Concomitant genomic features stratify prognosis to patients with advanced EGFR mutant lung cancer.

This study aimed to explore the clinical significance of genomics features including tumor mutation burden (TMB) and copy number alteration (CNA) for advanced EGFR mutant lung cancer. We retrospectively identified 1378 patients with advanced EGFR mutant lung cancer and next-generation sequencing tests from three cohorts. Multiple co-occurring genomics alternations occurred in a large proportion (97%) of patients with advanced EGFR mutant lung cancers. Both TMB and CNA were predictive biomarkers for these patients. A joint analysis of TMB and CNA found that patients with high TMB and high CNA showed worse responses to EGFR-TKIs and predicted worse outcomes. TMBhighCNAhigh, as a high-risk genomic feature, showed predictive ability in most of the subgroups based on clinical characteristics. These patients had larger numbers of metastatic sites, and higher rates of EGFR copy number amplification, TP53 mutations, and cell-cycle gene alterations, which showed more potential survival gain from combination treatment. Furthermore, a nomogram based on genomic features and clinical features was developed to distinguish prognosis. Genomic features could stratify prognosis and guide clinical treatment for patients with advanced EGFR mutant lung cancer.

Genome-scale CRISPR-Cas9 screen identifies PAICS as a therapeutic target for EGFR wild-type non-small cell lung cancer.

Epidermal growth factor receptor-targeted (EGFR-targeted) therapies show promise for non-small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild-type NSCLC. A genome-wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild-type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild-type NSCLC cells. Additionally, PAICS silencing led to cell-cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild-type NSCLC. PAICS silencing also caused DNA damage and cell-cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K-AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild-type NSCLC and represents a potential therapeutic target for this disease.

Pyroptosis: a double-edged sword in lung cancer and other respiratory diseases.

Pyroptosis is an active cell death process mediated by gasdermin family proteins including Gasdermin A (GSDMA), Gasdermin B (GSDMB), Gasdermin C (GSDMC), Gasdermin D (GSDMD), Gasdermin E (GSDME, DFNA5), and DFNB59. Emerging evidences have shown that pyroptosis contributes to many pulmonary diseases, especially lung cancer, and pneumonia. The exact roles of pyroptosis and gasdermin family proteins are tremendously intricate. Besides, there are evidences that pyroptosis contributes to these respiratory diseases. However, it often plays a dual role in these diseases which is a cause for concern and makes it difficult for clinical translation. This review will focus on the multifaceted roles of pyroptosis in respiratory diseases.

Development and Validation of a Modified Khorana Score for Predicting Venous Thromboembolism in Newly Diagnosed Stage IV Lung Cancer.

We aimed to establish an effective model to identify metastatic lung cancer patients at high risk of venous thromboembolism (VTE). Patients diagnosed with stage IV lung cancer from January 2011 to June 2019 were included in the development cohort; those recruited from July 2019 to June 2021 were included in the validation cohort. Univariable and multivariable analyses determined the risk factors for VTE. Then we assessed the value for predicting VTE of the Khorana score and modified Khorana score in these two cohorts; 575 patients were included in the development cohort, and 202 patients in the validation cohort. Adenocarcinoma, D-dimer, and the Khorana score were independent risk factors for VTE. In the development cohort, the area under the receiver operating characteristic curve (AUC) of the Khorana score in patients with newly diagnosed stage IV lung cancer was 0.598 (95% CI, 0.512-0.684). The AUC of the modified Khorana score was 0.747 (95% CI, 0.689-0.805). The difference was statistically significant (P <.001). The AUC of the modified Khorana score in the validation cohort was 0.763 (95% CI, 0.661-0.865). The modified Khorana score is more able to accurately predict VTE in patients with newly diagnosed stage IV lung cancer than the Khorana score.

Targeting CDK4/6 in glioblastoma via in situ injection of a cellulose-based hydrogel.

