclide therapy (RNT), realizes physical killing of local tumors and activates systemic anti-tumor immunity. However, these effects need to be further strengthened and the difference between EBRT and RNT should be discovered. Herein, bacterial outer membrane (OM) was biomineralized with manganese oxide (MnO2) to obtain OM@MnO2-PEG nanoparticles for enhanced radio-immunotherapy via amplifying EBRT/RNT-induced immunogenic cell death (ICD) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) activation. OM@MnO2-PEG can react with H2O2 and then gradually produce O2, Mn2+ and OM fragments in the tumor microenvironment. The relieved tumor hypoxia improves the radio-sensitivity of tumor cells, resulting in enhanced ICD and DNA damage. Mn2+ together with the DNA fragments in the cytoplasm activate the cGAS-STING pathway, further exhibiting a positive role in various aspects of innate immunity and adaptive immunity. Besides, OM fragments promote tumor antigen presentation and anti-tumor macrophages polarization. More importantly, our study reveals that OM@MnO2-PEG-mediated RNT triggers much stronger cGAS-STING pathway-involved immunotherapy than that of EBRT, owing to the duration difference of RT. Therefore, this study develops a powerful sensitizer of radio-immunotherapy and uncovers some differences between EBRT and RNT in the activation of cGAS-STING pathway-related anti-tumor immunity.

Tumor Vascular Destruction and cGAS-STING Activation Induced by Single Drug-Loaded Nano-Micelles for Multiple Synergistic Therapies of Cancer.

Cancer and its metastasis/recurrence still threaten human health, despite various advanced treatments being employed. It is of great significance to develop simple drug formulations to enhance the efficacy and synergistic integration of various monotherapies. Herein, DMXAA, a vasodestructive agent with cGAS-STING stimulation capacity, is integrated with polyethylene glycol grafted poly (lactic-co-glycolic) acid co-polymer (PLGA-PEG), obtaining PLGA-PEG/DMXAA (PPD) nanoparticles to induce the tumor-specific vascular destruction for multiple synergistic therapies of cancer. PPD could induce the formation of blood clots in the tumor after intravenous injection, which subsequently mediate photothermal therapy and further promote the release of oxygen for enhanced radiotherapy. Meanwhile, the enhanced vascular injury can induce perfect starvation therapy of tumor. More importantly, PPD-mediated therapies could trigger potent systemic anti-tumor immunity via inducing the immunogenic death of tumor cells and activating the cGAS-STING pathway. Together with anti-PD-L1, PPD-mediated therapies could not only remove the primary tumors, but also effectively eliminate the distant tumors, metastasis, and recurrence. Therefore, the modulation of tumor composition induced by a single drug-loaded nano-micelle could be utilized to enhance the therapeutic effect of multiple treatments for synergistic and systemic antitumor response, providing a practical strategy for cancer therapy.

Using Self-Nanoemulsifying System to Improve Oral Bioavailability of a Pediatric Antiepileptic Agent Stiripentol: Formulation and Pharmacokinetics Studies.

This study aimed to develop a self-nanoemulsifying drug delivery system (SNEDDS) for poorly water-soluble drug stiripentol (STP) with enhanced oral bioavailability. Optimal excipients were selected by constructing pseudo-ternary phase diagrams using determined solubilities of STP, and then the proper composition of SNEDDS was investigated by employing a central composite design method. The optimized SNEDDS was composed of oil (ethyl oleate 39.61%), surfactant (Cremophor® RH 40 43.18%), co-surfactant (1,2-propanediol 17.21%), and STP of 50 mg/mL. The hydrodynamic size, zeta potential, and polydispersity index (PDI) were found to be 45.52 ± 1.99 nm, - 21.67 ± 0.24 mV, and 0.076 ± 0.011, respectively. The optimized STP-SNEDDS showed good stability in accelerated and dilution stability studies. It was also helpful to suppress STP degradation in acidic solution. Compared with STP suspension, STP-SNEDDS presented much faster dissolution rate. STP-SNEDDS successfully resulted in superior levels of Cmax and AUC0 → 6 h (4048.38 ± 704.54 µg/L and 7754.58 ± 1489.37 h µg/L, respectively) to STP suspension (1894.09 ± 1077.64 µg/L and 3556.93 ± 2470.01 h µg/L, respectively). The relative oral bioavailability of STP was 218.01%. The brain biodistribution studies showed that STP-SNEDDS presented significantly higher STP concentrations in the brain at 0.5 h and 1 h than that of STP suspension after administration. These findings indicated that a SNEDDS-based oral formulation of STP would be helpful for increasing its therapeutic potential.

