H2O2 In Tumor Microenvironment Research Articles

Oxygen Self-Supply Engineering-Ferritin for the Relief of Hypoxia in Tumors and the Enhancement of Photodynamic Therapy Efficacy.

Hypoxia is a hallmark of the tumor microenvironment (TME) that promotes tumor development and metastasis. Photodynamic therapy (PDT) is a promising strategy in the treatment of tumors, but it is limited by the lack of oxygen in TME. In this work, an O2 self-supply PDT system is constructed by co-encapsulation of chlorin e6 (Ce6) and a MnO2 core in an engineered ferritin (Ftn), generating a nanozyme promoted PDT nanoformula (Ce6/Ftn@MnO2 ) for tumor therapy. Ce6/Ftn@MnO2 exhibits a uniform small size (15.5nm) and high stability due to the inherent structure of Ftn. The fluorescence imaging and immunofluorescence analysis demonstrate the pronounced accumulation of Ce6/Ftn@MnO2 in the tumors of mice, and the treatment significantly decreases the expression of hypoxia-inducible factor (HIF)-1α. The Ce6/Ftn@MnO2 nanoplatform exerts a more potent anti-tumor efficacy with negligible damage to normal tissues compared to the treatment with free Ce6. Moreover, the weak acidity and the presence of H2 O2 in TME significantly enhances the r1 relativity of Ce6/Ftn@MnO2 , resulting in a prominent enhancement of MRI imaging in the tumor. This bio-mimic Ftn strategy not only improves the in vivo distribution and retention of Ce6, but also enhances the effectiveness and precision of PDT by TME modulation.

Unveiling the active sites on ferrihydrite with apparent catalase-like activity for potentiating radiotherapy

The use of catalase-like nanozymes in relieving tumor hypoxia has been a promising strategy for adjuvant radiotherapy, yet their catalytic mechanism and toxic potential remain elusive. While most studies on catalase-like mechanisms focus on the substrates and products in the catalytic process, little is reported to analyze the dominating surface structure for catalytic activity of nanozymes. Here, we reported the catalase-like activity of ferrihydrite and revealed its structure-activity relationship. Among the ten main forms of iron oxide nanomaterials, ferrihydrite, especially 2-line ferrihydrite, exhibited the highest catalase-like activity. Importantly, the structure-activity fitting and density functional analysis revealed that the abundant surface iron-associated hydroxyl groups dominantly affect the catalase-like activity of ferrihydrites. In addition, the ferrihydrite exhibited no peroxidase-like and superoxide dismutase-like activities, and constantly catalyzed the decomposition of H2O2 to release O2 in the pH range of 4.0–8.7. With the help of steady and single catalase-like activity in the physiological environment, ferrihydrite safely and effectively catalyzed the H2O2 in tumor microenvironment to in-situ produce O2 and significantly enhanced the therapeutic effect of radiotherapy. Moreover, ferrihydrite exhibited excellent biosafety and biodegradability. These findings demonstrate the great potential of ferrihydrite as a biocompatible catalase-like nanozyme for relieving hypoxia in cancer therapy.

Ultra-small FePt/siRNA loaded mesoporous silica nanoplatform to deplete cysteine for enhanced ferroptosis in breast tumor therapy

The upregulation of redox systems inside malignant cells provides a powerful shelter against reactive oxygen species (ROS), hampering the antitumor response of ROS-based therapy. To address this issue, we report a strategy of cysteine depletion to block redox systems and enhance ferroptosis (a ROS-induced cell-death pathway) based on a mesoporous silica nanoplatform (sSFP) coloaded with FePt nanoparticles and siRNA. Through responding to high H2O2 in tumor microenvironment, the ferroptosis agent FePt triggered tumor cell ferroptosis via Fe2+-mediated Fenton reaction. In the meanwhile, siRNA released from sSFP interfered the over-expressed system xC– (the cystine/glutamate antiporter) subunit, xCT, in tumor cells and hindered cysteine intake, resulting the disturbance of redox systems including the glutathione redox system and the thioredoxin redox system. For the overexpressed xCT protein in tumor cells and tumor selectivity of Fenton reaction, this nanoplatform provides a high selectivity for destroying tumors. The subcutaneous xenograft model of breast tumor further verified the enhanced therapeutic effect.

