Hyperbaric Oxygen Activates Enzyme-Driven Cascade Reactions for Cooperative Cancer Therapy and Cancer Stem Cells Elimination.

Tumor starvation induced by intratumor glucose depletion emerges as a promising strategy for anticancer therapy. However, its antitumor potencies are severely compromised by intrinsic tumor hypoxia, low delivery efficiencies, and undesired off-target toxicity. Herein, a multifunctional cascade bioreactor (HCG), based on the self-assembly of pH-responsive hydroxyethyl starch prodrugs, copper ions, and glucose oxidase (GOD), is engineered, empowered by hyperbaric oxygen (HBO) for efficient cooperative therapy against aggressive breast cancers. Once internalized by tumor cells, HCG undergoes disassembly and releases cargoes in response to acidic tumor microenvironment. Subsequently, HBO activates GOD-catalyzed oxidation of glucose to H2 O2 and gluconic acid by ameliorating tumor hypoxia, fueling copper-catalyzed •OH generation and pH-responsive drug release. Meanwhile, HBO degrades dense tumor extracellular matrix, promoting tumor accumulation and penetration of HCG. Moreover, along with the consumption of glucose and the redox reaction of copper ions, the antioxidant capacity of tumor cells is markedly reduced, collectively boosting oxidative stress. As a result, the combination of HCG and HBO can not only remarkably suppress the growth of orthotopic breast tumors but also restrain pulmonary metastases by inhibiting cancer stem cells. Considering the clinical accessibility of HBO, this combined strategy holds significant translational potentials for GOD-based therapies.

Transport and deposition of solid phosphorus-based mineral particles in urine diversion systems.

The deposition of solid phosphorus-based mineral particles is a common problem in urine diversion systems, which occurs in transport systems, particularly in horizontal pipelines. In this work, particle deposition behaviour in turbulent flow in a 3D horizontal pipe was simulated by using the Euler-Lagrange method. The effects of particle diameter, particle density, particle shape factor and fluid flow velocity on particle deposition behaviour were investigated. The results showed that the deposition rate increased by 9.92%,6.88% and 6.88% with increasing particle diameter (10-90 µm), particle density (1400 kg/m3-2300 kg/m3), and particle shape factor (0.2-1), respectively. For particles with larger diameters (>90 µm) or larger density (>2300 kg/m3), the deposition rate of these particles was almost reached 100%. It was found that gravitational sedimentation was the dominant deposition mechanism in low fluid flow velocity range (0.1-0.5 m/s). As fluid flow velocity increased (>0.5 m/s), turbulent fluctuation became the dominant factor that affected particle motion behaviour, whereas the effect of gravitational sedimentation on particle deposition behaviour declined significantly, and the increase in fluid flow velocity no longer significantly affects deposition rate. It was found that the deposition rate decreased by 29.13% as the fluid flow velocity was increased from 0.1 m/s to 0.5 m/s, while the corresponding deposition rate only decreased by 14.24% when the fluid flow velocity was increased from 0.5 m/s to 2 m/s. The optimal flow velocity was found to range between 0.75 and 1.25 m/s, which may mitigate the deposition of mineral solids in urine diversion systems.

A two-pronged strategy to alleviate tumor hypoxia and potentiate photodynamic therapy by mild hyperthermia.

The application of photodynamic therapy (PDT) is limited by tumor hypoxia. To overcome hypoxia, catalase-like nanozymes are often used to catalyze endogenous H2O2 enriched in tumor tissues to O2. Nonetheless, the catalase activity may not be optimal at body temperature and the O2 supply may not meet the rapid O2 consumption of PDT. Herein, we provide a two-pronged strategy to alleviate tumor hypoxia based on hollow mesoporous Prussian blue nanoparticles (HMPB NPs). HMPB NPs can efficiently load the photosensitizer chlorin e6 (Ce6) and exhibit photothermal capability and temperature-dependent catalase activity. Under 808 nm laser irradiation, the photothermal effect of HMPB NPs elevated the catalase activity of HMPB NPs for O2 production. Furthermore, mild hyperthermia reduced cancer associated fibroblasts (CAFs) and induced extracellular matrix (ECM) degradation. The reduction of CAFs and the ECM decreased the solid stress of tumor tissues and normalized the tumor vasculature, which was beneficial for the external supplementation of O2 to tumors. Thereafter, under 606 nm laser irradiation, Ce6-mediated PDT generated excessive reactive oxygen species (ROS) that induced tumor cell apoptosis and achieved a high tumor inhibition rate of 92.2% in 4T1 breast tumors. Our work indicated that the alleviation of tumor hypoxia from both internal and external pathways significantly enhanced Ce6-mediated PDT against breast cancers.

