Cytotoxic Hydroxyl Research Articles

Multifunctional cascade nanocatalysts for NIR-II-synergized photonic hyperthermia-strengthened nanocatalytic therapy of epithelial and embryonal tumors

Chemodynamic therapy, which produces cytotoxic hydroxyl radicals through intratumoral Fenton reactions, has been extensively explored in nanomedicine for cancer treatment. However, the limited endogenous hydrogen peroxide (H2O2) levels, which serve as the reactant, weakens the anticancer effect of the Fenton reaction. In this work, a cascade catalytically reactive nanosystem has been constructed for the treatment of epithelial and embryonal tumors with high synergetic efficacy through the integration of natural glucose oxidase (GOD) and polyethylene glycol (PEG) onto the surface of Fe3S4 nanoplates (abbreviated as Fe3S4-PEG-GOD NPs). The GOD component consumes glucose in tumor and produces a large amount of H2O2, which provides rich substrates for the Fenton reaction catalyzed by the Fe catalytic center of the nanoplates. The intriguing photothermal conversion efficiency (45%) of the constructed composite nanocatalysts in the second near infrared (NIR-II) biowindow allows for photothermal treatment to substantially strengthen and synergize the anticancer effects of nanocatalysts both in vitro and in vivo. This synergy occurs through generation of a hyperthermic effect necessary for promoting the sequential catalytic reaction. The synergistic anticancer effect has been verified in both epithelial and embryonal tumor mouse models, and provides justification for the biomedical use of multifunctional nanocatalysts for versatile tumor nanotherapeutics.

Alleviation of the chronic stress response attributed to the antioxidant and anti-inflammatory effects of electrolyzed hydrogen water

Reactive oxygen species (ROS) are highly reactive and directly attack surrounding biomolecules to deteriorate cellular and tissue functions. Meanwhile, ROS also serve as signaling mediators to upregulate pro-inflammatory cytokine expression via activation of the nuclear factor kappa B signaling pathway, and the increased pro-inflammatory cytokines trigger respiratory burst of inflammatory cells that further accelerates ROS production in the inflamed tissue. Such crosstalk between ROS and inflammatory responses leads to a chain reaction of negativity, and cause progression of several chronic pathologies. Since molecular hydrogen is known to preferentially remove cytotoxic hydroxyl radicals and peroxynitrites, and to prevent cell and tissue damage, we here examined whether electrolyzed hydrogen water (EHW) enriched with molecular hydrogen and reactive hydrogen storing platinum nanoparticles dissolved from an electrode could alleviate oxidative stress and inflammation induced by continuous stress challenges. Five-day continuous stress loading to rats elevated reactive oxygen metabolites-derived compounds (d-ROMs), interleukin (IL)-1β, and adrenocorticotropic hormone (ACTH) levels and decreased the biological antioxidant potential (BAP) level. Drinking EHW during 5-day continuous stress loading significantly alleviated all of these changes. The results suggest that EHW could suppress stress-response-associated oxidative stress and IL-1β level elevation in vivo, and that drinking of EHW is effective for controlling stress responses via its antioxidant potential.

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.

Nanocatalytic Medicine of Iron-Based Nanocatalysts

Iron can be found in all mammalian cells and is of critical significance to diverse cellular activities within human bodies. Widespread applications and the underlying chemical and biological funda...

Biocatalysis of MnO2-Mediated Nanosystem for Enhanced Multimodal Therapy and Real-Time Tracking

Clearance of endogenous glutathione (GSH) to cytotoxic hydroxyl radicals (·OH) and insufficient cellular hydrogen peroxide (H2O2) limited the efficacy of chemodynamic therapy (CDT) to tumor. Herein...

Enhanced cancer therapy by hypoxia-responsive copper metal-organic frameworks nanosystem

Tumor hypoxia-responsive size-switchable nanosystems for precise delivery of drug into deep tumor show great prospects for killing cancer cells with high specificity and minimal invasiveness. However, the development of versatile nanosystems is still a challenge. Herein, for the first time, we report a novel hypoxia-responsive copper metal-organic framework nanoparticles (Cu-MOF NPs) for chemodynamic therapy and sonodynamic therapy (CDT/SDT). The large size Cu-MOF NPs show good stability under normal oxygen partial pressure and enhance tumor accumulation, and it quickly degraded and released Cu2+ and Ce6 when exposed to the hypoxic tumor microenvironment (TME), significantly reinforced the intratumoral penetration. The internalized Cu2+ reacts with local GSH to deplete GSH and reduce Cu2+ to Cu+, which subsequently reacts with endogenous H2O2 to produce cytotoxic hydroxyl radicals (•OH) through Fenton-like reaction for CDT. The released Ce6 further mediated SDT under US irradiation. The synergistic SDT/CDT efficacy was significantly enhanced owing to the GSH depletion, realizing selective and effective MCF-7 killing with minimal invasiveness. This work presents a novel hypoxia-responsive MOF nanosystem with intrinsic CDT properties, mainly, the MOF nanosystem is flexible to the integration with other therapy approaches. It provides a general strategy to design a hypoxia-responsive MOF nano theranostic platform.

