Titanium Sulfide Nanosheets Serve as Cascade Bioreactors for H2 S-Mediated Programmed Gas-Sonodynamic Cancer Therapy.

Gas-mediated sonodynamic therapy (SDT) has the potential to become an effective strategy to improve the therapeutic outcome and survival rate of cancer patients. Herein, titanium sulfide nanosheets (TiSX NSs) are prepared as cascade bioreactors for sequential gas-sonodynamic cancer therapy. TiSX NSs themselves as hydrogen sulfide (H2 S) donors can burst release H2 S gas. Following H2 S generation, TiSX NSs are gradually degraded to become S-defective and partly oxidized into TiOX on their surface, which endows TiSX NSs with high sonodynamic properties under ultrasound (US) irradiation. In vitro and in vivo experiments show the excellent therapeutic effects of TiSX NSs. In detail, large amounts of H2 S gas and reactive oxygen species (ROS) can simultaneously inhibit mitochondrial respiration and ATP synthesis, leading to cancer cell apoptosis. Of note, H2 S gas also plays important roles in modulating and activating the immune system to effectively inhibit pulmonary metastasis. Finally, the metabolizable TiSX NSs are excreted out of the body without inducing any significant long-term toxicity. Collectively, this work establishes a cascade bioreactor of TiSX NSs with satisfactory H2 S release ability and excellent ROS generation properties under US irradiation for programmed gas-sonodynamic cancer therapy.

Magnesium galvanic cells produce hydrogen and modulate the tumor microenvironment to inhibit cancer growth.

Hydrogen can be used as an anti-cancer treatment. However, the continuous generation of H2 molecules within the tumor is challenging. Magnesium (Mg) and its alloys have been extensively used in the clinic as implantable metals. Here we develop, by decorating platinum on the surface of Mg rods, a Mg-based galvanic cell (MgG), which allows the continuous generation of H2 in an aqueous environment due to galvanic-cell-accelerated water etching of Mg. By implanting MgG rods into a tumor, H2 molecules can be generated within the tumor, which induces mitochondrial dysfunction and intracellular redox homeostasis destruction. Meanwhile, the Mg(OH)2 residue can neutralize the acidic tumor microenvironment (TME). Such MgG rods with the micro-galvanic cell structure enable hydrogen therapy to inhibit the growth of tumors, including murine tumor models, patient-derived xenografts (PDX), as well as VX2 tumors in rabbits. Our research suggests that the galvanic cells for hydrogen therapy based on implantable metals may be a safe and effective cancer treatment.

Biodegradable Fe-Doped Vanadium Disulfide Theranostic Nanosheets for Enhanced Sonodynamic/Chemodynamic Therapy.

Sonodynamic therapy (SDT), a noninvasive and highly penetrating tumor therapy, which employs ultrasound and sonosensitizers, has attracted extensive attention because of its ability to treat deep tumors. However, many current sonosensitizers have drawbacks in phototoxicity and limited sonodynamic effect. Herein, as a novel kind of sonosensitizer, iron-doped vanadium disulfide nanosheets (Fe-VS2 NSs) are constructed by a high-temperature organic-solution method and further modified with polyethylene glycol (PEG). With Fe doping, the sonodynamic effect of Fe-VS2 NSs is greatly enhanced, owing to the prolonged electron-hole recombination time. Simultaneously, such Fe-VS2-PEG NSs as a good Fenton agent can be utilized for chemodynamic therapy (CDT) by using the endogenous H2O2 in the tumor microenvironment (TME). Moreover, the multivalent Fe and V elements in the Fe-VS2 NSs can consume glutathione to amplify the reactive oxygen species-induced oxidative stress by SDT and CDT. Utilizing the strong near-infrared optical absorbance and enhanced magnetic resonance (MR) contrast by Fe-VS2 NSs, photoacoustic/MR biomodal imaging reveals a high accumulation of Fe-VS2-PEG NSs in the tumor. The great tumor suppression effect is then achieved by the in vivo combined CDT&SDT treatment. Importantly, most of the injected Fe-VS2-PEG NSs can be gradually decomposed and excreted from the mice, making them as safe sonosensitizers for cancer treatment. Our work highlights a new type of biodegradable sonosensitizer with the ability of regulating TME for applications in cancer theranostics.

Ultrasmall Iron-Doped Titanium Oxide Nanodots for Enhanced Sonodynamic and Chemodynamic Cancer Therapy.

Sonodynamic therapy (SDT), which can generate reactive oxygen species (ROS) based on sonosensitizers under ultrasound (US) to kill tumor cells, has emerged as a noninvasive therapeutic modality with high tissue-penetration depth. Herein, ultrasmall iron-doped titanium oxide nanodots (Fe-TiO2 NDs) are synthesized via a thermal decomposition strategy as a type of sonosensitizers to enhance SDT. Interestingly, the Fe doping in this system appears to be crucial in not only enhancing the US-triggered ROS generation of those NDs but also offering NDs the Fenton-catalytic function to generate ROS from tumor endogenous H2O2 for chemodynamic therapy (CDT). After polyethylene glycol (PEG) modification, Fe-TiO2-PEG NDs demonstrate good physiological stability and biocompatibility. With efficient tumor retention after intravenous injection as revealed by in vivo magnetic resonance (MR) and fluorescent imaging, our Fe-TiO2 NDs demonstrate much better in vivo therapeutic performance than commercial TiO2 nanoparticles owing to the combination of CDT and SDT. Moreover, most of those ultrasmall Fe-TiO2 NDs can be effectively excreted within one month, rendering no obvious long-term toxicity to the treated mice. Our work thus presents a type of multifunctional sonosensitizer for highly efficient cancer treatment via simply doping TiO2 nanostructures with metal ions.

Preparation of TiH1.924 nanodots by liquid-phase exfoliation for enhanced sonodynamic cancer therapy.

Metal hydrides have been rarely used in biomedicine. Herein, we fabricate titanium hydride (TiH1.924) nanodots from its powder form via the liquid-phase exfoliation, and apply these metal hydride nanodots for effective cancer treatment. The liquid-phase exfoliation is an effective method to synthesize these metal hydride nanomaterials, and its efficiency is determined by the matching of surface energy between the solvent and the metal hydrides. The obtained TiH1.924 nanodots can produce reactive oxygen species (ROS) under ultrasound, presenting a highly efficient sono-sensitizing effect. Meanwhile, TiH1.924 nanodots with strong near-infrared (NIR) absorbance can serve as a robust photothermal agent. By using the mild photothermal effect to enhance intra-tumoral blood flow and improve tumor oxygenation, a remarkable synergistic therapeutic effect is achieved in the combined photothermal-sonodynamic therapy. Importantly, most of these TiH1.924 nanodots can be cleared out from the body. This work presents the promises of functional metal hydride nanomaterials for biomedical applications.