Despite aggressive treatments, including surgery, chemotherapy and radiotherapy, the prognosis of glioblastoma (GBM) remains poor, and tumor recurrence is inevitable. The FDA-approved CDK4/6 inhibitor palbociclib (PB) showed interesting anti-GBM effects, but its brain penetration is limited by the blood-brain barrier. The aim of this project is to find whether the cellulose-based hydrogel via in situ injection could provide an alternative route to PB brain delivery and generate sufficient drug exposure in orthotopic GBM. In brief, PB was encapsulated in a cellulose nanocrystal network structure crosslinked by polydopamine via divalent Cu2+ and hexadecylamine. The formed hydrogel (PB@PH/Cu-CNCs) exhibited sustained drug retention and acid-responsive network de-polymerization for controlled release in vivo. Specifically, the released Cu2+ catalyzed a Fenton-like reaction to generate reactive oxygen species (ROS), which was further enhanced by PB, and consequently, irreversible senescence and apoptosis were induced in GBM cells. Finally, PB@PH/Cu-CNCs demonstrated a more potent anti-GBM effect than those treated with free PB or PH/Cu-CNCs (drug-free hydrogel) in cultured cells or in an orthotopic glioma model. These results prove that the injection of the PB-loaded hydrogel in situ is an effective strategy to deliver the CDK4/6 inhibitor into the brain and its anti-GBM effect can be further enhanced by combining Cu2+-mediated Fenton-like reaction.

Redox ferrocenylseleno compounds modulate longitudinal and transverse relaxation times of FNPs-Gd MRI contrast agents for multimodal imaging and photo-Fenton therapy.

Developing a feasible way to feature longitudinal (T1) and transverse (T2) relaxation performance of contrast agents for magnetic resonance imaging (MRI) is important in cancer diagnosis and therapy. Improved accessibility to water molecule is essential for accelerating the relaxation rate of water protons around the contrast agents. Ferrocenyl compounds have reversible redox property for modulating the hydrophobicity/hydrophilicity of assemblies. Thus, they could be the candidates that can change water accessibility to the contrast agent surface. Herein, we incorporated ferrocenylseleno compound (FcSe) with Gd3+-based paramagnetic UCNPs, to obtain FNPs-Gd nanocomposites using T1-T2 MR/UCL trimodal imaging and simultaneous photo-Fenton therapy. When the surface of NaGdF4:Yb,Tm UNCPs was ligated by FcSe, the hydrogen bonding between hydrophilic selenium and surrounding water molecules accelerated their proton exchange to initially endow FNPs-Gd with high r1 relaxivity. Then, hydrogen nuclei from FcSe disrupted the homogeneity of the magnetic field around the water molecules. This facilitated T2 relaxation and resulted in enhanced r2 relaxivity. Notably, upon the near-infrared light-promoted Fenton-like reaction in the tumor microenvironment, hydrophobic ferrocene(II) of FcSe was oxidized into hydrophilic ferrocenium(III), which further increased the relaxation rate of water protons to obtain r1 = 1.90±0.12 mM-1 s-1 and r2 = 12.80±0.60 mM-1 s-1. With an ideal relaxivity ratio (r2/r1) of 6.74, FNPs-Gd exhibited high contrast potential of T1-T2 dual-mode MRI in vitro and in vivo. This work confirms that ferrocene and selenium are effective boosters that enhance the T1-T2 relaxivities of MRI contrast agents, which could provide a new strategy for multimodal imaging-guided photo-Fenton therapy of tumors. STATEMENT OF SIGNIFICANCE: T1-T2 dual-mode MRI nanoplatform with tumor-microenvironment-responsive features has been an attractive prospect. Herein, we designed redox ferrocenylseleno compound (FcSe) modified paramagnetic Gd3+-based UCNPs, to modulate T1-T2 relaxation time for multimodal imaging and H2O2-responsive photo-Fenton therapy. Selenium-hydrogen bond of FcSe with surrounding water molecules facilitated water accessibility for fast T1 relaxation. Hydrogen nucleus in FcSe perturbed the phase coherence of water molecules in an inhomogeneous magnetic field and thus accelerated T2 relaxation. In tumor microenvironment, FcSe was oxidized into hydrophilic ferrocenium via NIR light-promoted Fenton-like reaction which further increased both T1 and T2 relaxation rates; Meanwhile, the released toxic •OH performed on-demand cancer therapy. This work confirms that FcSe is an effective redox mediate for multimodal imaging-guided cancer therapy.

Clinical implications of ctDNA for EGFR-TKIs as first-line treatment in NSCLC.