MoS2-ALG-Fe/GOx hydrogel with Fenton catalytic activity for combined cancer photothermal, starvation, and chemodynamic therapy

Starvation therapy (ST) and chemodynamic therapy (CDT) are emerging tumor therapy methods in recent years. In this study, a simple approach was reported to prepare MoS2 and glucose oxidase (GOx)-containing sodium alginate (ALG)-Fe3+ (MAF) hydrogel. In the hydrogel, there exists an enzymatic reaction to consume glucose to form hydrogen peroxide (H2O2), and a redox reaction between Fe3+ and MoS2 to form Fe2+ and MoO42−. The formed Fe2+ could be oxidized to Fe3+, which reacts with MAF hydrogel again to continuously produce Fe2+. The consumption of glucose resulted in an obvious tumor ST. Moreover, the produced Fe2+ induced a Fenton reaction to enable the persistent conversion of H2O2 to cytotoxic hydroxyl radicals (·OH) for the CDT of tumors. Together with the high photothermal transforming capability of MoS2, the hydrogel was used for the combined tumor photothermal therapy (PTT), ST, and CDT. This work provides a window for the safe use of enzymes for achieving high tumor therapeutic efficacy.

Hollow NiAl(OH)x Nanocapsules to Enable Effective Glucose Oxidase Delivery and Synergistic Therapy.

Cellular starvation induced by glucose oxidase (GOx) had been extensively explored as a potential approach for tumor therapy. However, the therapeutic efficacy suffers daunting challenges due to the unsatisfactory intracellular transportation of GOx molecules. Herein for the first time, hydroxide nanoparticles with unique hollow microstructure (denoted as H-NiAl(OH)x) were designed and synthesized for GOx delivery. In this system, despite its intrinsic degradation properties in acidic tumor microenvironment, Ni2+ ions released during degradation may catalyze a Fenton reaction to induce considerable production of cytotoxic hydroxyl radicals (OH). The cavity of hollow nanocapsules provides large surface area, and favors GOx capsulation and delivery. The findings indicate the intracellular glucose can be effectively consumed by GOx transported, and the reaction products consisting of acid and H₂O₂ facilitate the OH induction of nanocapsules in a synergistic manner. Both in vitro and in vivo antitumor properties have been consequently achieved by H-NiAl(OH)x/GOx systems. This study offering catalytic nanocapsules based on Ni2+ ions may spark a series of follow-on explorations in constructing drug delivery and therapeutic systems for synergistic tumor treatment.

Integration of Fe3O4 with Bi2S3 for Multi-Modality Tumor Theranostics.

The combination of reactive oxygen species (ROS)-induced chemodynamic therapy (CDT) and photothermal therapy (PTT) holds a promising application prospect for their superb anticancer efficiency. Herein, we created a novel Fe3O4@polydopamine (PDA)@bovine serum albumin (BSA)-Bi2S3 composite as a theranostic agent, by chemically linking the Fe3O4@PDA with BSA-Bi2S3 via the amidation between the carboxyl groups of BSA and the amino groups of PDA. In this formulation, the Fe3O4 NPs could not only work as a mimetic peroxidase to trigger Fenton reactions of the innate H2O2 in the tumor and generate highly cytotoxic hydroxyl radicals (•OH) to induce tumor apoptosis but also serve as the magnetic resonance imaging (MRI) contrast agent to afford the precise cancer diagnosis. Meanwhile, the PDA could prevent the oxidization of Fe3O4, thus supporting the long-term Fenton reactions and the tumor apoptosis in the tumor. The Bi2S3 component exhibits excellent photothermal transducing performance and computed tomography (CT) imaging capacity. In addition, the PDA and Bi2S3 endow the Fe3O4@PDA@BSA-Bi2S3 composite with an excellent photothermal transforming ability whichcould lead to tumor hyperthermia. All of these merits play the synergism with the tumor microenvironment and qualify the Fe3O4@PDA@BSA-Bi2S3 NPs for a competent agent in the MRI/CT-monitored enhanced PTT/CDT synergistic therapy. Findings in this research will evoke new interests in future cancer therapeutic strategies based on biocompatible nanomaterials.

