Mesoporous carbon nanoparticles embedded with iron in hydrogen-photothermal synergistic therapy.

We developed a new method to synthesize polyethylene glycol modified ultra small iron embedded in mesoporous carbon nanoparticle (C/Fe-PEG NP) for hydrogen (H2) assisted photothermal synergistic therapy. Herein, we use a simple in-situ reduction method to obtain the C/Fe NP in one-step carbonizing process, which is further modified by the biocompatible polyethylene glycol (PEG) on the surface of C/Fe NP to acquire high stability in physiological solutions. Utilizing the excellent photothermal property from the mesoporous carbon and the controllable H2 release property in the weakly acidic tumor microenvironment by the ultra-small Fe, the obtained C/Fe-PEG NPs can effective kill the cancer cells, meanwhile, protect normal cells without drugs. This selective anti-cancer mechanism of C/Fe-PEG NPs may because the produced H2 selective change the mitochondrial energy metabolism. In vivo results prove that the C/Fe-PEG NPs achieve excellent tumor ablation therapeutic effect and normal tissue protecting ability benefit from the H2-assisted photothermal therapy, promising the use of novel nanomaterials with more safety method for future cancer therapy.

NIR-Activatable Heterostructured Nanoadjuvant CoP/NiCoP Executing Lactate Metabolism Interventions for Boosted Photocatalytic Hydrogen Therapy and Photoimmunotherapy.

Near-infrared (NIR) laser-induced photoimmunotherapy has aroused great interest due to its intrinsic noninvasiveness and spatiotemporal precision, while immune evasion evoked by lactic acid (LA) accumulation severely limits its clinical outcomes. Although several metabolic interventions have been devoted to ameliorate immunosuppression, intracellular residual LA still remains a potential energy source for oncocyte proliferation. Herein, an immunomodulatory nanoadjuvant based on a yolk-shell CoP/NiCoP (CNCP) heterostructure loaded with the monocarboxylate transporter 4 inhibitor fluvastatin sodium (Flu) is constructed to concurrently relieve immunosuppression and elicit robust antitumor immunity. Under NIR irradiation, CNCP heterojunctions exhibit superior photothermal performance and photocatalytic production of reactive oxygen species and hydrogen. The continuous heat then facilitates Flu release to restrain LA exudation from tumor cells, whereas cumulative LA can be depleted as a hole scavenger to improve photocatalytic efficiency. Subsequently, potentiated photocatalytic therapy can not only initiate systematic immunoreaction, but also provoke severe mitochondrial dysfunction and disrupt the energy supply for heat shock protein synthesis, in turn realizing mild photothermal therapy. Consequently, LA metabolic remodeling endows an intensive cascade treatment with an optimal safety profile to effectually suppress tumor proliferation and metastasis, which offers a new paradigm for the development of metabolism-regulated immunotherapy.

Hyperbaric hydrogen therapy improves secondary brain injury after head trauma.

Background: The pathophysiology of traumatic brain injury (TBI) is caused by the initial physical damage and by the subsequent biochemical damage (secondary brain injury). Oxidative stress is deeply involved in secondary brain injury, so molecular hydrogen therapy may be effective for TBI. Hydrogen gas shows the optimal effect at concentrations of 2% or higher, but can only be used up to 1.3% in the form of a gas cylinder mixed with oxygen gas, which may not be sufficiently effective. The partial pressure of hydrogen increases in proportion to the pressure, so hyperbaric hydrogen therapy (HBH2) is more effective than that at atmospheric pressure. Methods: A total of 120 mice were divided into three groups: TBI + non-treatment group (TBI group; n = 40), TBI + HBH2 group (n = 40), and non-TBI + non-treatment group (sham group; n = 40). The TBI and TBI + HBH2 groups were subjected to moderate cerebral contusion induced by controlled cortical impact. The TBI + HBH2 group received hyperbaric hydrogen therapy at 2 atmospheres for 90 minutes, at 30 minutes after TBI. Brain edema, neuronal cell loss in the injured hippocampus, neurological function, and cognitive function were evaluated. Results: The TBI + HBH2 group showed significantly less cerebral edema (p ≺ 0.05). Residual hippocampal neurons were significantly more numerous in the TBI + HBH2 group on day 28 (p ≺ 0.05). Neurological score and behavioral tests showed that the TBI + HBH2 group had significantly reduced hyperactivity on day 14 (p ≺ 0.01). Conclusion: Hyperbaric hydrogen therapy may be effective for posttraumatic secondary brain injury.

pH-Responsive Injectable Multifunctional Pluronic F127/Gelatin-Based Hydrogels with Hydrogen Production for Treating Diabetic Wounds.