PURPOSE: This study aimed to explore the clinical implications of ctDNA for epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as the first-line treatment in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) in real-world settings. METHODS: A total of 122 patients with NSCLC who underwent tissue and liquid next generation sequencing (NGS) tests were included. 66 patients with detected EGFR mutation in both tumor-tissue and plasma were included into the EGFRt+, p+ group, and 56 patients with EGFR mutation detected only in tumor-tissue were included into the EGFRt+, p- group. The differences in clinical characteristics, concomitant mutations and prognosis between the two groups were compared. RESULTS: The detection rate of the EGFRt+, p+ group was 54.1% (66/122). EGFRt+, p+ in the NGS test was particularly relevant to the size of tumors, liver metastasis, bone metastasis and TP53 mutation. In patients with TP53 mutation in ctDNA, the detection rate of EGFR mutation in ctDNA was up to 91.3%. EGFRt+, p+ could be an independent prognostic factor for first-line EGFR-TKIs treatment. Combination therapy seems to be a promising approach to improve the outcome for EGFRt+, p+ (P = 0.017, HR 0.509 [95% CI 0.288-0.897]). Moreover, the combination of TP53 mutated status and EGFRm status in plasma showed a better completion of risk stratification for PFS (Log-rank P < 0.001). CONCLUSIONS: Co-detection of EGFR mutation in tumor tissue and plasma is an independent prognostic factor for first-line EGFR-TKIs treatment. Moreover, combination therapy could be a promising approach to improve the outcome for these patients.

Toxic reactive oxygen species enhanced chemodynamic therapy by copper metal-nanocellulose based nanocatalysts.

When compared with traditional petroleum-based materials, bio-based materials show greater application potential in the field of biomedicine owing to the good biocompatibility, in specifical, the application of natural macromolecular polymers in chemotherapeutics has become a hot topic in anticancer treatment. In this study, cellulose nanocrystals (CNCs) were selected as carriers, and Au nanoparticles (NPs) were directly conjugated on their surface, with the highly reactive Cu2+ ions serving as an ion-ligand bridge, to construct a multifunctional nanocatalyst. These findings suggest that the nanosystem delivers a large amount of highly reactive Cu2+ ions (3.75 wt%) and DOX (7.71 wt%) by the surface loading of cellulose nanocrystals, which greatly improves ROS yield and promotes the application of the Fenton reaction system in cancer therapy.

Glutathione-triggered nanoplatform for chemodynamic/metal-ion therapy.

The integration of metal-ion therapy and hydroxyl radical (˙OH)-mediated chemodynamic therapy (CDT) holds great potential for anticancer treatment with high specificity and efficiency. Herein, Ag nanoparticles (Ag NPs) were enveloped with Cu2+-based metal-organic frameworks (MOFs) and further decorated with hyaluronic acid (HA) to construct a glutathione (GSH)-activated nanoplatform (Ag@HKU-HA) for specific chemodynamic/metal-ion therapy. The obtained nanoplatform could avoid the premature leakage of Ag in circulation, but realize the release of Ag at the tumor site owing to the degradation of external MOFs triggered by Cu2+-reduced glutathione. The generated Cu+ could catalyze endogenous H2O2 to the highly toxic ˙OH by a Fenton-like reaction. Meanwhile, Ag NPs were oxidized to toxic Ag ions in the tumor environment. As expect, the effect of CDT combined with metal-ion therapy exhibited an excellent inhibition of tumor cells growth. Therefore, this nanoplatform may provide a promising strategy for on-demand site-specific cancer combination treatment.

A biocompatible and pH-responsive nanohydrogel based on cellulose nanocrystal for enhanced toxic reactive oxygen species generation.

Traditional therapeutic regimens are currently far from satisfactory, and the integration of biocompatible carbohydrate polymers and nanotechnologies with conventional therapeutics has become a focus of research in cancer therapy. Herein, A novel biocompatible and pH-responsive nanohydrogel composed of two functional polymeric chains was developed from cellulose nanocrystals (CNCs) and 5-aminolevulinic acid (ALA), or dopamine (DPA). The biological molecules PDA and ALA were respectively conjugated to CNC through the coordination of iron ions to form two functional polymeric chains (PDA/Fe@CNC and ALA/Fe@CNC). The PDA/Fe@CNC chain increased the adhesion of the nanohydrogels to cells, while the ALA/Fe@CNC chain significantly increased reactive oxygen species (ROS) production. Furthermore, PTX molecules loaded into the nanohydrogels combined with ROS to efficiently kill tumor cells. The nanohydrogels displayed excellent cell affinity, high ROS yield (8.0-fold greater than that in control), and strong cytotoxicity (2.7 % of cell viability). The present study highlights the great potential of biocompatible natural polysaccharide-based materials for biomedical applications, and provides a new strategy for reducing the toxicity and side effects associated with traditional chemotherapy, demonstrating a novel antitumor treatment paradigm with high-efficiency but with only minor side effects.

One-for-all intelligent core-shell nanoparticles for tumor-specific photothermal-chemodynamic synergistic therapy.