H2O2‐Responsive Nanogel for Enhancing Chemodynamic Therapy

AbstractAs a typical chemodynamic therapy (CDT), the Fenton reaction holds great promise in cancer therapy for its effective generation of the cytotoxic hydroxyl radical (.OH) in situ which induces cancer cell apoptosis. However, the tumor microenvironment is insufficient to meet the optimal conditions for Fenton reaction, which greatly reduces the rate of Fenton reaction and the therapeutic effect of CDT, thereby hindering its application in cancer therapy. Herein, a novel biocompatible nanogel comprised of ferroferric oxide modified β‐cyclodextrin (Fe3O4@β‐CD), glucose oxidase (GOX), and ferrocene (Fc) was fabricated using the host‐guest self‐assembly method for synergistic tumor therapy (Fe3O4−GOX nanogel, FGgel). In the tumor microenvironment, the intratumoral hydrogen peroxide (H2O2) could oxidize Fc, leading to the disintegration of the FGgel and the release of GOX. Subsequently, the released GOX could catalyze glucose to produce gluconic acid and promote the production of H2O2. Meanwhile, in acidic conditions, F3O4 served as the Fenton reagent to convert excessive H2O2 into highly toxic .OH which finally induces tumor cell apoptosis. Extensive in vitro and in vivo studies have confirmed that FGgel can effectively inhibit tumor cell growth with high tumor specificity and good biocompatibility. The excellent anticancer efficiency of FGgel indicates that it is an ideal H2O2‐activated nanosystem. As an excellent platform to harness the highly toxic reactive oxygen species in nanomedicine for specific cancer therapy, this strategy may open new doors for further development of progressive therapeutic systems.

Stimuli-activatable nanomedicines for chemodynamic therapy of cancer.

Chemodynamic therapy (CDT) takes the advantages of Fenton-type reactions triggered by endogenous chemical energy to generate highly cytotoxic hydroxyl radicals. As a novel modality for cancer treatment, CDT shows minimal invasiveness and high tumor specificity by responding to the acidic and the highly concentrated hydrogen peroxide microenvironment of tumor. The CDT approach for spatiotemporal controllable reactive oxygen species generation exhibits preferable therapeutic performance and satisfying biosafety. In this review article, we summarized the recent advances of stimuli-activatable nanomedicines for CDT. We also overviewed the strategies for augmenting CDT performance, including increasing the catalytic efficacy through rational design of the nanomaterials, modulating the reaction condition, inputting external energy field, and regulating the tumor microenvironment. Furthermore, we discussed the potential and challenges of stimuli-activatable nanomedicine for clinical translation and future development of CDT. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

A simultaneously GSH-depleted bimetallic Cu(ii) complex for enhanced chemodynamic cancer therapy.

A bimetallic Cu(ii) complex as a novel antitumor chemodynamic therapy agent with glutathione (GSH) depletion properties is successfully synthesized and well characterized. In tumor cells, the Cu2+ ions of the complex are reduced to Cu+ ions by GSH and then catalyzed by the overexpressed H2O2 to generate highly cytotoxic hydroxyl radicals (˙OH) that kill cancer cells. The complex is quickly taken up by cancer cells and distributed in multiple organelles including mitochondria and the nucleus. The complex demonstrates good cytotoxicity toward various cancer cell lines. However, its toxicity toward normal cells is significantly lower than that toward cancer cells due to the limited expression of H2O2. In addition, the complex could arrest the cell cycle of the G0/G1 phase, thereby inducing apoptosis rather than necrosis.

Dual Fenton Catalytic Nanoreactor for Integrative Type-I and Type-II Photodynamic Therapy Against Hypoxic Cancer Cells.

Tumor hypoxia is a noteworthy impediment to effective photodynamic therapy (PDT), as it would sharply weaken the effectiveness of oxygen-dependent PDT. To enable effective PDT in both hypoxia as well as normoxia circumstances, here, we report a multifunctional nanoreactor (C3N4/MnO2 NPs), which guarantees effective type-II PDT (oxygen-dependent) in hypoxia by in situ oxygen generation via the Fenton reaction. In addition, the C3N4/MnO2 NPs can also be used for oxygen-independent type-I PDT by evolving the cytotoxic hydroxyl radical to reduce reliance on intracellular oxygen content. In vitro cytotoxicity assays made evident that the C3N4/MnO2 NPs exhibit a much higher cancer-cell-killing ability than C3N4 NPs not only in normoxia but also in hypoxic circumstances. The smart integration of type-I and type-II PDT into the therapeutic nanoplatform enables effective PDT even though intracellular oxygen is not satisfactory.