Titania/iron oxide nanoplatform operates as hydrogen peroxide enriched vector for amplification of fenton catalytic efficiency in cancer theranostics

The •OH induced apoptosis is a promising strategy for tumor treatment. Many current •OH generating systems are highly dependent on H2O2 in tumor microenvironment (TME). However, the H2O2 level in the TME is not high enough to produce sufficient •OH. Herein, we develop a biomimetic nano-catalyst based on TiO2/Fe3O4 platform (designed as “FTP”) to initiate a cascade of biochemical reactions to produce •OH in TME. In this platform, the modified TiO2 acting as H2O2 adsorber can promote the concentration of H2O2 around and significantly amplify Fenton reaction efficiency of Fe3O4 to induce more cell apoptosis through •OH mediated mechanism, thereby resulting in remarkable inhibition of tumor growth. The as-synthesized FTP, with diameter of 7.20 ± 1.80 nm, could efficiently accumulate in tumor via the enhanced permeability and retention (EPR) effect and act as negative T2-weighted MRI contrast agent. The results showed that the FTP could induce a significantly higher cytotoxicity profile than naked Fe3O4 nanoparticles. More specifically, the FTP exhibited significant therapeutic performance of tumors than naked Fe3O4, TiO2, and control groups.

Biocompatible nanoreactors of catalase and nanozymes for anticancer therapeutics

AbstractSignificant progress has laid the groundwork in understanding the fundamental role of catalase enzyme and catalase‐like nanozymes, notably with the emergence of nano‐bioreactors which are promoting nanomaterials‐based antitumor therapeutic strategies. The radiotherapy techniques such as photodynamic, photothermal, photoacoustic and along with chemotherapy are extensively used for interrupting microenvironment by exerting to locally applied ionizing‐radiations. Nevertheless, tumor therapy not only deficient in therapeutic efficiency for various solid tumors but also alerts significant side effects. The convergence of nano‐bioreactor driven catalase delivery at the lysosome of tumor cells with photodynamic therapy (PDT) tool along with the engineered catalase‐like nanozymes enable outstanding efficacy of radiotherapy for in vivo target specific cell population. Herein, the state of the art of catalase delivering nano‐bioreactors that activate the catalase delivery in tumor microenvironment (TME) are reviewed. This was linked with the functional mimic catalase‐like engineered nanozymes for improving the challenges in the TME for a wide‐range of cell lines in vivo. Such nanoarchitecture‐based strategies of catalase and synthetic nanozymes include lysosomal upregulation of H2O2 in TME, image‐based probing, and mechanism of catalase action for reactive oxygen species generation which are likely to amplify efficiency of cancer therapy.

Cu-MOF chemodynamic nanoplatform via modulating glutathione and H2O2 in tumor microenvironment for amplified cancer therapy

Chemodynamic therapy (CDT) utilizes Fenton catalysts to convert intracellular hydrogen peroxide (H2O2) into cytotoxic hydroxyl radical (OH∙) for tumor therapy, but endogenous H2O2 is usually insufficient to achieve satisfactory tumor therapy effect. Engineering an efficient CDT nanoplatform for satisfactory cancer therapy remains a challenge. Herein, we rationally designed a Cu-based metal-organic framework-199 (MOF-199) nanoplatform integrating vitamin k3 (Vk3) for amplified CDT-mediated cancer therapy, which could accumulate efficiently in tumor tissues through enhanced permeability and retention (EPR) effect. The MOF-199 nanoparticles (MOF-199 NPs) were dissociated by glutathione (GSH) into MOF-199 fragments, which triggered Fenton-like reaction for CDT. On the one hand, Vk3 was catalyzed by NAD(P)H quinone oxidoreductase-1 (NQO1) to produce sufficient H2O2 to activate Fenton-like reaction. On the other hand, GSH was largely consumed in the tumor microenvironment. Thus, this nanoplatform enabled sufficient cytotoxic reactive oxygen species (ROS) for amplified CDT effect, demonstrating effective tumor growth inhibition with minimal side-effect in vivo. Our work provides an innovative strategy to modulate GSH and H2O2 levels for amplified CDT.

