Chemodynamic Therapy Agents Research Articles

X-ray-triggered fenton-like nanocomposites for passive-activation and non-spontaneous chemodynamic therapy

Currently, many studies focused on the TME-regulating strategies to address the unsatisfactory therapeutic effect of single chemodynamic therapy (CDT). However, most of TME-regulating strategies were nonspecific, the CDT agents with spontaneous CDT activity would result in augmented killing effect not only in tumor but also in normal tissues. Furthermore, CDT efficiency was subject to attenuation due to the gradually exhausted active sites in CDT agents. Herein, the passive-activation and non-spontaneous CDT strategy was proposed by constructing a completely X-ray-triggered CDT agent (F-SCNPs) to target the therapeutic dilemma between the augmented CDT efficacy and high tumor specificity. In this study, the designed F-SCNPs can launch Fe2+ sites generation to initiate CDT activity only when they were exposed to X-ray, which were totally different from the traditional CDT agents including other stimuli-responsive CDT agents that always spontaneously exert CDT activity no matter they had accepted the stimuli or not. The X-ray-activated feature of F-SCNPs endowed their tumor specificity with less affect by nonspecific TME-regulating strategies. Meanwhile, X-ray can promote the Fe2+/Fe3+ cycling of F-SCNPs to enhance the •OH yield. This X-ray-mediated nanosystem with remarkable synergistic therapy of CDT and radiotherapy provided a promising avenue for high-efficiency and precise cancer treatments.

Proton nanomodulators for enhanced Mn2+-mediated chemodynamic therapy of tumors via HCO3− regulation

BackgroundMn2+-mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO3− level in the system. Although the physiological buffers (H2CO3/HCO3−) provide certain amounts of HCO3−, the acidity of the tumor microenvironment (TME) would seriously affect the HCO3− ionic equilibrium (H2CO3 ⇌ H+ + HCO3−). As a result, HCO3− level in the tumor region is actually insufficient to support effective Mn2+-mediated CDT.ResultsIn this study, a robust nanomodulator MnFe2O4@ZIF-8 (PrSMZ) with the capability of in situ self-regulation HCO3− is presented to enhance therapeutic efficacy of Mn2+-mediated CDT. Under an acidic tumor microenvironment, PrSMZ could act as a proton sponge to shift the HCO3− ionic equilibrium to the positive direction, significantly boosting the generation of the HCO3−. Most importantly, such HCO3− supply capacity of PrSMZ could be finely modulated by its ZIF-8 shell thickness, resulting in a 1000-fold increase in reactive oxygen species (ROS) generation. Enhanced ROS-dependent CDT efficacy is further amplified by a glutathione (GSH)-depletion ability and the photothermal effect inherited from the inner core MnFe2O4 of PrSMZ to exert the remarkable antitumor effect on mouse models.ConclusionsThis work addresses the challenge of insufficient HCO3− in the TME for Mn2+-mediated Fenton catalysts and could provide a promising strategy for designing high-performance Mn2+-mediated CDT agents to treat cancer effectively.

A novel tetrahedral framework nucleic acid-derived chemodynamic therapy agent for effective glioblastoma treatment.

Chemodynamic therapy (CDT) has garnered significant attention for treating diverse malignant tumours due to its minimally invasive nature, reduced damage to healthy tissues, and potential mitigation of side effects. However, its application in glioblastoma (GBM) is hindered by the diminished capacity of CDT agents to traverse the blood-brain barrier (BBB), inadequate tumour targeting efficiency, and restricted availability of H2O2 within the tumour microenvironment (TME). To address these challenges, we devised a novel CDT agent (Fe@tFNAs-ANG-3AT) based on a tetrahedral framework nucleic acids (tFNAs). Fe@tFNAs-ANG-3AT was constructed by anchoring iron ions (Fe3+) onto the dual appendages-modified tFNAs. Specifically, one appendage, Angiopep-2 (ANG, a penetrating peptide), facilitates Fe@tFNAs-ANG-3AT penetration across the BBB and selective targeting of tumour cells. Simultaneously, the second appendage, 3-Amino-1,2,4-triazole (3AT, a H2O2 enzyme inhibitor), augments the H2O2 levels required for effective CDT treatment. Upon tumour cell internalization, the loaded Fe3+ in Fe@tFNAs-ANG-3AT is reduced to Fe2+ by the overexpressed glutathione (GSH) in the TME, catalysing the generation of cytotoxic hydroxyl radicals (·OH) and inducing tumour cell death via elevated oxidative stress levels within tumour cells. It is anticipated that Fe@tFNAs-ANG-3AT holds promise as a transformative treatment strategy for GBM.