A Short Peptide Derived from the ZorO Toxin Functions as an Effective Antimicrobial.

Antimicrobial peptides are potential molecules for the development of novel antibiotic agents. The ZorO toxin of a type I toxin–antitoxin system in Escherichia coli O157:H7 is composed of 29 amino acids and its endogenous expression inhibits E. coli growth. However, little is known about its inhibitory mechanism. In this study, we demonstrate that the ZorO localized in the inner membrane affects the plasma membrane integrity and potential when expressed in E. coli cells, which triggers the production of cytotoxic hydroxyl radicals. We further show that five internal amino acids (Ala–Leu–Leu–Arg–Leu; ALLRL) of ZorO are necessary for its toxicity. This result prompted us to address the potential of the synthetic ALLRL peptide as an antimicrobial. Exogenously-added ALLRL peptide to Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and a fungus, Candida albicans, trigger cell membrane damage and exhibit growth defect, while having no effect on Gram-negative bacterium, E. coli. The ALLRL peptide retains its activity under the physiological salt concentrations, which is in contrast to natural antimicrobial peptides. Importantly, this peptide has no toxicity against mammalian cells. Taken together, an effective and short peptide, ALLRL, would be an attractive antimicrobial to Gram-positive bacteria and C. albicans.

Synergistic Amplification of Oxidative Stress-Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF-Fe2.

Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal-organic framework (MOF)-Fe2+ (MD@Lip) has been developed, which can efficiently stimulate ROS-mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF-Fe2+ , but also generate an acidic microenvironment to activate a MOF-Fe2+ -based Fenton reaction. Importantly, MD@Lip promotes DCA-mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H2 O2 ), which can be consequently converted to highly cytotoxic hydroxyl radicals (•OH) via MOF-Fe2+ , leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome-based combination therapy of DCA and MOF-Fe2+ provides a promising oxidative stress-associated antitumor strategy for the management of malignant tumors.

Platinum Nanoparticles to Enable Electrodynamic Therapy for Effective Cancer Treatment

Electrochemical therapy (EChT), by inserting electrodes directly into tumors to kill cancer cells under direct current (DC), is clinically used in several countries. In EChT, the drastic pH variation nearby the inserted electrodes is the main cause of tumor damage. However, its limited effective area and complex electrode configuration have hindered the clinical application of EChT in treating diverse tumor types. Herein, a conceptually new electric cancer treatment approach is presented through an electro-driven catalytic reaction with platinum nanoparticles (PtNPs) under a square-wave alternating current (AC). The electric current triggers a reaction between water molecules and chloride ions on the surface of the PtNPs, generating cytotoxic hydroxyl radicals. Such a mechanism, called electrodynamic therapy (EDT), enables effective killing of cancer cells within the whole electric field, in contrast to EChT, which is limited to areas nearby electrodes. Remarkable tumor destruction efficacy is further demonstrated in this in vivo EDT treatment with PtNPs. Therefore, this study presents a new type of cancer therapy strategy with a tumor-killing mechanism different from existing methods, using nanoparticles with electrocatalytic functions. This EDT method appears to be minimally invasive, and is able to offer homogeneous killing effects to the entire tumor with a relatively large size.

Amplification of Tumor Oxidative Stresses with Liposomal Fenton Catalyst and Glutathione Inhibitor for Enhanced Cancer Chemotherapy and Radiotherapy.

Amplification of intracellular oxidative stress has been found to be an effective strategy to induce cancer cell death. To this end, we prepare a unique type of ultrasmall gallic acid-ferrous (GA-Fe(II)) nanocomplexes as the catalyst of Fenton reaction to enable persistent conversion of H2O2 to highly cytotoxic hydroxyl radicals (•OH). Then, both GA-Fe(II) and l-buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, are coencapsulated within a stealth liposomal nanocarrier. Interestingly, the obtained BSO/GA-Fe(II)@liposome is able to efficiently amplify intracellular oxidative stress via increasing •OH generation and reducing GSH biosynthesis. After chelating with 99mTc4+ radioisotope, such BSO/GA-Fe(II)@liposome could be tracked under in vivo single-photon-emission-computed-tomography (SPECT) imaging, which illustrates the time-dependent tumor homing of such liposomal nanoparticles after intravenous injection. With GA-Fe(II)-mediated •OH production and BSO-mediated GSH depletion, treatment with such BSO/GA-Fe(II)@liposome would lead to dramatically enhanced intratumoral oxidative stresses, which then result in remarkably improved therapeutic efficacies of concurrently applied chemotherapy or radiotherapy. This work thus presents the concise fabrication of biocompatible BSO/GA-Fe(II)@liposome as an effective adjuvant nanomedicine to promote clinically used conventional cancer chemotherapy and radiotherapy, by greatly amplifying the intratumoral oxidative stress.