Intelligent MoS2–CuO heterostructures with multiplexed imaging and remarkably enhanced antitumor efficacy via synergetic photothermal therapy/ chemodynamic therapy/ immunotherapy

Rational design of biocompatible nanoplatforms simultaneously realizing multimodal imaging and therapeutic functions is meaningful to cancer treatment. Herein, the MoS2–CuO heteronanocomposites are designed by integrating semiconductor CuO and flower-like MoS2 via a two-step hydrothermal method. After loading bovine serum albumin (BSA) and immunoadjuvant imiquimod (R837), the obtained MoS2–CuO@BSA/R837 (MCBR) nanoplatforms realize the excellent computed tomography/infrared thermal/magnetic resonance multi-mode bioimaging as well as significantly enhanced antitumor efficacy of synergetic photothermal therapy (PTT)/chemodynamic therapy (CDT)/immunotherapy. In this nanoplatform, the semiconductor CuO exhibits peroxidase-like activity, which can react with over-expressed H2O2 in tumor microenvironment (TME) to generate OH for CDT via Haber-Weiss and Fenton-like reactions. And this process can be further accelerated by the generated heat of MoS2 under 808 nm laser irradiation. More importantly, the obtained multifunctional MCBR nanoplatforms under near-infrared (NIR) irradiation would destroy tumor cells to generate tumor associated antigens (TAAs), which combine with R837 as an adjuvant to trigger strong antitumor immune responses for effectively eliminating primary tumors and metastatic tumors.

Catalase-like nanosystem for interlocking trimodal cancer therapy with hypoxia relief

Hypoxia is a hallmark of solid tumors, and it significantly impairs the overall anticancer efficacy, particularly photodynamic therapy (PDT). Herein, a catalase-like nanovesicle with near-infrared light-responsiveness, that is, platinum/gold nanoshell encapsulated chlorin e6 (Ce6)/resveratrol (Res) liposome (Pt@Au-Ce6/Res-Lip), was developed to surmount this intractable issue. The Pt@Au-Ce6/Res-Lip can decompose overexpressed H2O2 in tumor microenvironment to produce vast amounts of O2 for further enhancement of the PDT. Under the 808 nm laser irradiation, the Au nanoshells induced hyperthermia at the lesion site to ablate tumor cells, simultaneously inducing the controlled release of photosensitizer Ce6 and chemotherapeutic agent Res. Moreover, stimulated by 660 nm laser, numerous reactive oxygen species were formed to induce apoptosis and necrosis of tumor cells. With the cascade of trimodal therapeutic modality options (chemotherapy, photothermal therapy, and PDT), the Pt@Au-Ce6/Res-Lip showed ultrahigh tumor inhabitation rate in in vitro and in vivo studies, signifying that the Pt@Au-Ce6/Res-Lip nanovesicle is a promising candidate for effective cancer therapy.

Converting Immune Cold into Hot by Biosynthetic Functional Vesicles to Boost Systematic Antitumor Immunity.

SummaryImmune cold tumor characterized by low immunogenicity, insufficient and exhausted tumor-infiltrating lymphocytes, and immunosuppressive microenvironment is the main bottleneck responsible for low patient response rate of immune checkpoint blockade. Here, we developed biosynthetic functional vesicles (BFVs) to convert immune cold into hot through overcoming hypoxia, inducing immunogenic cell death, and immune checkpoint inhibition. The BFVs present PD1 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the surface, whereas load catalase into their inner core. The TRAIL can specifically induce immunogenic death of cancer cells to initiate immune response, which is further synergistically strengthened by blocking PD1/PDL1 checkpoint signal through ectogenic PD1 proteins on BFVs. The catalase can produce O2 to overcome tumor hypoxia, in turn to increase infiltration of effector T cells while deplete immunosuppressive cells in tumor. The BFVs elicit robust and systematic antitumor immunity, as demonstrated by significant regression of tumor growth, prevention of abscopal tumors, and excellent inhibition of lung metastasis.

