Novel molecular photosensitizer with simultaneously GSH depletion, aggregation inhibition and accelerated elimination for improved and safe photodynamic therapy.

The major challenges in photodynamic therapy (PDT) are the neutralization of cytotoxic reactive oxygen species (ROS) by the excessive antioxidant glutathione (GSH) in tumor cells, high self-aggregation of most photosensitizers (PSs), and long time to protect from light after treatment. Thus, to develop the molecular PSs for the improved and safe PDT in clinic, a novel and versatile PS (Mal-Pc) has been designed by di-substituting maleimides to the axial positions of silicon (Ⅳ) phthalocyanine. Owning to the conjugation of maleimides, Mal-Pc can not only entry tumor cells more easily and faster, but also can react with the intracellular overexpressed GSH after entry. In addition, upon electrophilic reaction with GSH, the inhibition of self-aggregation of Mal-Pc has been demonstrated by the restoration of the fluorescence emission in aqueous media. As a result, the intracellular ROS levels and photocytotoxicity of Mal-Pc are dramatically enhanced. Finally, the high hydrophilicity of the product GS-conjugates facilitates Mal-Pc eliminate from the normal cells more rapidly. Overall, this work revealed the high potential of the versatile molecular Mal-Pc for highly efficient and safe PDT in clinical translation.

Neuroprotective evaluation of novel substituted 1,3,4-oxadiazole and aroylhydrazone derivatives.

The paper reports on the facile and convenient synthesis of a series of novel 2,5-substituted 1,3,4-oxadiazoles 3a-f and that of aroylhydrazone-based molecular hybrids 5a-g from readily available starting materials. The structure of the compounds was confirmed by IR, 1H NMR, 13C NMR and HRESI-MS spectral data. The toxicological potential of the compounds was evaluated by monitoring the synaptosomal viability and the levels of reduced glutathione in rat brain synaptosomes, isolated by Percoll gradient. The neuroprotective effects were assessed in vitro in a model of 6-hydroxydopamine-induced neurotoxicity. Administered alone, at a concentration of 40 µM, most of the 1,3,4-oxadiazole derivatives and all of the hydrazone derivatives exhibited weak statistically significant neurotoxic effects, compared to the control. Two of the compounds from the novel oxadiazoles 3a and 3d did not have any toxicity. In a model of 6-OHDA-induced oxidative stress, again 3a and 3d and all aroylhydrazone derivatives 5a-g revealed statistically significant neuroprotective effect by preserving the synaptosomal viability and the level of reduced glutathione, against the toxic agent. Some of the compounds may have neuroprotective effects due to possible stabilization of the synaptosomal membrane and/or because of the preserved reduced glutathione. Additionally, all the compounds display a good predicted ADME profile.

Taurine supplementation protects lens against glutathione depletion.

OBJECTIVE: Cataract which is defined as opacification of eye lens forms approximately 40% of total blindness causes all through the world. Age is the biggest risk factor for cataracts and oxidative stress is known to be one of the most important factors causing cataract formation. Age-related nuclear cataract (ARN) is associated with a loss of glutathione in the center of the lens. Taurine is an important antioxidant in lens tissue. Although, there is a high amount of taurine in lenses in early life, its concentration declines with age. In this study, we aimed to investigate the effects of supplemental taurine in lens tissues in an in vivo oxidative stress model which is induced by glutathione depletion to mimic ARN. MATERIALS AND METHODS: Glutathione depletion was induced in rabbits subcutaneously with l-Buthionine -(S,R)-sulfoximine (BSO)- a glutathione inhibitor and the rabbits were treated with taurine. Total GSH, reduced GSH, GSH/GSSG ratio and MDA levels were measured. RESULTS: BSO lowered the reduced GSH and total GSH levels and GSH/GSSG ratio. Taurine reversed these effects. On the other hand, BSO enhanced MDA level which is normalized by taurine. CONCLUSIONS: These findings suggest that glutathione depletion with BSO may be a useful model to mimic ARN and dietary intake of taurine, may have an important role in decelerating the process of cataract formation.

Mitochondrial regulation of ferroptosis.

Ferroptosis is a form of iron-dependent regulated cell death driven by uncontrolled lipid peroxidation. Mitochondria are double-membrane organelles that have essential roles in energy production, cellular metabolism, and cell death regulation. However, their role in ferroptosis has been unclear and somewhat controversial. In this Perspective, I summarize the diverse metabolic processes in mitochondria that actively drive ferroptosis, discuss recently discovered mitochondria-localized defense systems that detoxify mitochondrial lipid peroxides and protect against ferroptosis, present new evidence for the roles of mitochondria in regulating ferroptosis, and outline outstanding questions on this fascinating topic for future investigations. An in-depth understanding of mitochondria functions in ferroptosis will have important implications for both fundamental cell biology and disease treatment.