Diabetic chronic wounds remain a major clinical challenge with long-term inflammatory responses and extreme oxidative damage. Hence, a pH-responsive injectable multifunctional hydrogel [Gel/CUR-FCHO/Mg (GCM) micromotors] via a Schiff base reaction between gelatin and benzaldehyde-grafted Pluronic F127 drug-loaded micelles (FCHO) was fabricated for the first time. Dynamic Schiff base linkage endowed the GCM hydrogel with the ability to be self-healing, injectable, and pH-responsive for on-demand drug delivery at the wound site. Curcumin (CUR), a hydrophobic drug with antioxidative, anti-inflammatory, and antibacterial activities, was encapsulated into the hydrogel matrix by micellization (CUR-FCHO micelles). Simultaneously, magnesium-based micromotors (Mg micromotors) were physically entrapped into the system for providing active hydrogen (H2) to scavenge reactive oxygen species and alleviate inflammatory responses. As a result, the GCM micromotor hydrogel displayed an inherent antibacterial property, extraordinary antioxidative performance, and remarkable biocompatibility. In the diabetic mouse with a full-thickness cutaneous defect wound, the GCM hydrogel could remodel the inflammatory microenvironment and stimulate vascularization and collagen deposition, thereby facilitating wound closure and enhancing tissue regeneration, which offered a promising therapeutic option for diabetic chronic wound management.

Smart PdH@MnO2 Yolk-Shell Nanostructures for Spatiotemporally Synchronous Targeted Hydrogen Delivery and Oxygen-Elevated Phototherapy of Melanoma.

Hydrogen therapy, an emerging therapeutic strategy, has recently attracted much attention in anticancer medicine. Evidence suggests that hydrogen (H2) can selectively reduce intratumoral overexpressed hydroxyl radicals (•OH) to break the redox homeostasis and thereby lead to redox stress and cell damage. However, the inability to achieve stable hydrogen storage and efficient hydrogen delivery hinders the development of hydrogen therapy. Furthermore, oxygen (O2) deficiency in the tumor microenvironment (TME) and the electron-hole separation inefficiency in photosensitizers have severely limited the efficacy of photodynamic therapy (PDT). Herein, a smart PdH@MnO2/Ce6@HA (PHMCH) yolk-shell nanoplatform is designed to surmount these challenges. PdH tetrahedrons combine stable hydrogen storage and high photothermal conversion efficiency of palladium (Pd) nanomaterials with near-infrared-controlled hydrogen release. Subsequently, the narrow bandgap semiconductor manganese dioxide (MnO2) and the photosensitizer chlorin e6 (Ce6) are introduced into the PHMCH nanoplatform. Upon irradiation, the staggered energy band edges in heterogeneous materials composed of MnO2 and Ce6 can efficiently facilitate electron-hole separation for increasing singlet oxygen (1O2). Moreover, MnO2 nanoshells generate O2 in TME for ameliorating hypoxia and further improving O2-dependent PDT. Finally, the hyaluronic acid-modified PHMCH nanoplatform shows negligible cytotoxicity and selectively targets CD44-overexpressing melanoma cells. The synergistic antitumor performance of the H2-mediated gas therapy combined with photothermal and enhanced PDT can explore more possibilities for the design of gas-mediated cancer therapy.

Near-Infrared Light Triggered H2 Generation for Enhanced Photothermal/Photodynamic Therapy against Hypoxic Tumor.

The principle of photochemical transformation has shown significant inspiration on phototherapy of solid tumors. However, both photodynamic therapy (PDT) and photothermal therapy (PTT) can induce stress response of tumor cells, which draw the attention in recent. Herein, an asymmetric and lollipop like nanostructure consisting of gold nanorod/titanium dioxide (l-TiO2 -GNR) is developed by controlling single head growth of titanium dioxide (TiO2 ) on gold nanorods (GNR). Through the reasonable utilization of hot electrons of GNR by 808 nm light irradiation, l-TiO2 -GNR perform type I-PDT, mild PTT (48 °C), and H2 therapy which is efficient for hypoxic tumors. In particular, H2 can downregulate both triphosadenine and heat shock protein which are found to be main source of tumor stress response. l-TiO2 -GNR opens a new window for treatment of hypoxic tumor by the perfect synergy of type I-PDT, mild PTT, and H2 therapy.

Magnesium-Based Micromotors as Hydrogen Generators for Precise Rheumatoid Arthritis Therapy.

Hydrogen therapy is an emerging and highly promising strategy for the treatment of inflammation-related diseases. However, nonpolarity and low solubility of hydrogen under the physiological conditions results in a limited therapeutic effect. Herein, we develop a biocompatible magnesium micromotor coated with hyaluronic acid as a hydrogen generator for precise rheumatoid arthritis management. The hydrogen bubbles generated locally not only function as a propellant for the motion but also function as the active ingredient for reactive oxygen species (ROS) and inflammation scavenging. Under ultrasound guidance, the micromotors are injected intra-articularly, and the dynamics of the micromotors can be visualized. By scavenging ROS and inflammation via active hydrogen, the oxidative stress is relieved and the levels of inflammation cytokines are reduced by our micromotors, showing prominent therapeutic efficacy in ameliorating joint damage and suppressing the overall arthritis severity toward a collagen-induced arthritis rat model. Therefore, our micromotors show great potential for the therapy of rheumatoid arthritis and further clinical transformation.