Fe3O4@MIL-100(Fe)-UCNPs heterojunction photosensitizer: Rational design and application in near infrared light mediated hypoxic tumor therapy

Currently, photodynamic therapy (PDT) has been greatly restricted by the tumor hypoxia. To overcome this problem, here, we designed a novel nanoplatform, Fe3O4@MIL-100(Fe)-UCNPs (abbreviated as FMU), in which UCNPs were acted as energy transducers to transfer NIR-UV/vis light to the heterojunction photosensitizer Fe3O4@MIL-100(Fe) (abbreviated as FM), producing cytotoxic hydroxyl radicals (OH) with a high tumor cell oxidation capability independent of tumor oxygen. In particular, the recombination of electrons and holes has been markedly inhibited due to the formation of heterojunctions in the interfaces between MIL-100(Fe) and Fe3O4 nanoparticles, thus greatly enhancing the capability for OH production. Meanwhile, the Fe3+/Fe2+ ions were used to provide the photochemotherapy (PCT) effect based on the photo-Fenton reaction, thereby achieving combined PDT and PCT synergistic therapy. The outstanding antitumor efficiency was verified by in vivo and in vitro assays, and it was shown that the therapeutic process can be monitored by computed tomography (CT) and upconversion luminescence (UCL) imaging, suggesting that the resultant nanoplatform has potential for use in imaging-guided cancer therapy.

Nano-Fenton Reactors as a New Class of Oxidative Stress Amplifying Anticancer Therapeutic Agents.

Cancer cells, compared to normal cells, are under oxidative stress associated with an elevated level of reactive oxygen species (ROS) and are more vulnerable to oxidative stress induced by ROS generating agents. Thus, manipulation of the ROS level provides a logical approach to kill cancer cells preferentially, without significant toxicity to normal cells, and great efforts have been dedicated to the development of strategies to induce cytotoxic oxidative stress for cancer treatment. Fenton reaction is an important biological reaction in which irons convert hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals that escalate ROS stress. Here, we report Fenton reaction-performing polymer (PolyCAFe) micelles as a new class of ROS-manipulating anticancer therapeutic agents. Amphiphilic PolyCAFe incorporates H2O2-generating benzoyloxycinnamaldehyde and iron-containing compounds in its backbone and self-assembles to form micelles that serve as Nano-Fenton reactors to generate cytotoxic hydroxyl radicals, killing cancer cells preferentially. When intravenously injected, PolyCAFe micelles could accumulate in tumors preferentially to remarkably suppress tumor growth, without toxicity to normal tissues. This study demonstrates the tremendous translatable potential of Nano-Fenton reactors as a new class of anticancer drugs.

Formation of hydroxyl radicals contributes to the bactericidal activity of ciprofloxacin againstPseudomonas aeruginosabiofilms

Antibiotic-tolerant, biofilm-forming Pseudomonas aeruginosa has long been recognized as a major cause of chronic lung infections of cystic fibrosis patients. The mechanisms involved in the activity of antibiotics on biofilm are not completely clear. We have investigated whether the proposed induction of cytotoxic hydroxyl radicals (OH˙) during antibiotic treatment of planktonically grown cells may contribute to action of the commonly used antibiotic ciprofloxacin on P. aeruginosa biofilms. For this purpose, WT PAO1, a catalase deficient ΔkatA and a ciprofloxacin resistant mutant of PAO1 (gyrA), were grown as biofilms in microtiter plates and treated with ciprofloxacin. Formation of OH˙ and total amount of reactive oxygen species (ROS) was measured and viability was estimated. Formation of OH˙ and total ROS in PAO1 biofilms treated with ciprofloxacin was shown but higher levels were measured in ΔkatA biofilms, and no ROS production was seen in the gyrA biofilms. Treatment with ciprofloxacin decreased the viability of PAO1 and ΔkatA biofilms but not of gyrA biofilms. Addition of thiourea, a OH˙ scavenger, decreased the OH˙ levels and killing of PAO1 biofilm. Our study shows that OH˙ is produced by P. aeruginosa biofilms treated with ciprofloxacin, which may contribute to the killing of biofilm subpopulations.