Glucose oxidase loaded Cu2+ based metal-organic framework for glutathione depletion/reactive oxygen species elevation enhanced chemotherapy.

INTRODUCTION: The development of multidrug resistance (MDR) is a major cause for the failure of chemotherapy, which requires the aid of nanomedicine. METHODS: Here in our study, a Cu2+ based metal-organic framework (COF) was firstly developed and employed as a carrier for the delivery of glucose oxidase (GOx) and doxorubicin (Dox) (COF/GOx/Dox) for the therapy of MDR lung cancers. RESULTS: Our results showed that the GOx can catalyze glucose and produce H2O2. In the mean time, the Cu2+ can react with GSH and then transform into Cu+, which resulted in GSH depletion. Afterwards, the produced Cu+ and H2O2 trigger Fenton reaction to generate ROS to damage the redox equilibrium of cancer cells. Both effects contributed to the reverse of MDR in A549/Dox cells and finally resulted in significantly enhanced in vitro/in vivo anticancer performance. DISCUSSION: The combination of glutathione depletion/reactive oxygen species elevation might be a promising strategy to enhance the efficacy of chemotherapy and reverse MDR in cancers.

STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer.

Bioenergetic perturbations driving neoplastic growth increase the production of reactive oxygen species (ROS), requiring a compensatory increase in ROS scavengers to limit oxidative stress. Intervention strategies that simultaneously induce energetic and oxidative stress therefore have therapeutic potential. Phenformin is a mitochondrial complex I inhibitor that induces bioenergetic stress. We now demonstrate that inflammatory mediators, including IFNγ and polyIC, potentiate the cytotoxicity of phenformin by inducing a parallel increase in oxidative stress through STAT1-dependent mechanisms. Indeed, STAT1 signaling downregulates NQO1, a key ROS scavenger, in many breast cancer models. Moreover, genetic ablation or pharmacological inhibition of NQO1 using ß-lapachone (an NQO1 bioactivatable drug) increases oxidative stress to selectively sensitize breast cancer models, including patient derived xenografts of HER2+ and triple negative disease, to the tumoricidal effects of phenformin. We provide evidence that therapies targeting ROS scavengers increase the anti-neoplastic efficacy of mitochondrial complex I inhibitors in breast cancer.

NMR reveals the metabolic changes induced by auranofin in A2780 cancer cells: evidence for glutathione dysregulation.

NMR metabolomics represents a powerful tool to characterize the cellular effects of drugs and gain detailed insight into their mode of action. Here, we have exploited NMR metabolomics to illustrate the changes in the metabolic profile of A2780 ovarian cancer cells elicited by auranofin (AF), a clinically approved gold drug now repurposed as an anticancer agent. An early and large increase in intracellular glutathione is highlighted as the main effect of the treatment accompanied by small but significant changes in the levels of a few additional metabolites; the general implications of these findings are discussed in the frame of the current mechanistic knowledge of AF.

The Interaction of Human Glutathione Transferase GSTA1-1 with Reactive Dyes.

Human glutathione transferase A1-1 (hGSTA1-1) contributes to developing resistance to anticancer drugs and, therefore, is promising in terms of drug-design targets for coping with this phenomenon. In the present study, the interaction of anthraquinone and diazo dichlorotriazine dyes (DCTD) with hGSTA1-1 was investigated. The anthraquinone dye Procion blue MX-R (PBMX-R) appeared to interact with higher affinity and was selected for further study. The enzyme was specifically and irreversibly inactivated by PBMX-R, following a biphasic pseudo-first-order saturation kinetics, with approximately 1 mol of inhibitor per mol of the dimeric enzyme being incorporated. Molecular modeling and protein chemistry data suggested that the modified residue is the Cys112, which is located at the entrance of the solvent channel at the subunits interface. The results suggest that negative cooperativity exists upon PBMX-R binding, indicating a structural communication between the two subunits. Kinetic inhibition analysis showed that the dye is a competitive inhibitor towards glutathione (GSH) and mixed-type inhibitor towards 1-chloro-2,4-dinitrobenzene (CDNB). The present study results suggest that PBMX-R is a useful probe suitable for assessing by kinetic means the drugability of the enzyme in future drug-design efforts.