NIR-Driven Water Splitting H2 Production Nanoplatform for H2-Mediated Cascade-Amplifying Synergetic Cancer Therapy.

As a newly emerging treatment strategy for many diseases, hydrogen therapy has attracted a lot of attention because of its excellent biosafety. However, the high diffusivity and low solubility of hydrogen make it difficult to accumulate in local lesions. Herein, we develop a H2 self-generation nanoplatform by in situ water splitting driven by near-infrared (NIR) laser. In this work, core-shell nanoparticles (CSNPs) of NaGdF4:Yb,Tm/g-C3N4/Cu3P (UCC) nanocomposites as core encapsulated with zeolitic imidazolate framework-8 (ZIF-8) modified with folic acid as shell are designed and synthesized. Due to the acid-responsive ZIF-8 shell, enhanced permeability and retention (EPR) effect, and folate receptor-mediated endocytosis, CSNPs are selectively captured by tumor cells. Upon 980 nm laser irradiation, CSNPs exhibit a high production capacity of H2 and active oxygen species (ROS), as well as an appropriate photothermal conversion temperature. Furthermore, rising temperature increases the Fenton reaction rate of Cu(I) with H2O2 and strengthens the curative effect of chemodynamic therapy (CDT). The excess glutathione (GSH) in tumor microenvironment (TME) can deplete positive holes produced in the valence band of g-C3N4 in the g-C3N4/Cu3P Z-scheme heterojunction. GSH also can reduce Cu(II) to Cu(I), ensuring a continuous Fenton reaction. Thus, a NIR-driven H2 production nanoplatform is constructed for H2-mediated cascade-amplifying multimodal synergetic therapy.

Hydrogen gas improves photothermal therapy of tumor and restrains the relapse of distant dormant tumor.

Inflammation during photothermal therapy (PTT) of tumor usually results in adverse consequences. Here, a biomembrane camouflaged nanomedicine (mPDAB) containing polydopamine and ammonia borane was designed to enhance PTT efficacy and mitigate inflammation. Polydopamine, a biocompatible photothermal agent, can effectively convert light into heat for PTT. Ammonia borane was linked to the surface of polydopamine through the interaction of hydrogen bonding, which could destroy redox homoeostasis in tumor cells and reduce inflammation by H2 release in tumor microenvironment. Owing to the same origin of outer biomembranes, mPDAB showed excellent tumor accumulation and low systemic toxicity in a breast tumor model. Excellent PTT efficacy and inflammation reduction made the mPDAB completely eliminate the primary tumors, while also restraining the outgrowth of distant dormant tumors. The biomimetic nanomedicine shows potentials as a universal inflammation-self-alleviated platform to ameliorate inflammation-related disease treatment, including but not limited to PTT for tumor.

Sustained release of bioactive hydrogen by Pd hydride nanoparticles overcomes Alzheimer's disease.

Oxidative stress-induced mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer's disease (AD). Hydrogen molecule, a special antioxidant, can selectively scavenge highly cytotoxic reactive oxygen species such as ·OH, exhibiting a potential to treat AD by reducing oxidative stress. However, there is no effective route to realize the continuous and efficient accumulation of administrated hydrogen in AD brain owing to its low solubility. Here, we develop the small-sized Pd hydride (PdH) nanoparticles for high payload of hydrogen and in situ sustained hydrogen release in AD brain. By virtue of the catalytic hydrogenation effect of Pd, the released hydrogen from PdH nanoparticles exhibits high bio-reductivity in favor of effectively scavenging cytotoxic ·OH in a self-catalysis way. Bio-reductive hydrogen is able to recover mitochondrial dysfunction, inhibit Aß generation and aggregation, block synaptic and neuronal apoptosis and promote neuronal energy metabolism by eliminating oxidative stress and activating the anti-oxidative pathway, consequently ameliorating the cognitive impairment in AD mice. The proposed hydrogen-releasing nanomedicine strategy would open a new window for the treatment of AD.

Hydrogen as a complementary therapy against ischemic stroke: A review of the evidence.

Ischemic stroke is one of the most common sources of mortality in the world. Researchers have been trying to find a complementary therapy to treat ischemic stroke in order to improve its prognosis and expand the therapeutic window for reperfusion treatment. For this reason, many experimental and clinical trials studying the effects of hydrogen against ischemic stroke have been published. Hydrogen gas has been found to eliminate hydroxyl free radical and peroxynitrite anions as well as producing therapeutic effect in patients with ischemic stroke. Many studies have been published illustrating its anti-oxidative, anti-inflammatory and anti-apoptotic effects. The purpose of this article is to review the literature concerning treatment of cerebral I/R injury or ischemic stroke with hydrogen therapy. Specifically, we will examine the appropriate laboratory methods, mechanisms of hydrogen therapy, and outcomes of relevant clinical trials. We conclude this review with a discussion on future investigations of hydrogen therapy to treat ischemic stroke.