Reasonable management of the one-for-all nanoplatform can facilitate improved cancer therapy. Here, the metal-organic frameworks (MOFs) based on iron(iii) carboxylate material (MIL-101-NH2) were in situ decorated on stabilized polydopamine nanoparticles (PDANPs), which subsequently loaded glucose oxidase (GOx) via hyaluronic acid (HA) coating to structure the one-for-all intelligent core-shell nanoparticles (HG-MIL@PDANPs). Because of the inner PDANPs, the HG-MIL@PDANPs could realize near-infrared (NIR)-controllable site-specific photothermal therapy (PTT). Additionally, the core-shell nanoparticles exhibited a pH-triggered and NIR-reinforced release of Fe3+ and GOx owing to the controllable degradation of the outer shell. Hydroxyl radicals (˙OH) were produced for chemodynamic therapy (CDT) employing the Fe2+-driven Fenton reaction, which could be greatly promoted by Fe3+-involved glutathione (GSH) depletion and GOx-catalyzed acidity recovery and H2O2 self-sufficiency. Moreover, the HA ligand could enhance the tumor accumulation of the HG-MIL@PDANPs through the long blood circulation time and CD44-targeted cell recognition. The ingenious integration of PTT and CDT in one fully equipped system presented excellent synergistic antitumor efficiency in vitro and in vivo with favorable biosafety. The one-for-all intelligent core-shell nanoparticles with CD44 targeting provide a new avenue for engineering on-demand tumor-specific therapy.

Dual catalytic cascaded nanoplatform for photo/chemodynamic/starvation synergistic therapy.

In this study, manganese dioxide (MnO2) was attached to prussian blue (PB) by a one-pot method to prepare PBMO. Then, the GOD was loaded onto PBMO through the electrostatic interaction of hyaluronic acid (HA) to form tumor-targeted nanoplatform (PBMO-GH). Hydrogen peroxide (H2O2) and gluconic acid were produced through the GOD-catalyzed enzymatic reaction. Meanwhile, PB could not only catalyze H2O2 for oxygen generation to further promote glucose consumption but also possess the property of photothermal conversion. As a result, glucose was continuously consumed to achieve the starvation therapy (ST), and the photothermal therapy (PTT) could be realized under near-infrared (NIR) light. Besides, the Mn2+ generated by the reaction of MnO2 with glutathione (GSH) could exert Fenton-like reaction to produce highly toxic hydroxyl radicals (·OH) from H2O2, which thereby realized self-reinforcing chemodynamic therapy (CDT). In vitro and in vivo experiments demonstrated that PBMO-GH could effectively inhibit the growth of tumor cells via ST/CDT/PTT synergistic effect. Therefore, the as-prepared nanoplatform for multi-modal therapy will provide a promising paradigm for overcoming cancer.

Enhanced antitumor effect via amplified oxidative stress by near-infrared light-responsive and folate-targeted nanoplatform.

The efficiency of producing hydroxyl radicals (·OH) from hydrogen peroxide (H2O2) catalyzed by different iron compounds have been explored extensively. Exclusively, ferrocenecarboxylic acid (FCA) showed the best catalyzed activity for ·OH generation. Then, we designed and prepared near-infrared (NIR) light-responsive and folate-targeted nanoplatform, which co-delivered FCA, cisplatin and indocyanine green (ICG) for improving antitumor therapy through amplified oxidative stress. The noteworthy observation is that under the irradiation of NIR light, the lecithin structure could able to depolymerize through the photothermal conversion mechanism of encapsulated dye ICG, which has achieved an intelligent release of drugs. In addition, the released cisplatin is not only fully effective to damage the DNA of cancer cells but it is able to induce the production of intracellular H2O2, which could further be catalyzed by FCA to generate toxic ·OH for oxidative damage via Fenton and Haber-Weiss reaction. This original strategy may provide an efficient way for improved chemotherapy via amplified oxidative stress.

Smart Porous Core-Shell Cuprous Oxide Nanocatalyst with High Biocompatibility for Acid-Triggered Chemo/Chemodynamic Synergistic Therapy.