Suppression of uric acid generation and blockade of glutathione dysregulation by L-arginine ameliorates dichlorvos-induced oxidative hepatorenal damage in rats.

Dichlorvos is a known risk factor for organ toxicity. The liver and kidney are essential metabolic tissues but it is unclear whether or not there is associated redox dyshomeostasis in both organs in physiological and pathological states. Uric acid accumulation and glutathione dysregulation have been implicated in the aetiopathogenesis of organ damage. The antioxidant potentials of L-arginine have been shown in various conditions. The present study was thus designed to investigate the synchrony in hepatic and renal uric acid and glutathione status in dichlorvos-induced hepatorenal damage and to probe the possible therapeutic role of L-arginine. Twenty-one male Wistar rats were treated with standard rat diet and water, dichlorvos, or dichlorvos and L-arginine. Our findings revealed that dichlorvos significantly impaired hepatic and renal functions, increased hepatic and renal malondialdehyde, but reduced glutathione and activities of superoxide dismutase, catalase, and glutathione peroxidase. These events were accompanied by increased accumulation of plasma, hepatic, and renal uric acid as well as reduced body weight gain, and hepatic and renal weights. Histopathological examinations revealed hepatic and renal architectural derangement and cellular necrosis and degeneration in dichlorvos-exposed rats. Interestingly, L-arginine reversed dichlorvos-induced systemic, hepatic and renal synchronous redox dyshomeostasis. L-arginine administration also improved hepatic and renal cytoarchitecture. It is thus concluded that dichlorvos triggered synchronous uric acid generation and glutathione alterations in the liver and kidney. L-arginine confers protection against dichlorvos-induced hepatorenal damage via suppression of uric acid generation and blockade of glutathione dysregulation.

In Vivo Antitumor, Pharmacological and Toxicological Study of Pyrimido[ 4',5':4,5] thieno(2,3-b)quinoline with 9-hydroxy-4-(3-diethylaminopropylamino) and 8-methoxy-4-(3-diethylaminopropylamino) Substitutions.

BACKGROUND: We previously synthesized two DNA intercalative Pyrimido[4',5':4,5]thieno(2,3-b) quinolines (PTQ), 9-hydroxy-4-(3-diethylaminopropylamino)pyrimido[4',5':4,5]thieno(2,3-b) quinolines (Hydroxy- DPTQ) and 8-methoxy-4-(3-diethylaminopropylamino) pyrimido[4',5':4,5]thieno(2,3-b) quinolines (Methoxy-DPTQ), and reported their cytotoxicity against cancer cell lines. METHODS: In the present study, we sought to analyze the antitumor activity of Hydroxy-DPTQ and Methoxy-DPTQ on Ehrlich's ascites carcinoma in vivo models, along with other pharmacological activities and toxicity. RESULTS: In this study, both the test molecules studied possess potent in vivo antitumor activity without any hematological, biochemical or nephrotoxicity. Significant tumor regression was observed after treatment with both the test molecules, which is suggested by the decrease in the bodyweight of tumour-bearing mice. Mean survival time of mice with tumor was increased from 16 days to 25 and 29 days after 40 and 80 mg/kg Hydroxy- DPTQ treatment, respectively, with a similar result for Methoxy-DPTQ. A dose-dependent increase in lifespan up to 80-85% was also displayed by both Hydroxy-DPTQ and Methoxy-DPTQ. Reduction in the tumor volume of mice, upon treatment with molecules also confirmed their antitumor activity. These molecules also exhibited pharmacological activities such as antioxidant, anti-inflammatory and analgesic activities. Administration of Hydroxy-DPTQ and Methoxy-DPTQ not only reduced the level of lipid peroxidation in tumor bearing mice but also restored the superoxide dismutase, glutathione, and catalase levels to normal, substantiating the antioxidant property. Also, treatment of Hydroxy-DPTQ and Methoxy-DPTQ inhibited the pain to approximately 60-80% and 19-33%, respectively. Further, the treatment with Hydroxy-DPTQ and Methoxy-DPTQ reversed the abnormality in the RBC, WBC and haemoglobin levels, and gentamicin induced nephrotoxicity. CONCLUSION: Hydroxy-DPTQ and Methoxy-DPTQ are good antitumor molecules with pharmacological properties.

A "Golden Age" for the discovery of new antileishmanial agents: Current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system.