Cascade catalyzed dual-responsive Gold-Ferri “bomb-like” nanoreactors for positive feedback penetrating in sequential targeted triple glioblastoma therapy

Glioblastoma (GBM) is the most common malignant primary brain tumor, with an overall median survival of less than two years after resection. The urgent goal in pre-clinical investigations is to develop effective therapeutic strategies to prolong the GBM patients’ survival and improve the poor prognosis. Although various inorganic nanoplatforms have been applied in GBM treatment, they still face obstacles such as poor brain targeting, low tumor effective penetration, and serious monotherapy resistance. Here, we designed an environmental-dependent tumor-killing nanoreactor (RFcAD) with a gold-ferri nanoagglomerates form structure that effectively inhibits GBM proliferation via catalyzing reactive oxygen species (ROS) generation, exhausting glucose, and NIR-based photothermal therapy. With iRGD decoration, RFcAD can effectively penetrate the blood–brain barrier and target GBM. The “bomb-like” structured RFcAD exhibited a glutathione (GSH)-responsive release of toxicity agent DM1 and pH-dependent nanoagglomerates degradation with gold particles and superparamagnetic iron oxide nanoparticles (SPIONS) release. Gold particles and SPIONS destroy GBM cells as chemodynamic therapy agents via exhibiting a glucose oxidase (GOx)-like and peroxide (POx)-like catalytic ability to generate cytotoxic ROS and exhaust intracellular glucose, respectively. Synergistic with DM1-based chemotherapy and NIR-induced photothermal therapy, RFcAD can significantly reduce GBM proliferation both in vitro and in vivo. This work highlights that the RFcAD nanoreactor can benefit GBM inhibition by improving tumor targeting, tissue penetration, and cytotoxicity.

Antitumor Therapy through Photothermal Performance Synergized with Catalytic Activity Based on the Boron Cluster Supramolecular Frameworks.

Chemodynamic therapy (CDT) has received widespread attention as a tumor optical treatment strategy in the field of malignant tumor therapy. Nonmetallic multifunctional nanomaterials as CDT agents, due to their low toxicity, long-lasting effects, and safety characteristics, have promising applications in the integrated diagnosis and treatment of cancer. Here, we modified the supramolecular framework of boron clusters, coupled with a variety of dyes to develop a series of metal-free agent compounds, and demonstrated that these nonmetallic compounds have excellent CDT activities through experiments. Subsequently, the best performing Methylene Blue/[closo-B12H12]2- (MB@B12H12) was used as an example. Through theoretical calculations, electron paramagnetic resonance spectroscopy, and 808 nm light irradiation, we confirmed that MB@B12H12 exhibited photothermal performance and CDT activity further. More importantly, we applied MB@B12H12 to melanoma cells and subcutaneous tumor, demonstrating its effective suppression of melanoma growth in vitro and in vivo through the synergistic effects of photothermal performance and CDT activity. This study emphasizes the generalizability of the coupling of dyes to [closo-B12H12]2- with important clinical translational potential for CDT reagents. Among them, MB@B12H12 may have a brighter future, paving the way for the rapid development of metal-free CDT reagents.

Bimetallic DNAsome Decorated with G4-DNA as a Nanozyme for Targeted and Enhanced Chemo/Chemodynamic Cancer Therapy.