Mesoporous polydopamine-based multifunctional nanoparticles for enhanced cancer phototherapy.

Cancer phototherapy has attracted increasing attention for its effectiveness, relatively low side effect, and noninvasiveness. The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has been shown to exhibit promising prospects in cancer treatment. However, the tumor hypoxia, high level of intracellular glutathione (GSH), and insufficient photosensitizer uptake significantly limit the PDT efficacy. In this work, we combine oxygen supply, GSH depletion, and tumor targeting in one nanoplatform, folate-decorated mesoporous polydopamine nanoparticles (FA-MPPD) co-loaded with new indocyanine green (IR-820) and perfluorooctane (PFO) (IR-820/PFO@FA-MPPD), to overcome the PDT resistance for enhanced cancer PDT/PTT. IR-820/PFO@FA-MPPD exhibit efficient singlet oxygen generation and photothermal effect under 808 nm laser irradiation, GSH-promoted IR-820 release, and efficient cellular uptake, resulting in high intracellular reactive oxygen species (ROS) level under 808 nm laser irradiation and strong photocytotoxicity in vitro. Following intratumoral injection, IR-820/PFO@FA-MPPD can relieve tumor hypoxia sustainably by PFO-mediated oxygen transport and deplete intracellular GSH by the Michael addition reaction, which boost the PDT effect and lead to the most potent antitumor effect upon 808 nm laser irradiation. The multifunctional IR-820/PFO@FA-MPPD developed in this work offer a relatively simple and effective strategy to potentiate PDT for efficient cancer phototherapy.

A DiR loaded tumor targeting theranostic cisplatin-icodextrin prodrug nanoparticle for imaging guided chemo-photothermal cancer therapy.

Imaging-guided diagnosis and chemo-photothermal combination therapy have promising applications for the treatment of cancer. Nevertheless, the accurate diagnosis and efficient treatment of tumors are not yet satisfactory. Herein, a tumor targeting DiR loaded cisplatin-icodextrin prodrug nanoparticle, with selective drug release, was fabricated as a multifunctional theranostic nanoplatform for chemo-photothermal combination therapy. By loading DiR into the hydrophobic domain of folic acid-icodextrin-polycaprolactone (FA-ICO-PCL, FIP) and cisplatin-icodextrin-polycaprolactone (Pt-ICO-PCL, PtIP) co-assembly, the resultant DiR@(PtIP + FIP) (DPtFIP) NPs had a diameter of around 70 nm and showed excellent tumor targeting ability and negligible side effects. Moreover, the DPtFIP NPs achieved real-time NIR fluorescence imaging of solid tumors with high contrast. By the accurate tumor imaging, local laser irradiation dramatically enhanced the chemotherapy for triple-negative breast cancer. Such a biocompatible nanotherapeutic holds great potential for tumor diagnosis and imaging-guided combinational cancer therapy.

Hyperbaric Oxygen Boosts PD-1 Antibody Delivery and T Cell Infiltration for Augmented Immune Responses Against Solid Tumors.

Aberrant mechanical properties and immunosuppression are the two key factors that limit the antitumor efficacy of T cell immune checkpoint blockade inhibitors, e.g., programmed cell death-1 antibody (PD-1 Ab), against solid tumors in the clinic. This study leverages hyperbaric oxygen (HBO) for the first time to address these two issues and reports the PD-1-Ab-mediated immune responses against various stroma-rich solid malignancies. The results demonstrate that HBO promoted PD-1 Ab delivery and T cells infiltration into tumor parenchyma by depleting the extracellular matrix's main components, such as collagen and fibronectin. Furthermore, HBO disrupts hypoxia-mediated immunosuppression and helps PD-1 Ab trigger robust cytotoxic T lymphocytes and long-lasting immunological memory to inhibit tumor relapses. Such enhanced immune responses are effective in solid tumors from rodents and the cancer cells from hepatocellular carcinoma patients. The results illustrate that HBO bolsters antitumor efficacy of PD-1 Ab, and the HBO-PD-1 Ab combination is a promising stroma-rich solid tumors' treatment in the clinic.

Boosting Nanomedicine Efficacy with Hyperbaric Oxygen Therapy.