Leishmaniasis is one of the most neglected diseases worldwide and is considered a serious public health issue. The current therapeutic options have several disadvantages that make the search for new therapeutics urgent. Gold compounds are emerging as promising candidates based on encouraging in vitro and limited in vivo results for several AuI and AuIII complexes. The antiparasitic mechanisms of these molecules remain only partially understood. However, a few studies have proposed the trypanothione redox system as a target, similar to the mammalian thioredoxin system, pointed out as the main target for several gold compounds with significant antitumor activity. In this review, we present the current status of the investigation and design of gold compounds directed at treating leishmaniasis. In addition, we explore potential targets in Leishmania parasites beyond the trypanothione system, taking into account previous studies and structure modulation performed for gold-based compounds.

Silver/chitosan nanocomposites induce physiological and histological changes in freshwater bivalve.

BACKGROUND: Bivalves can accumulate and concentrate most pollutants, even if they are present in somewhat low concentrations. The present study aimed to use freshwater bivalveas for the first time as vital indicator for silver/chitosan nanocomposites (Ag-CS NCs) in the freshwater environment. METHODS: Following the preparation and characterization of Ag-CS NCs by using UV-vis spectrophotometer, X-ray diffraction, transmission electron microscopy, and acute toxicity study, the animals exposed to three different dose of nano chitosan (CS), AgNPs, and Ag-CS NCs (12.5, 25 and 50 mg/L) for consecutive 6 days. RESULTS: Ag-CS particles were in size range of 8-19 nm. The nominal concentrations for Ag-CS NCs were 12.5, 25 and 50 mg Ag L-1 were corresponding to measured concentration of AgNPs 0.37, 0.81, and 1.65 mg Ag L-1, respectively. All concentrations of Ag-CS NCs caused a significant increase in MDA and NO, while GSH and CAT levels decreased significantly in all organs. Histological investigation of the gills, labial palp and foot tissues showed alternation after exposure to Ag-CS NCs, especially at dose 50 mg/L. CONCLUSION: The present study showed that exposure to Ag-CS NCs caused oxidative stress responses in Coelatura aegyptiaca and histological changes in the organs. These physiological and histological changes observed after exposure to Ag-CS NCs were most likely the result of the action of AgNPs themselves while the effect of chitosan on these changes was negligible. We concluded that Coelatura aegyptiaca was a sensitive bio-indicator for monitoring of the past and the present water pollution by nanoparticles.

Biodegradable Charge-Transfer Complexes for Glutathione Depletion Induced Ferroptosis and NIR-II Photoacoustic Imaging Guided Cancer Photothermal Therapy.

Suffering from the laborious synthesis and undesirable tumor microenvironment response, the exploitation of novel NIR-II absorbing organic photothermal agents is of importance to promote phototherapeutic efficacy. Herein, two kinds of charge-transfer complex nanoparticles (TMB-F4TCNQ and TMB-TCNQ) are prepared by supramolecular assembly. Because of the larger energy gap between donor and acceptor, TMB-F4TCNQ presents higher charge-transfer degree (72 %) than that of TMB-TCNQ (48 %) in nanoaggregates. Therefore, TMB-F4TCNQ exhibits stronger NIR-II absorption ability with a mass extinction coefficient of 15.4 Lg-1 cm-1 at 1300 nm and excellent photothermal effect. Impressively, the specific cysteine response can make the TMB-F4TCNQ effectively inhibit the intracellular biosynthesis of GSH, leading to redox dsyhomeostasis and ROS-mediated ferroptosis. TMB-F4TCNQ can serve as a contrast agent for NIR-II photoacoustic imaging to guide precise and efficient photothermal therapy in vivo.

Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy.

The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11high) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucose- and glutamine-dependency in SLC7A11high cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11high cancer. In this review, we summarize diverse regulatory mechanisms of SLC7A11 in cancer, discuss ferroptosis-dependent and -independent functions of SLC7A11 in promoting tumor development, explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells, and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment. This review will provide the foundation for further understanding SLC7A11 in ferroptosis, nutrient dependency, and tumor biology and for developing novel effective cancer therapies.

Cell line-dependent difference in glutathione levels affects the cigarette sidestream smoke-induced inhibition of nucleotide excision repair.