Cancer is indisputably one of the major threats to mankind, and hence the design of new approaches for the improvement of existing therapeutic strategies is always wanted. Herein, the design of a tumor microenvironment-responsive, DNA-based chemodynamic therapy (CDT) nanoagent with dual Fenton reaction centers for targeted cancer therapy is reported. Self-assembly of DNA amphiphile containing copper complex as the hydrophobic Fenton reaction center results in the formation of CDT-active DNAsome with Cu2+-based Fenton catalytic site as the hydrophobic core and hydrophilic ssDNA protrude on the surface. DNA-based surface addressability of the DNAsome is then used for the integration of second Fenton reaction center, which is a peroxidase-mimicking DNAzyme noncovalently loaded with Hemin and Doxorubicin, via DNA hybridization to give a CDT agent having dual Fenton reaction centers. Targeted internalization of the CDT nanoagent and selective generation of •OH inside HeLa cell are also shown. Excellent therapeutic efficiency is observed for the CDT nanoagent both in vitro and in vivo, and the enhanced efficacy is attributed to the combined and synergetic action of CDT and chemotherapy.

Electron Orbital Hybridization‐Enhanced Copper‐Nanocatalysis for Anti‐Infection

AbstractRecurrent bacterial infections, impenetrable microbial biofilms, and irremediable antibiotic resistance are the most perilous threats in orthopedic implant‐associated infections (IAIs). Recently, chemodynamic therapy (CDT) has been considered a promising therapy, while the clinical practices for existing CDT agents are limited by the low therapeutic efficiency in physiological circumstances. Herein, it is demonstrated that silica‐copper nanosheets (Si@Cu NSs) exhibit a combined therapeutic photothermal‐chemodynamic strategy for IAIs treatment with superior capacity and biocompatibility. This unique design endows the nanostructure with enhanced copper‐based Fenton‐like properties via p‐d orbital hybridization by incorporating copper nanoclusters (Cu NCs) on silicene nanosheets (Si NSs) matrix, integrating inherent photothermal performance of Si NSs with specific catalytic anti‐infection of Cu NCs against planktonic bacteria and biofilms both in vitro and in vivo. This study not only reveals the promising bio‐application prospects of 2D nanocatalytic biomaterials but also demonstrates the feasibility of constructing novel CDT agents by orbital hybridization for the catalytic treatment of IAIs.

Redox‐Active Ferrocene Quencher‐Based Supramolecular Nanomedicine for NIR‐II Fluorescence‐Monitored Chemodynamic Therapy

AbstractReal‐time monitoring of hydroxyl radical (⋅OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although ⋅OH probe‐integrated CDT agents can track ⋅OH production by themselves, they often require complicated synthetic procedures and suffer from self‐consumption of ⋅OH. Here, we report the facile fabrication of a self‐monitored chemodynamic agent (denoted as Fc‐CD‐AuNCs) by incorporating ferrocene (Fc) into β‐cyclodextrin (CD)‐functionalized gold nanoclusters (AuNCs) via host–guest molecular recognition. The water‐soluble CD served not only as a capping agent to protect AuNCs but also as a macrocyclic host to encapsulate and solubilize hydrophobic Fc guest with high Fenton reactivity for in vivo CDT applications. Importantly, the encapsulated Fc inside CD possessed strong electron‐donating ability to effectively quench the second near‐infrared (NIR‐II) fluorescence of AuNCs through photoinduced electron transfer. After internalization of Fc‐CD‐AuNCs by cancer cells, Fenton reaction between redox‐active Fc quencher and endogenous hydrogen peroxide (H2O2) caused Fc oxidation and subsequent NIR‐II fluorescence recovery, which was accompanied by the formation of cytotoxic ⋅OH and therefore allowed Fc‐CD‐AuNCs to in situ self‐report ⋅OH generation without undesired ⋅OH consumption. Such a NIR‐II fluorescence‐monitored CDT enabled the use of renal‐clearable Fc‐CD‐AuNCs for efficient tumor growth inhibition with minimal side effects in vivo.