The rational integration of chemotherapy and hydroxyl radical (·OH)-mediated chemodynamic therapy (CDT) holds great potential for cancer treatment. Herein, a smart biocompatible nanocatalyst based on porous core-shell cuprous oxide nanocrystals (Cu2 O-PEG (polyethylene glycol) NCs) is reported for acid-triggered chemo/chemodynamic synergistic therapy. The in situ formed high density of hydrophilic PEG outside greatly improves the stability and compatibility of NCs. The porosity of Cu2 O-PEG NCs shows the admirable capacity of doxorubicin (DOX) loading (DOX@Cu2 O-PEG NCs) and delivery. Excitingly, Cu (Cu+/2+ ) and DOX can be controllably released from DOX@Cu2 O-PEG NCs in a pH-responsive approach. The released Cu+ exerts Fenton-like catalytic activity to generate toxic ·OH from intracellular overexpressed hydrogen peroxide (H2 O2 ) for CDT via reactive oxygen species (ROS)-involved oxidative damage. Exactly, DOX can not only induce cell death for chemotherapy but also enhance CDT by self-supplying endogenous H2 O2 . After the intravenous injection, Cu2 O-PEG NCs can effectively accumulate in tumor region via passive targeting improved by external high-density PEG shell. Additionally, the effect of boosted CDT combined with chemotherapy presents excellent in vivo antitumor ability without causing distinct systemic toxicity. It is believed that this smart nanocatalyst responding to the acidity provides a novel paradigm for site-specific cancer synergetic therapy.

A pH-activated autocatalytic nanoreactor for self-boosting Fenton-like chemodynamic therapy.

The emergence of hydroxyl radical (˙OH)-mediated chemodynamic therapy (CDT) by the Fenton or Fenton-like reaction holds great potential for improving anticancer efficacy. Herein, an activatable autocatalytic nanoreactor (HT@GOx-DMONs) was developed for self-boosting Fenton-like CDT via decorating Cu2+-based metal-organic frameworks (MOFs) on glucose oxidase (GOx)-loaded dendritic mesoporous organosilica nanoparticles (DMONs) for the first time. The obtained nanoreactor could prevent the premature leakage of Cu2+ and GOx in neutral physiological environments conducted by the gatekeeper of growing carboxylate MOF (HKUST-1), but the explosive release of agents was realized due to the activated degradation of external HKUST-1 in acidic condition of endo/lysosomes, which thereby endowed this nanoreactor with the performance of pH-triggered ˙OH generation driven by Cu+-mediated autocatalytic Fenton-like reaction. Excitingly, Cu2+-induced glutathione (GSH) depletion and GOx-catalyzed H2O2 self-sufficiency unlocked by acid dramatically enhanced ˙OH generation. As expected, the effect of self-amplified CDT based on Cu2+-containing HT@GOx-DMONs presented wonderful in vitro toxicity and in vivo antitumor ability without leading to significant side-effects. The resulting nanoreactor with GSH consumption and H2O2 self-supply activated by acid may provide a promising paradigm for on-demand CDT.

Dendritic Mesoporous Organosilica Nanoparticles: A pH-Triggered Autocatalytic Fenton Reaction System with Self-supplied H2O2 for Generation of High Levels of Reactive Oxygen Species.

Dendritic mesoporous silica nanoparticles represent a new biomedical application platform due to their special central radial pore structure for the loading of drugs and functional modification. Herein, we report functionalized dendritic mesoporous organosilica nanoparticles (DMONs), a pH-triggered Fenton reaction generator (TA/Fe@GOD@DMONs), incorporating natural glucose oxidase (GOD) in the DMONs with tannic acid (TA) grafted using Fe3+ on the surface, that have been designed and constructed for efficient tumor ablation with self-supplied H2O2 and accelerated conversion of Fe3+/Fe2+ by TA. In view of the deficiency of endogenous H2O2, the self-supply through the TA/Fe@GOD@DMONs platform represented a high-yielding source of peroxygen. Furthermore, the production of Fe2+ induced by TA greatly improved the efficiency of the Fenton reaction resulting in significant tumor inhibition. This new design represents as novel paradigm for the development of autocatalytic Fenton nanosystems for effective treatment of tumors.

A novel versatile yolk-shell nanosystem based on NIR-elevated drug release and GSH depletion-enhanced Fenton-like reaction for synergistic cancer therapy.