Nanomedicine has been a hot topic in the field of tumor therapy in the past few decades. Because of the enhanced permeability and retention effect (EPR effect), nanomedicine can passively yet selectively accumulate at tumor tissues. As a result, it can improve drug concentration in tumor tissues and reduce drug distribution in normal tissues, thereby contributing to enhanced antitumor effect and reduced adverse effects. However, the therapeutic efficacy of anticancer nanomedicine is not satisfactory in clinical settings. Therefore, how to improve the clinical therapeutic effect of nanomedicine has become an urgent problem. The grand challenges of nanomedicine lie in how to overcome various pathophysiological barriers and simultaneously kill cancer cells effectively in hypoxic tumor microenvironment (TME). To this end, the development of novel stimuli-responsive nanomedicine has become a new research hotspot. While a great deal of progress has been made in this direction and preclinical results report many different kinds of promising multifunctional smart nanomedicine, the design of these intelligent nanomedicines is often too complicated, the requirements for the preparation processes are strict, the cost is high, and the clinical translation is difficult. Thus, it is more practical to find solutions to promote the therapeutic efficacy of commercialized nanomedicines, for example, Doxil®, Oncaspar®, DaunoXome®, Abraxane®, to name a few. Increasing attention has been paid to the combination of modern advanced medical technology and nanomedicine for the treatment of various malignancies. Recently, we found that hyperbaric oxygen (HBO) therapy could enhance Doxil® antitumor efficacy. Inspired by this study, we further carried out researches on the combination of HBO therapy with other nanomedicines for various cancer therapies, and revealed that HBO therapy could significantly boost antitumor efficacy of nanomedicine-mediated photodynamic therapy and photothermal therapy in different kinds of tumors, including hepatocellular carcinoma, breast cancer, and gliomas. Our results implicate that HBO therapy might be a universal strategy to boost therapeutic efficacy of nanomedicine against hypoxic solid malignancies.

A Simple Glutathione-Responsive Turn-On Theranostic Nanoparticle for Dual-Modal Imaging and Chemo-Photothermal Combination Therapy.

Constructing a tumor microenvironment stimuli activatable theranostic nanoparticle with simple components and preparation procedures for multimodality imaging and therapy remains a major challenge for current theranostic systems. Here we report a novel and simple glutathione (GSH)-responsive turn-on theranostic nanoparticle for dual-modal imaging and combination therapy. The theranostic nanoparticle, DHP, consisting of a disulfide-bond-linked hydroxyethyl starch paclitaxel conjugate (HES-SS-PTX) and a near-infrared (NIR) cyanine fluorophore DiR, is prepared with a simple one-step dialysis method. As DiR is encapsulated within the hydrophobic core formed by HES-SS-PTX, the fluorescence of DiR is quenched by the aggregation-caused quenching (ACQ) effect. Nonetheless, once DHP is internalized by cancer cells, the disulfide bond of HES-SS-PTX can be cleaved by intracellular GSH, leading to the synchronized release of conjugated PTX and loaded DiR. The released PTX could exert its therapeutic effect, while DiR could adsorb onto nearby endosome/lysosome membranes and regain its fluorescence. Thus, DHP could monitor the release and therapeutic effect of PTX through the fluorescence recovery of DiR. Remarkably, DHP can also be used as an in vivo probe for both fluorescent and photoacoustic imaging and at the same time achieves potent antitumor efficacy through chemo-photothermal combination therapy. This study provides novel insights into designing clinically translatable turn-on theranostic systems.

Potentiating photodynamic therapy of ICG-loaded nanoparticles by depleting GSH with PEITC.

Photodynamic therapy (PDT) is a clinically approved cancer treatment which utilizes reactive oxygen species (ROS) to eradicate cancer cells. But the high concentration of GSH inside tumor cells can neutralize the generated ROS during PDT, resulting in an insufficient therapeutic effect. To address this issue, we combined ICG-loaded nanoparticles with PEITC for potent PDT. ICG encapsulated in novel hydroxyethyl starch-oleic acid conjugate (HES-OA) nanoparticles (∼50 nm) exhibited excellent stability and efficient singlet oxygen generation under laser irradiation, promoted cellular uptake, and enhanced tumor accumulation, whilst PEITC depleted intracellular GSH significantly. As a result, PDT based on ICG-loaded NPs combined with PEITC synergistically suppressed cancer cells both in vitro and in vivo. Potentiating ICG-loaded NPs with PEITC represents a novel and efficient strategy to enhance PDT efficacy.

Albumin-coordinated assembly of clearable platinum nanodots for photo-induced cancer theranostics.