Redox-Active Ferrocene Quencher-Based Supramolecular Nanomedicine for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Real-time monitoring of hydroxyl radical (⋅OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although ⋅OH probe-integrated CDT agents can track ⋅OH production by themselves, they often require complicated synthetic procedures and suffer from self-consumption of ⋅OH. Here, we report the facile fabrication of a self-monitored chemodynamic agent (denoted as Fc-CD-AuNCs) by incorporating ferrocene (Fc) into β-cyclodextrin (CD)-functionalized gold nanoclusters (AuNCs) via host-guest molecular recognition. The water-soluble CD served not only as a capping agent to protect AuNCs but also as a macrocyclic host to encapsulate and solubilize hydrophobic Fc guest with high Fenton reactivity for in vivo CDT applications. Importantly, the encapsulated Fc inside CD possessed strong electron-donating ability to effectively quench the second near-infrared (NIR-II) fluorescence of AuNCs through photoinduced electron transfer. After internalization of Fc-CD-AuNCs by cancer cells, Fenton reaction between redox-active Fc quencher and endogenous hydrogen peroxide (H2 O2 ) caused Fc oxidation and subsequent NIR-II fluorescence recovery, which was accompanied by the formation of cytotoxic ⋅OH and therefore allowed Fc-CD-AuNCs to in situ self-report ⋅OH generation without undesired ⋅OH consumption. Such a NIR-II fluorescence-monitored CDT enabled the use of renal-clearable Fc-CD-AuNCs for efficient tumor growth inhibition with minimal side effects in vivo.

Discovery of mitochondrion-targeting copper(II)-plumbagin and -bipyridine complexes as chemodynamic therapy agents with enhanced antitumor activity.

Four copper(II)-plumbagin and -bipyridine complexes (Cu1-Cu4) were synthesized as chemodynamic therapy agents with enhanced antitumor activity. As lipophilic and positively charged compounds, Cu1-Cu4 were preferentially accumulated in mitochondria and activated the mitochondrial apoptosis pathway. Mechanistic studies showed that Cu1-Cu4 reacted with GSH to reduce Cu2+ ions to Cu+ ions, catalyzed the formation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H2O2) through a Fenton-like reaction, induced mitochondrial dysfunction, and activated caspase-9/3, which eventually led to apoptosis. Cu1-Cu4 arrested HeLa cells in the S phase and eventually killed cancer cells. Cu2 showed a favorable pharmacokinetic profile in mice. Moreover, Cu2 effectively inhibited the growth of HeLa xenografts in nude mice and showed low toxicity in vivo.

Fe-doped nanodiamond-based photo-Fenton catalyst for dual-modal fluorescence imaging and improved chemotherapeutic efficacy against tumor hypoxia.

The deficiency of oxygen in most solid tumors plays a profound role in their proliferation, metastasis, and invasion and contributes to their resistance to treatments such as radiation, chemotherapy, and photodynamic therapy (PDT). A therapeutic approach based on the Fenton reaction has received considerable interest as a means of treating cancer with ROS-based nano catalytic medicine, referred to as chemodynamic therapy (CDT). A range of modified treatment strategies are being explored to enhance both CDT and conventional methods of therapy. These include Fenton-like reactions, photo-enhanced Fenton reactions, and Fenton catalytic-enhanced synergistic therapies. In this article, we propose and demonstrate a photochemotherapy (PCT) strategy for cancer treatment utilizing near-infrared (NIR)-induced Fenton reactions using Fe-doped nanodiamond (FeND). When FeND is exposed to human lung cancer cells A549, it exhibits outstanding biocompatibility. However, when particle-treated cells are exposed to NIR laser radiation, the particle exhibits cytotoxicity to a certain degree. The anticancer medication doxorubicin (DOX) was adsorbed onto the FeND to address this issue. The conjugated DOX could undergo a redox cycle to generate excess H2O2 inside the cells, and in addition, DOX can also cause tumor cell apoptosis. Combining chemotherapy (via DOX) with a Fenton reaction results in enhanced therapeutic effectiveness. Moreover, the intrinsic fluorescence of the nanodiamond in FeND can be used to monitor the interaction of particles with cells as well as their localization, thus making it an excellent imaging probe. In our study, we found that FeND could serve as a CDT agent, biomarker, drug carrier, and potentially valuable candidate for CDT agents and contribute to the further development of more effective CDT platforms using nanodiamond.

Delivery of Cu(II) and Mn(II) by polydopamine-modified nanoparticles for combined photothermal and chemotherapy.