A Heterojunction Structured WO2.9-WSe2 Nanoradiosensitizer Increases Local Tumor Ablation and Checkpoint Blockade Immunotherapy upon Low Radiation Dose.

Radiotherapy (RT) in practical use often suffers from off-target side effects and ineffectiveness against hypoxic tumor microenvironment (TME) as well as remote metastases. With regard to these problems, herein, we provide semiconductor heterojunction structured WO2.9-WSe2-PEG nanoparticles to realize a synergistic RT/photothermal therapy (PTT)/checkpoint blockade immunotherapy (CBT) for enhanced antitumor and antimetastatic effect. Based on the heterojunction structured nanoparticle with high Z element, the nanosystem could realize non-oxygen-dependent reactive oxygen species generation by catalyzing highly expressed H2O2 in TME upon X-ray irradiation, which could further induce immunogenic cell death. Meanwhile, this nanosystem could also induce hyperthermia upon near-infrared irradiation to enhance RT outcome. With the addition of anti-PD-L1 antibody-based CBT, our results give potent evidence that local RT/PTT upon mild temperature and low radiation dose could efficiently ablate local tumors and inhibit tumor metastasis as well as prevent tumor rechallenge. Our study provides not only one kind of radiosensitizer based on semiconductor nanoparticles but also a versatile nanoplatform for simultaneous triple-combined therapy (RT/PTT/CBT) for treating both local and metastasis tumors.

A theranostic nanocomposite with integrated black phosphorus nanosheet, Fe3O4@MnO2-doped upconversion nanoparticles and chlorin for simultaneous multimodal imaging, highly efficient photodynamic and photothermal therapy

As a novel photosensitizer for photodynamic therapy (PDT), black phosphorus (BP) has attracted increasing attention recently. However, some of its inherent drawbacks hinder its further biomedical applications. As with most conventional photosensitizers, the PDT efficiency of BP is severely limited by the hypoxia tumor microenvironment and low tissue penetration of ultraviolet/visible light. Moreover, BP also faces additional problems, such as mismatch wavelength between photothermal therapy (PTT) and PDT, as well as no imaging ability for cancer diagnosis. Herein, we addressed these challenges through the combination of Fe3O4@MnO2-doped upconversion nanoparticles (UCNPs) and black phosphorus nanosheets (BPNs). By applying polyacrylic acid (PAA) as a chemical crosslinker, polylysine (PL) modified black phosphorus nanosheets were integrated with magnetic Fe3O4@MnO2-doped NaYF4:Yb/Er/Nd upconversion nanoparticles (MUCNPs) which could convert near-infrared (NIR) light into visible light. Then, a biocompatible photosensitizer, chlorin e6 (Ce6) was attached onto the obtained [email protected] to prepare [email protected] nanocomposites. BPNs and Ce6 were exploited to activate PTT and PDT under a single irradiation light of 808 nm with strong tissue penetration ability. Meanwhile, the doped Fe3O4 and MnO2 nanoparticles could provide T1 and T2 magnetic resonance (MR) imaging, which could form a multimodal imaging system with fluorescence imaging of Ce6. In addition, MnO2 could decompose overexpressed H2O2 in tumor microenvironment to generate O2 to enhance PDT. The magnetic BPNs-based nanocomposites provided multimodal imaging (including MR, fluorescence, optoacoustic, ultrasonic imaging) and displayed dramatically enhanced ability for tumor cell death with visualized synergistic phototherapy, which greatly facilitated the application of BPNs in biomedicine.