We recently reported that cigarette sidestream smoke (CSS) induced inhibition of nucleotide excision repair (NER) and the cause was NER molecule degradation by aldehydes contained in CSS [Carcinogenesis39, 56-65, 2018; Mutat. Res.834, 42-50, 2018]. In this study, we examined the relationship between intracellular glutathione (GSH) levels and CSS-induced NER inhibition. CSS treatment decreased the intracellular GSH level in human keratinocytes HaCaT, in which the repair of pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) after UVB irradiation was suppressed. We used l-buthionine-(S,R)-sulfoximine (BSO) to artificially deplete intracellular GSH level. BSO treatment remarkably accelerated the CSS-induced NER inhibition. The NER inhibition by CSS was attributed to the delay of accumulation of NER molecules (TFIIH and XPG) to DNA damaged sites, which was further enhanced by BSO treatment. CSS degraded TFIIH, and BSO promoted it as expected. Formaldehyde (FA), a major constituent of CSS, showed similar intracellular GSH reduction and NER inhibition, and BSO promoted its inhibitory effect. Five cultured cell lines showed considerable variability in intrinsic GSH levels, and CSS-induced NER inhibitory effect was significantly correlated with the GSH levels. Chemicals like aldehydes are known to react not only with proteins but also with DNA, causing DNA lesions targeted by NER. Our results suggest that the tissues and cells with low intrinsic GSH levels are susceptible to treatment with CSS and electrophilic compounds like aldehydes through NER inhibition, thus leading to higher genotoxicity and carcinogenicity.

Electrophilic reactivity of the Busulfan metabolite, EdAG, towards cellular thiols and inhibition of human thioredoxin-1.

Busulfan is an alkylating agent used in chemotherapy conditioning regimens prior to hematopoietic stem cell transplantation (HSCT). However, its administration is associated with a great risk of adverse toxicities, which have been historically attributed to busulfan's mechanism of non-specific DNA alkylation. A phase II generated metabolite of busulfan, EdAG (γ-glutamyldehydroalanylglycine), is a dehydroalanine analog of glutathione (GSH) with an electrophilic moiety, suggesting it may bind to proteins and disrupt biological function. However, EdAG's reactions with common cellular thiols such as glutathione (GSH) and l-cysteine are understudied, along with possible inhibition of glutathionylation-dependent enzymes (with active site cysteine residues). We established a physiologically-relevant in vitro model to readily measure thiol loss over time. Using this model, we compared the apparent rates of thiol depletion in the presence of EdAG or arecoline, a toxic constituent of the areca (betel) nut and known GSH depletor. Simulated kinetic modeling revealed that the mean (±SE) alpha (α) second order rate constants describing GSH and l-cysteine depletion in the presence of EdAG were 0.00522 (0.00845) µM-1∙min-1 and 0.0207 (0.00721) µM-1∙min-1, respectively; in the presence of arecoline, the apparent rates of depletion were 0.0619 (0.009) µM-1∙min-1 and 0.2834 (0.0637) µM-1∙min-1 for GSH and l-cysteine, respectively. Under these experimental conditions, we conclude that EdAG was a weaker electrophile than arecoline. Arecoline and EdAG both depleted apparent l-cysteine concentrations to a much greater extent than GSH, approximately 4.58-fold and 3.97-fold change greater, respectively. EdAG modestly inhibited (∼20%) the human thioredoxin-1 (hTrx-1) catalyzed reduction of insulin with a mean IC50 of 93 µM [95% CI: 78.6-110 µM). In summary, EdAG's ability to spontaneously react with endogenous thiols and inhibit hTrx-1 are potentially biochemically relevant in humans. These findings continue to support the growing concept that EdAG, an underrecognized phase II metabolite of busulfan, plays a role in untoward cellular toxicities during busulfan pharmacotherapy.

Glutathione Conjugation and Protein Adduction by Environmental Pollutant 2,4-Dichlorophenol In Vitro and In Vivo.

2,4-Dichlorophenol (2,4-DCP), an environmental pollutant, was reported to cause hepatotoxicity. The biochemical mechanisms of 2,4-DCP induced liver injury remain unknown. The present study showed that 2,4-DCP is chemically reactive and spontaneously reacts with GSH and bovine serum albumin to form GSH conjugates and BSA adducts. The observed conjugation/adduction apparently involved the addition of GSH and departure of chloride via the ipso substitution pathway. Two biliary GSH conjugates and one urinary N-acetyl cysteine conjugate were observed in rats given 2,4-DCP. The N-acetyl cysteine conjugate was chemically synthesized and characterized by mass spectrometry and NMR. As expected, 2,4-DCP was found to modify hepatic protein at cysteine residues in vivo by the same chemistry. The observed protein adduction reached its peak at 15 min and revealed dose dependency. The new findings allowed us to better understand the mechanisms of the toxic action of 2,4-DCP.