Chemodynamic therapy (CDT) has been recognized as an emerging therapeutic strategy. It has attracted considerable attention in recent years as it can generate the most harmful reactive oxygen species (ROS)-hydroxyl radicals (•OH) through the Fenton reaction or a Fenton-like reaction under the catalysis of versatile metal cations, such as, Fe(II), Fe(III), Cu(I), Mn(II), and Mn(III). However, a large number of reducing species (e.g., GSH) in tumors inhibit the therapeutic effects of CDT. This study proposes a nanocarrier strategy that can release versatile metal cations in the initial stage to consume the reducing substances, which can be convenient for subsequent CDT treatment. A novel nano-delivery system based on H-MnO2@PDA/Cu-CD@Ad-TK-Ad@Ploy-CD (abbreviated as MNZ) was proposed to resolve the above problems. Herein, hollow mesoporous manganese dioxide nanoparticles (H-MnO2) were coated with PDA and modified with copper ions on the surface of PDA. The PDA was then functionalized with β-cyclodextrin (β-CD) substitutions that were further assembled with N-((1S,3R,5S)-adamantan-1-yl)-3-((2-((3-(((3s,5s,7s)-adamantan-1-yl)amino)-3-oxopropyl)thio)propan-2-yl)thio)propenamide (Ad-TK-Ad). Poly-CD was assembled with CD to improve the stability of the reactor. The MNZ nanotheranostic platform can release Cu(II) and Mn(II), which could react with intracellular GSH to consume the reducing substances in tumors. Subsequently, H2O2 can be converted into •OH, and the effect is improved with increasing temperatures. Cytotoxicity of MNZ (200 μg mL-1) was studied by cell counting kit-8 (CCK-8) assay using HeLa cells as the models. Results indicated that cell viability was clearly reduced to 22% by the nanoparticles alone, to 18% by the nanoparticles with H2O2, and to 9% by the nanoparticles with H2O2 and NIR, under weak acidic condition (pH 6.8). This work provides a beneficial exploration for the application of nano-delivery strategies for combined photothermal and chemodynamic therapy agents.

Engineering polyvinyl alcohol microspheres with capability for use in photothermal/chemodynamic therapy for enhanced transarterial chemoembolization.

Transarterial chemoembolization (TACE) is widely recognized as a non-surgical treatment approach for advanced liver cancer, combining chemotherapy with the blockage of blood vessels supplying the tumor. To enhance the efficacy of TACE and address chemotherapy resistance, there is growing interest in the development of multifunctional embolic microspheres. In this study, multifunctional PVA microspheres, which encapsulate MIT as a chemotherapeutic drug, PPY as a photothermal agent, and Fe3O4 as a chemodynamic therapy agent, were prepared successfully. The results demonstrated that the developed multifunctional PVA microspheres not only exhibit favorable drug release, photothermal therapy, and chemodynamic therapy performance, but also show a promising synergistic therapeutic effect both in vitro and in vivo. Consequently, the engineered multifunctional PVA microspheres hold tremendous promise for enhancing TACE effectiveness and have the potential to overcome limitations associated with traditional liver cancer treatments.

A bismuth-based double-network hydrogel-mediated synergistic photothermal-chemodynamic therapy for accelerated wound healing.

Multidrug-resistant bacterial infections present a significant challenge to wound healing. Non-antibiotic approaches such as photothermal therapy (PTT) and chemodynamic therapy (CDT) are promising but have suboptimal anti-bacterial efficacy. Herein, we developed a green bismuth-based double-network hydrogel (Bi@P-Cu) as a PTT/CDT synergistic platform for accelerated drug-resistant bacteria-infected wound healing. Bismuth (Bi) nanoparticles fabricated using a microwave method were used as a highly efficient and biocompatible PTT agent while the integration of a small amount of CDT agent Cu2+ endowed the hydrogel with excellent mechanical and self-healing properties, markedly increased photothermal efficiency, promoted cell migration ability, and negligible toxicity. Importantly, PTT enhanced the production of hydroxyl radicals in CDT and the destruction of bacterial cell membranes, which in turn enhanced the thermal sensitivity of bacteria. This synergistic anti-bacterial effect, together with the demonstrated capability to promote angiogenesis and anti-inflammation as well as enhanced fibroblast proliferation, led to accelerated wound healing in a full-thickness mouse model of resistant bacterial infection. This study provides an effective and safe strategy to eliminate drug-resistant bacteria and accelerate wound healing through green, non-antibiotic, double-network hydrogel-mediated synergistic PTT and CDT.