Crack Inhibition and Performance Modification of NiCoCr-Based Superalloy with Y2O3 Nanoparticles by Laser Metal Deposition.

A new precipitation strengthening NiCoCr-based superalloy with favorable mechanical performance and corrosion resistance was designed for ultra-supercritical power generation equipment. The degradation of mechanical properties and steam corrosion at high temperatures put forward higher requirements for alternative alloy materials; however, when the superalloy is processed to form complex shaped components through advanced additive manufacturing techniques such as laser metal deposition (LMD), hot cracks are prone to appear. This study proposed that microcracks in LMD alloys could be alleviated with powder decorated by Y2O3 nanoparticles. The results show that adding 0.5 wt.% Y2O3 can refine grains significantly. The increase in grain boundaries makes the residual thermal stress more uniform to reduces the risk of hot cracking. In addition, the addition of Y2O3 nanoparticles enhanced the ultimate tensile strength of the superalloy at room temperature by 18.3% compared to original superalloy. The corrosion resistance was also improved with 0.5 wt.% Y2O3, which was attributed to the reduction of defects and the addition of inert nanoparticles.

Recent advances in biological membrane-based nanomaterials for cancer therapy.

Nanomaterials have shown significant advantages in cancer theranostics, owing to their enhanced permeability and retention effect in tumors and multi-function integration capability. Biological membranes, which are collected from various cells and their secreted membrane structures, can further be applied to establish membrane-based nanomaterials with perfect biocompatibility, tumor-targeting capacity, immune-stimulatory activity and adjustable versatility for cancer therapy. In this review, according to their source, membranes are divided into four groups: (1) cell membranes; (2) secretory membranes; (3) engineered membranes; and (4) hybrid membranes. First, cell membranes can be extracted from natural cells of the body, tumor tissue cells, and bacteria. Furthermore, secretory membranes mainly refer to exosome, apoptotic body and bacterial outer membrane vesicle, and membranes with specific protein/peptide expression or therapeutic inclusions are obtained from engineered cells. Finally, a hybrid membrane will be constituted by two or more of the abovementioned membranes. These membranes can form drug-carrying nanoparticles themselves or coat multi-functional nanoparticles, further realizing efficient cancer therapy. We summarize the application of various biological membrane-based nanomaterials in cancer therapy and point out their advantages as well as the places that need to be further improved, providing systematic knowledge of this field and a strategy for further optimization.

Emerging strategies based on nanomaterials for ionizing radiation-optimized drug treatment of cancer.

Drug-radiotherapy is a common and effective combinational treatment for cancer. This study aimed to explore the ionizing radiation-optimized drug treatment based on nanomaterials so as to improve the synergistic efficacy of drug-radiotherapy against cancer and limit the adverse effect on healthy organs. In this review, these emerging strategies were divided into four parts. First, the delivery of the drug-loaded nanoparticles was optimized owing to the strengthened passive targeting process, active targeting process, and cell targeting process of nanoparticles after ionizing radiation exposure. Second, nanomaterials were designed to respond to the ionizing radiation, thus leading to the release of the loading drugs controllably. Third, radiation-activated pro-drugs were loaded onto nanoparticles for radiation-triggered drug therapy. In particular, nontoxic nanoparticles with radiosensitization capability and innocuous radio-dynamic contrast agents can be considered as radiation-activated drugs, which were discussed in this review. Fourth, according to the various synergetic mechanisms, radiotherapy could improve the drug response of cancer, obtaining optimized drug-radiotherapy. Finally, relative suggestions were provided to further optimize these aforementioned strategies. Therefore, a novel topic was selected and the emerging strategies in this region were discussed, aiming to stimulate the inspiration for the development of ionizing radiation-optimized drug treatment based on nanomaterials.

Diagnostic Radionuclides Labeled on Biomimetic Nanoparticles for Enhanced Follow-Up Photothermal Therapy of Cancer.