Photoactive noble metal nanoparticles are of increasing importance toward personalized cancer therapy in the field of precision nanomedicine. A critical challenge remains in the exploration of clinically potential noble metal nanoparticles for highly efficient cancer theranostics. Here, we introduce albumin-coordinated assembly of clearable Pt nanodots (Pt-NDs) with monodisperse nanostructure as high-performance theranostic agents for imaging-guided photothermal tumor ablation. We precisely manipulate the reduction and growth of tetravalent Pt ions into ultrasmall nanodots through albumin-directed growth kinetics, thereby leading to the synthesis of monodisperse 6.7 nm Pt-NDs with albumin molecules as the corona. Pt-NDs exhibit the surface plasmon resonance at 225 nm with enhanced near-infrared (NIR) absorbance, ideal resistance to photo-bleaching, distinct photoacoustic and X-ray signals, as well as remarkable photothermal effect through non-radiative relaxation under NIR light irradiation. In particular, Pt-NDs possess preferable tumor accumulation, and effective in vivo excretory capability. Thus, these nanodots promote preferable in vivo microscopic photoacoustics and spatially anatomic CT imaging with enhanced contrast, as well as potent hyperthermia-mediated tumor ablation. These findings represent a facile and general approach to fabricate high-performance noble metal nanostructures with clinical potential for cancer theranostics.

Nanocolloidosomes with Selective Drug Release for Active Tumor-Targeted Imaging-Guided Photothermal/Chemo Combination Therapy.

Selective drug release is highly desirable for photothermal/chemo combination therapy when two or even more theranostic agents are encapsulated together within the same nanocarrier. A conventional nanocarrier can hardly achieve this goal. Herein, doxorubicin and indocyanine green (DOX/ICG)-loaded nanocolloidosomes (NCs), with selective drug release, were fabricated as a novel multifunctional theranostic nanoplatform for photothermal/chemo combination therapy. Templating from galactose-functionalized hydroxyethyl starch-polycaprolactone (Gal-HES-PCL) nanoparticles-stabilized Pickering emulsions, the resultant DOX/ICG@Gal-HES-PCL NCs had a diameter of around 140 nm and showed an outstanding tumor-targeting ability, preferable tumor penetration capability, and promotion of photothermal effect. Moreover, these NCs can be used for NIR fluorescence imaging and thus render real-time imaging of solid tumors with high contrast. Collectively, such NCs achieved the best in vivo antitumor efficacy combined with laser irradiation compared with DOX/ICG@HES-PCL NCs and DOX/ICG mixture. These NCs are valuable for active tumor-targeted imaging-guided combination therapy against liver cancer and potentially other diseases.

Catalytic reduction of nitrate in secondary effluent of wastewater treatment plants by Fe(0) and Pd-Cu/γ-Al2O3.

Total nitrogen, in which NO3(-) is dominant in the effluent of most wastewater treatment plants, cannot meet the requirements of the Chinese wastewater discharge standard (<15 mg/L), making nitrate (NO3(-)) elimination attract considerable attention. In this study, reductant iron (Fe(0)) and γ-Al2O3 supported palladium-copper bimetallic catalysts (Pd-Cu/γ-Al2O3) were innovatively used for the chemical catalytic reduction of nitrate in wastewater. A series of specific operational conditions (such as mass ratio of Pd:Cu, catalyst amounts, reaction time and pH of solution) were optimized for nitrate reduction in the artificial solution, and then the selected optimal conditions were further applied for investigating the nitrate elimination of secondary effluent of a wastewater treatment plant in Beijing, China. Results indicated that a better catalytic performance (74% of nitrate removal and 62% of N2 selectivity) could be obtained under the optimal condition: 5 g/L Fe(0), 3:1 mass ratio (Pd:Cu), 4 g/L catalyst, 2 h reaction time and pH 5.1. It is noteworthy to point out that nitrogen gas (N2) predominated in the byproducts without another system to treat ammonium and nitrite. Therefore, the chemical catalytic reduction combining Fe(0) with Pd-Cu/γ-Al2O3 could be regarded as a better alternative for nitrate removal in wastewater treatment.

Comparative research on phosphorus removal by pilot-scale vertical flow constructed wetlands using steel slag and modified steel slag as substrates.

This research mainly focused on the phosphorus removal performance of pilot-scale vertical flow constructed wetlands with steel slag (SS) and modified steel slag (MSS). First, bench-scale experiments were conducted to evaluate the phosphorus adsorption capacity. Results showed that the Langmuir model could better describe the adsorption characteristics of the two materials; the maximum adsorption of MSS reached 12.7 mg/g, increasing by 34% compared to SS (9.5 mg/g). Moreover, pilot-scale constructed wetlands with SS and MSS were set up outdoors. Then, the influence of hydraulic retention time (HRT) and phosphorus concentration in phosphorus removal for two wetlands were investigated. Results revealed that better performance of the two systems could be achieved with an HRT of 2 d and phosphorus concentration in the range of 3-4.5 mg/L; the system with MSS had a better removal efficiency than the one with SS in the same control operation. Finally, the study implied that MSS could be used as a promising substrate for wetlands to treat wastewater with a high phosphorus concentration. However, considering energy consumption, SS could be regarded as a better alternative for substrate when treating sewage with a low phosphorus concentration.