In this study, a versatile doxorubicin (DOX)-loaded yolk-shell nano-particles (HMCMD) assembled with manganese dioxide (MnO2) as the core and copper sulfide (HMCuS) as the mesoporous (∼ 6.4 nm) shell, was designed and synthesized. The resulting HMCMD possess excellent photothermal conversion efficiency. The DOX release from the yolk-shell nanoparticles could be promoted by laser irradiation, which increased the chemotherapy of DOX. Meanwhile, Mn2+ could be released from the HMCMD through a redox reaction between MnO2 and abundant glutathione (GSH) in tumor cells. The released Mn2+ could promote the decomposition of the intracellular hydrogen peroxide (H2O2) by Fenton-like reaction to generate the highly toxic hydroxyl radicals (·OH), thus exhibiting the effective chemodynamic therapy (CDT). Additionally, the efficiency of Mn2+-mediated CDT could be effectively enhanced by NIR irradiation. Further modification of polyethylene glycol (PEG) would improve the water solubility of the HMCMD to promote the uptake by MCF-7 cells. Hence, the HMCMD with synergistic effects of chemotherapy and chemodynamic/photothermal therapy would provide an alternative strategy in antitumor research.

Photothermal-Enhanced Inactivation of Glutathione Peroxidase for Ferroptosis Sensitized by an Autophagy Promotor.

Until now, ferroptotic therapeutic strategies remain simple, although ferroptosis has aroused extensive interest owing to its escape from the biocarriers of conventional therapeutic modalities. Herein, we construct a photothermal (PT)- and autophagy-enhanced ferroptotic therapeutic modality based on MnO2@HMCu2-xS nanocomposites (HMCMs) for efficient tumor ablation. The HMCMs possess PT-enhanced glutathione (GSH) depletion capability, thereby inducing PT-enhanced ferroptosis via the reinforced inactivation of glutathione peroxidase 4 (GPX4). Thereafter, the GSH-responsed Mn2+ release could generate reactive oxygen species (ROS) by a Fenton-like reaction to reinforce the intracellular oxidative stress for the lipid hydroperoxide (LPO) accumulation in ferroptosis. Additionally, an autophagy promotor rapamycin (Rapa) was loaded into HMCM for sensitizing cells to ferroptosis due to the indispensable role of autophagy in the ferroptosis process. The in vitro and in vivo data demonstrated that the HMCM exhibited superior anticancer effect in human breast cancer models and that the combined therapeutic system afforded the next generation of ferroptotic therapy for combatting malignant tumors.

Enhanced Reactive Oxygen Species Levels by an Active Benzothiazole Complex-Mediated Fenton Reaction for Highly Effective Antitumor Therapy.

Breaking the threshold of intracellular reactive oxygen species (ROS) levels can cause nonspecific oxidative damage to proteins and lead to the Fenton reaction-mediated exogenous ROS production to be a new promising anticancer strategy. However, the problems, including the inefficient transport of metal catalysts and insufficient endogenous hydrogen peroxide (H2O2) content in cells, still need to be improved. In this study, a functional nanosystem encapsulated with benzothiazole complexes (FeTB2) and the photosensitizer indocyanine green (ICG) was designed for highly effective antitumor therapy. The surface of the nanocarriers was modified with dihydroartemisinin (DHA)-grafted polyglutamic acid. The induced hyperthermia enables the lipid-polymer shell to depolymerize, releasing FeTB2. The released FeTB2 could kill tumor cells in two different ways by inhibiting DNA replication and catalyzing H2O2 to produce active •OH. Moreover, the conjugated DHA could increase the amount of peroxides in tumor cells and significantly enhance the ROS yield. This work has provided solid evidence that the present nanosystem enables a significant effect on tumor killing through the combined inhibition of DNA replication and ROS-mediated oxidative damage by regulation of the tumor microenvironment, providing a ROS-mediated high-efficiency antitumor strategy.

Three peroxidovanadium(v) compounds mediated by transition metal cations for enhanced anticancer activity.

Three peroxidovanadium(v) compounds with different ligands (L1-L3) {L1 = N-tris(hydroxymethyl)methylglycine; L2 = ethylenediamine-N,N'-diacetic acid; L3 = 2,2-[(2-amino-2-oxoethyl)imino]diacetic acid} were first synthesized, characterized and further investigated for their anticancer activities under the mediation of transition metal cations. Encouragingly, all compounds showed preferentially enhanced cytotoxicity toward cancer cells (MCF-7 and A549) compared to normal cells (BEAS-2B) under the mediation of transition metal cations (Mn2+ or Fe2+), especially for Mn2+. It was noted that cell death was triggered by the transition metal cation-mediated peroxidovanadium(v) compounds through the induction of early apoptosis, inhibition of cell cycles, and boosting the generation of intracellular reactive oxygen species (ROS). Mechanistic studies further elucidated the vital roles of an acidic environment and transition metal cations for the anticancer activity of peroxidovanadium(v) compounds. Therefore, this study will offer precious insight into the development of the transition metal cation-mediated peroxidovanadium(v) compounds for further clinical translation.