Imaging-guided local therapy is the most effective strategy to treat primary cancers in patients. However, the local therapeutic effect should be further improved under the premise of absence of induction of additional side effects. It would be meaningful to analyze the potential assistance of nuclear imaging to the follow-up treatments. In this study,cancer-targeted copper sulfide nanoparticles with 99m Tc labeling (99m Tc-M-CuS-PEG) are prepared using-cancer cell membranes as a synthesis reactor and applied for the potential single-photon emission computed tomography/photoacoustic imaging-guided and 99m Tc-amplified photothermal therapy of cancer. Owing to the homologous targeting capability of the cancer cell membrane, M-CuS-PEG selectively accumulates in homologous tumor sites. After labeling with 99m Tc, M-CuS-PEG with a high near-infrared light absorbance can realize bimodal imaging-guided photothermal therapy of cancer. Furthermore, the labeled 99m Tc significantly enhances the cell uptake of M-CuS-PEG by inducing G2/M arrest of the cell cycle, further improving the photothermal antitumor effect, which is positively correlated with endocytosis of the photothermal conversion reagent. Therefore, a novel cancer-targeted theranostic nanoplatform is developed and it is revealed that the labeled 99m Tc can not only guide but also amplify the subsequent therapy of cancer, providing a conceptual strategy for cancer theranostics with a high biosafety.

Photo-Driven Delivery of 125I-Labeled Nanomicelles for Nucleus-Targeted Internal Conversion Electron-Based Cancer Therapy.

As a kind of high linear energy transfer (LET) radiation, internal conversion electrons are emitted from some radionuclides, such as 125I, triggering severe DNA damage to tumor cells when transported into the nucleus. Herein, we develop a curcumin-loaded nanomicelle composed of a photosensitizer chlorin e6 (Ce6) and amphiphilic poly(ethylene glycol) (poly(maleic anhydride-alt-1-octadecene)-poly(ethylene glycol) (C18-PMH-PEG)) to deliver 125I into the nucleus under 660 nm laser irradiation, leading to the optimized imaging-guided internal conversion electron therapy of cancer. Ce6-containing nanomicelles (Ce6-C18-PEG) self-assemble with nucleus-targeted curcumin (Cur), obtaining Ce6-C18-PEG/Cur nanoparticles. After labeling Cur with 125I, Ce6-C18-PEG/Cur enables single-photon emission computed tomography and fluorescence imaging of the tumor, serving as a guide for follow-up laser irradiation. Notably, the 660 nm laser-triggered photodynamic reaction of Ce6 optimizes the delivery of Ce6-C18-PEG/125I-Cur at various stages, including tumor accumulation, cellular uptake, and lysosome escape, causing plenty of 125I-Cur to enter the nucleus. By this strategy, Ce6-C18-PEG/125I-Cur showed optimal antitumor efficacy and high biosafety in mice treated with local 660 nm laser irradiation using efficient energy deposition of internally converted electrons over short distances. Therefore, our work provides a novel strategy to optimize 125I delivery for tumor treatment.

Uncertainty Modeling of Fatigue Crack Growth and Probabilistic Life Prediction for Welded Joints of Nuclear Stainless Steel.

Welded joints are widely used in the pipeline connection of nuclear power plants. Defects in these joints are an important factor leading to the failure of welded joints. It is critical to study the fatigue crack growth and life prediction methods for the welded joints with defects, to reduce their likelihood. In this paper, we present our study of the uncertainty of fatigue crack propagation and probabilistic life prediction for welded joints of nuclear stainless steel. The standard compact tension (CT) specimens were fabricated according to the American Society for Testing and Materials (ASTM) standard. Fatigue crack propagation tests with different stress ratios were performed on CT specimens, using the Mei Te Si (MTS) fatigue test system. A fatigue crack propagation rate model considering the uncertainty of material parameters, and based on the Paris formula and crack propagation experimental data, was established. A probabilistic life prediction method based on Monte Carlo simulation was developed. The fatigue crack propagation prediction result of a CT specimen was compared with the actual tested result, to verify the effectiveness of the proposed method. Finally, the method was applied to an embedded elliptical crack in welded joints of nuclear stainless steel, to predict the fatigue crack growth life and evaluate the reliability.