Hydrogel-immobilized nanotherapeutics: Inhibition of protective autophagy to amplify STING signals for postsurgical tumor immunotherapy

Activating the inherent stimulator of interferon gene (STING) pathway of cancer cells can inhibit tumor growth but can also induce protective autophagy of tumor cells to inhibit the STING-mediated immunotherapy. Therefore, amplification of STING activation and inhibition of autophagy could potentiate the cancer immunotherapy. Here, hydrogel-immobilized nanoparticles loaded with glucose oxidase (GOx), manganese ions (Mn2+) and hydroxychloroquine (HCQ) are prepared at the postsurgical site to enhance cancer therapy via activating the STING pathway and regulating the autophagy pathway. The delivered GOx and Mn2+ exert a chemo-dynamic therapy (CDT) to induce dsDNA damage, which can further initiate the STING pathway. HCQ can effectively inhibit protective autophagy associated with STING pathway activation, further amplify the antitumor immune responses. The synergistic delivery of CDT agents (i.e., GOx and Mn2+), STING agonists (i.e., Mn2+) and autophagy inhibitors (i.e., HCQ) results in a specific immune response, significantly inhibit tumor recurrence and metastatic tumor growth, which could extend the survival rate of mice suffered from the triple-negative breast cancer (TNBC).

Engineering a self-fueling and self-reported theranostic nanocatalyst for amplified cancer imaging and chemodynamic therapy

Chemodynamic therapy (CDT) has sparked increasing interest in selective cancer treatment. However, it remains a challenge to achieve an efficient and sustained therapeutic effect due to the restricted Fenton chemistry and deficient catalytic substrates within the tumor microenvironment (TME). Meanwhile, the lack of strategies to timely monitor the delivery and execution of CDT agents increases the risks of unwanted side effects. Here, we present that integration of TME-triggered cascade catalysis with tumor metabolism reprogramming to engineer activatable theranostic nanocatalysts is an effective way to tackle these challenges. A self-fueling and self-reported theranostic nanocatalyst is reported in this study by modifying multi-enzyme mimic MnO2 nanosturctures with antisense oligonucleotides (ASO). This catalyst can produce free radicals through logic multi-enzymatic catalysis to induce oxidative damage to cancer cells, yet keeping inert in normal cells. Furthermore, the loaded ASO can silence MCT4 that overexpresses in tumor cells, resulting in efflux blockage of intracellular lactate and decrease of intracellular pH, which remarkably facilitates the cascade catalysis for amplified CDT. Meanwhile, such acidification triggers an MRI enhancement for reporting gene silencing. Results from in vivo testing further support the potential of our design for more effective CDT. This study offers different insights into the design and construction of advanced platforms for noninvasive imaging-guided treatment of a wide range of cancers.

NIR-switchable local hydrogen generation by tandem bimetallic MOFs nanocomposites for enhanced chemodynamic therapy.

The inadequate quantity of hydrogen peroxide (H2O2) in cancer cells promptly results in the constrained success of chemodynamic therapy (CDT). Significant efforts made throughout the years; nevertheless, researchers are still facing the great challenge of designing a CDT agent and securing H2O2 supply within the tumor cell. In this study, taking advantage of H2O2 level maintenance mechanism in cancer cells, a nanozyme-based bimetallic metal-organic frameworks (MOFs) tandem reactor is fabricated to elevate intracellular H2O2 levels, thereby enhancing CDT. In addition, under near-infrared excitation, the upconversion nanoparticles (UCNPs) loaded into the MOFs can perform photocatalysis and generate hydrogen, which increases cellular susceptibility to radicals induced from H2O2, inhibits cancer cell energy, causes DNA damages and induces tumor cell apoptosis, thus improving CDT therapeutic efficacy synergistically. The proposed nanozyme-based bimetallic MOFs-mediated CDT and UCNPs-mediated hydrogen therapy act as combined therapy with high efficacy and low toxicity.

Applications of Boron Cluster Supramolecular Frameworks as Metal-Free Chemodynamic Therapy Agents for Melanoma.