Confined nanoparticles growth within hollow mesoporous nanoreactors for highly efficient MRI-guided photodynamic therapy

Mesoporous silica nanoparticles (MSNs) have been extensively applied as a promising carrier in biomedical application due to their excellent structure with tunable function. Based on the fact that the surfactant trimethoxyoctadecylsilane (C18TMS) could present different on/off states in different solvents, herein, an intelligent “on/off” switching strategy of site-specific co-loading MnOx and Ce6 into MSNs was proposed for the first time. The multifunctional theranostic nanoplatform, i.e., Ce6/MnOx@HMSNs-PEG (CMHP), shows a sensitive longitudinal relaxation signal to the over-expressed hydrogen peroxide (H2O2) and weak acidic pH in the tumor microenvironment (TME). Furthermore, MnOx component could react with H2O2 in TME to generate O2, which enable to relieve tumorous hypoxia and afterwards accelerate the generation of singlet oxygen (1O2) upon laser irradiation when combined with Ce6. Both in vitro and in vivo results confirm that this constructed nanosystem can be applied to MRI-guided sufficient photodynamic therapy (PDT) with reduced side-effects.

Programmable Therapeutic Nanodevices with Circular Amplification of H2 O2 in the Tumor Microenvironment for Synergistic Cancer Therapy.

Tumor microenvironment activated nanodevices have remarkable superiority to enhance therapeutic efficacy and minimize side effects, but their practical applications are dramatically reduced by the low abundance and heterogeneous distribution of specific stimuli at the tumor site. Herein, programmable vesicular nanodevices based on the triblock copolymer containing poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) with peroxalate esters (PO) as hydrogen peroxide-responsive linkage (PEG-PO-PCL-PO-PEG), are developed for co-delivery of hypoxia-activated prodrug (AQ4N) and glucose oxidase (GOD). The obtained nanodevices (PAG) can be activated by the high level of H2 O2 in tumor microenvironment to improve the permeability of membranes for glucose entrance. Afterward, the oxidation of glucose catalyzed by GOD produces amplified H2 O2 amounts which in turn induce complete destruction of PAG for fast release of AQ4N and GOD. Ultimately, the PAG can exert programmable therapeutic effects from the following aspects: 1) starvation therapy by cutting off the energy supply from glucose through GOD catalysis; 2) oxidative cytotoxicity after H2 O2 amplification; 3) chemotherapy of AQ4N activated by the intensified tumor hypoxia microenvironment after oxygen consumption. The stimuli amplification, controlled drug release, synergistic therapy, and corresponding mechanisms of PAG are demonstrated. Therefore, the presented work could provide significant new insights for cancer treatment.

Quad-Model Imaging-Guided High-Efficiency Phototherapy Based on Upconversion Nanoparticles and ZnFe2O4 Integrated Graphene Oxide.

The strategy of diagnosis-to-therapy to realize the integration of imaging and high antitumor efficiency has become the most promising method. Light-induced therapeutic technologies have drawn considerable interest. However, the limited penetration depth of UV/vis excitation and relatively low efficiency are the main obstacles for its further clinic application. For this concern, we presented a facile method to anchor ultrasmall ZnFe2O4 nanoparticles and upconversion luminescence nanoparticles (UCNPs) on graphene oxide (GO) nanosheets (GO/ZnFe2O4/UCNPs, abbreviated as GZUC). To solve the penetration question, here we introduced Tm3+-doped UCNPs to convert the high-penetrated near-infrared (NIR) light into UV/vis photons to activate the photodynamic process. In this system, the dual phototherapy from GO and ZnFe2O4 has been realized upon NIR laser irradiation. Combined with the photodynamic therapy (PDT) based on Fenton reaction that ZnFe2O4 nanoparticles react with excessive H2O2 in tumor microenvironment to produce toxic hydroxyl radicals (·OH), an excellent anticancer efficiency has been achieved. Furthermore, 4-fold imaging including upconversion luminescence (UCL), computed tomography (CT), magnetic resonance imaging (MRI) and photoacoustic tomography (PAT) has been obtained due to its intrinsic properties, thereby successfully realizing diagnosis-monitored therapy. Our demonstration provided a feasible strategy to solve the main problems in current light-triggered theranostic.