Combination of magnetic targeting with synergistic inhibition of NF-κB and glutathione via micellar drug nanomedicine enhances its anti-tumor efficacy.

Breast cancer is not only one of the most prevalent types of cancer, but also it is a prime cause of death in women aged between 20 and 59. Although chemotherapy is the most common therapy approach, multiple side effects can result from lack of specificity and the use of overdose as safe doses may not completely cure cancer. Therefore, we aimed in this study is to combine the merits of NF-κB inhibiting potential of celastrol (CST) with glutathione inhibitory effect of sulfasalazine (SFZ) which prevents CST inactivation and thus enhances its anti-tumor activity. Inspired by the CD44-mediated tumor targeting effect of the hydrophilic polysaccharide chondroitin sulphate (ChS), we chemically synthesized amphiphilic zein-ChS micelles. While the water insoluble SFZ was chemically coupled to zein, CST was physically entrapped within the hydrophobic zein/SFZ micellar core. Moreover, physical encapsulation of oleic acid-capped SPIONs in the hydrophobic core of micelles enabled both magnetic tumor targeting as well as MRI theranostic capacity. Combining magnetic targeting to with the active targeting effect of ChS resulted in enhanced cellular internalization of the micelles in MCF-7 cancer cells and hence higher cytotoxic effect against MCF-7 and MDA-MB-231 breast cancer cells. In the in vivo experiments, magnetically-targeted micelles (154.4 nm) succeeded in achieving the lowest percentage increase in the tumor volume in tumor bearing mice, the highest percentage of tumor necrosis associated with significant reduction in the levels of TNF-α, Ki-67, NF-κB, VEGF, COX-2 markers compared to non-magnetically targeted micelles-, free drug-treated and positive control groups. Collectively, the developed magnetically targeted micelles pave the way for design of cancer nano-theranostic drug combinations.

Near-infrared photothermal liposomal nanoantagonists for amplified cancer photodynamic therapy.

Photodynamic therapy (PDT) has been demonstrated to be a promising strategy for the treatment of cancer, while its therapeutic efficacy is often compromised due to excessive concentrations of glutathione (GSH) as a reactive oxygen species (ROS) scavenger in cancer cells. Herein, we report the development of near-infrared (NIR) photothermal liposomal nanoantagonists (PLNAs) for amplified PDT through through the reduction of intracellular GSH biosynthesis. Such PLNAs were constructed via encapsulating a photosensitizer, indocyanine green (ICG) and a GSH synthesis antagonist, l-buthionine sulfoximine (BSO) into a thermal responsive liposome. Under NIR laser irradiation at 808 nm, PLNAs generate mild heat via a ICG-mediated photothermal conversion effect, which leads to the destruction of thermal responsive liposomes for a controlled release of BSO in a tumor microenvironment, ultimately reducing GSH levels. This amplifies intracellular oxidative stresses and thus synergizes with PDT to afford an enhanced therapeutic efficacy. Both in vitro and in vivo data verify that PLNA-mediated phototherapy has an at least 2-fold higher efficacy in killing cancer cells and inhibiting tumor growth compared to sole PDT. This study thus demonstrates a NIR photothermal drug delivery nanosystem for amplified photomedicine.

Anti-leukemia activities of selenium nanoparticles embedded in nanotube consisted of triple-helix ß-d-glucan.

Acute myeloid leukemia (AML) is a difficult therapeutic hematological tumor. It is urgent to find a non-toxic natural drug to treat AML. Herein, the selenium nanoparticles (SeNPs) embedded in nanotubes consisted of triple helix ß-(1, 3)-d-glucan (BFP) from the black fungus that were wrapped to form stable inclusion complex BFP-Se, which was self-assembled and exhibited high stability in water. In vitro, the BFP-Se significantly inhibited the proliferation of AML cells and increased the cytotoxicity on AML cells. On single-cell levels, the U937 cells were gradually swelled and lysed with BFP-Se treatment on optofluidics chips. Further, the blood and bone marrow analysis indicated the anti-leukemia effects of BFP-Se in vivo. Moreover, BFP-Se increased the total antioxidant capacity of AML cells and decreased the expression of c-Jun activation domain-binding protein 1 and thioredoxin 1. Our results suggest that this biocompatible polysaccharide nanotube containing Se nanoparticles would provide a novel strategy for AML therapy.