Chemodynamic therapy (CDT) is a highly targeted approach to treat cancer since it converts hydrogen peroxide into harmful hydroxyl radicals (OH·) through Fenton or Fenton-like reactions. However, the systemic toxicity of metal-based CDT agents has limited their clinical applications. Herein, a metal-free CDT agent: 2,4,6-tri(4-pyridyl)-1,3,5-triazine (TPT)/ [closo-B12 H12 ]2- (TPT@ B12 H12 ) is reported. Compared to the traditional metal-based CDT agents, TPT@B12 H12 is free of metal avoiding cumulative toxicity during long-term therapy. Density functional theory (DFT) calculation revealed that TPT@B12 H12 decreased the activation barrier more than 3.5 times being a more effective catalyst than the Fe2+ ion (the Fenton reaction), which decreases the barrier about twice. Mechanismly, the theory calculation indicated that both [B12 H12 ]-· and [TPT-H]2+ have the capacity to decompose hydrogen into 1 O2 , OH·, and O2 -· . With electron paramagnetic resonance and fluorescent probes, it is confirmed that TPT@B12 H12 increases the levels of 1 O2 , OH·, and O2 -· . More importantly, TPT@B12 H12 effectively suppress the melanoma growth both in vitro and in vivo through 1 O2 , OH·, and O2 -· generation. This study specifically highlights the great clinical translational potential of TPT@B12 H12 as a CDT reagent.

Chemodynamic therapy agent optimized mesoporous TiO2 nanoparticles for Glutathione-Enhanced and Hypoxia-Tolerant synergistic Chemo-Sonodynamic therapy

Sonodynamic therapy (SDT) can generate reactive oxygen species to kill cancer cells by activating sonosensitizers under ultrasound (US) irradiation. Nevertheless, its application is greatly limited by low quantum yield of sonosensitizers, high levels of endogenous glutathione (GSH) and tumor hypoxia. Herein, a GSH-activated sonosensitizers with synergistic therapy effect (chemodynamic therapy (CDT) and SDT) are developed by depositing Fe(III)-artemisinin infinite coordination polymers (Fe(III)-ART CPs) in pores of mesoporous TiO2 nanoparticles (NPs). The formed Fe(III)-ART-TiO2 NPs have high sono-induced electron-hole separation efficiency because the deposited Fe(III)-ART CPs can provide isolated intermediate bands to capture sono-induced electrons in TiO2 NPs. Meanwhile, Fe3+ in Fe(III)-ART-TiO2 NPs are reduced to Fe2+ by GSH with oxygen-deficient sites generated to further capture sono-induced electrons in TiO2 NPs. Based on this, the reaction efficiency between water molecules and sono-induced holes is high enough to generate numerous hydroxyl radicals (•OH) without oxygen participated for overcoming tumor hypoxia. Additionally, through consuming GSH, the generated Fe2+ can catalyze ART to produce C-centered free radicals for CDT. Owing to these characteristics, Fe(III)-ART-TiO2 NPs show significant tumor suppression ability and good biocompatibility in vivo. The strategy of using CDT agent to modify sonosensitizers offers new options to improve SDT effect without introducing harmful substances.

Iron‐siRNA Nanohybrids for Enhanced Chemodynamic Therapy via Ferritin Heavy Chain Downregulation

AbstractFerrous iron (Fe2+) has more potent hydroxyl radical (⋅OH)‐generating ability than other Fenton‐type metal ions, making Fe‐based nanomaterials attractive for chemodynamic therapy (CDT). However, because Fe2+ can be converted by ferritin heavy chain (FHC) to nontoxic ferric form and then sequestered in ferritin, therapeutic outcomes of Fe‐mediated CDT agents are still far from satisfactory. Here we report the synthesis of siRNA‐embedded Fe0 nanoparticles (Fe0‐siRNA NPs) for self‐reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH‐responsive Fe0‐siRNA NPs are degraded to release Fe2+ and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O2). The accompanied O2 depletion causes an intracellular pH decrease, which further promotes the degradation of Fe0‐siRNA NPs. In addition to initiating chemodynamic process, Fe2+‐catalyzed ⋅OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation‐enhanced CDT.