Personalized SO2 Prodrug for pH-Triggered Gas Enhancement in Anti-Tumor Radio-Immunotherapy.

The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis. As a non-invasive therapeutic method, radiotherapy is utilized for tumor ablation. In this study, we aimed to improve the therapeutic impact of radiotherapy and trigger an immune response by formulating a benzothiazole sulfinate (BTS)-loaded fusion liposome (BFL) nanoplatform, which was then combined with radiotherapy for anti-cancer treatment. The platelet cell membrane, equipped with distinctive surface receptors, enables BFL to effectively target tumors while evading the immune system and adhering to tumor cells. This facilitates BFL's engulfment by cancer cells, subsequently releasing BTS within them. Following the release, the BTS produces sulfur dioxide (SO2) for gas therapy, initiating the oxidation of intracellular glutathione (GSH). This process demonstrates efficacy in repairing damage post-radiotherapy, thereby achieving effective radiosensitization. It was revealed that an immune response was triggered following the enhanced radiosensitization facilitated by BFL. This approach facilitated the maturation of dendritic cell (DC) within lymph nodes, leading to an increase in the proportion of T cells in distant tumors. This resulted in significant eradication of primary tumors and inhibition of growth in distant tumors. In summary, the integration of personalized BFL with radiotherapy shows potential in enhancing both tumor immune response and the elimination of tumors, including metastasis.

Biomimetic copper-doped polypyrrole nanoparticles induce glutamine metabolism inhibition to enhance breast cancer cuproptosis and immunotherapy.

Cuproptosis, a newly discovered mechanism of inducing tumor cell death, primarily relies on the intracellular accumulation of copper ions. The utilization of Cu-based nanomaterials to induce cuproptosis holds promising prospects in future biomedical applications. However, the presence of high levels of glutathione (GSH) within tumor cells hinders the efficacy of cuproptosis. In this study, we have developed a BPTES-loaded biomimetic Cu-doped polypyrrole nanoparticles (CuP) nanosystem (PCB) for enhanced cuproptosis and immune modulation. PCB comprises an internal BPTES and CuP core and an external platelet membrane (PM) that facilitates active targeting to tumor sites following intravenous administration. Subsequently, PCB effectively suppresses glutaminase (GLS1) activity, thereby reducing GSH content. Moreover, CuP catalyze intracellular H2O2, amplifying oxidative stress while simultaneously inducing dihydrolipoyl transacetylase (DLAT) oligomerization through released Cu2+, resulting in cuproptosis. PCB not only inhibits primary tumors but also exhibits inhibitory effects on abscopal tumors. This work represents the first instance where GLS inhibition has been employed to enhance cuproptosis and immunotherapy. It also provides valuable insights into further investigations on cuproptosis.

Biomimetic Copper-Doped Polypyrrole Nanoparticles for Enhanced Cancer Low-Temperature Photothermal Therapy.

Introduction: Photothermal therapy (PTT) has a significant potential for its application in precision tumour therapy. However, PTT-induced hyperthermia may damage healthy tissues and trigger the expression of heat shock proteins (HSPs), thereby compromising the long-term therapeutic efficacy of PTT. Methods: In this study, a biomimetic drug delivery system comprising CuP nanozymes as the inner core and platelet membrane (PM) as the outer shell was successfully developed for administering synergistic chemodynamic therapy and mild PTT. PM is encapsulated on CuP to form this biomimetic nanoparticle (PM-coated CuP nanoparticles, PC). PC possesses peroxidase (POD) activity, can facilitate the conversion of hydrogen peroxide into ·OH, thereby inhibiting the expression of HSPs. Results: Upon exposure to low-power laser irradiation (0.5 W/cm2, 1064 nm), PC can convert near-infrared II laser energy into heat energy, thereby enabling the administration of enhanced mild PTT. In vitro and in vivo experiments have demonstrated that this synergistic approach can induce over 90% tumour eradication with favourable biocompatibility. Discussion: PC exhibits high efficacy and biocompatibility, making it a promising candidate for future applications.

The gut microbiome dysbiosis and regulation by fecal microbiota transplantation: umbrella review.

Background: Gut microbiome dysbiosis has been implicated in various gastrointestinal and extra-gastrointestinal diseases, but evidence on the efficacy and safety of fecal microbiota transplantation (FMT) for therapeutic indications remains unclear. Methods: The gutMDisorder database was used to summarize the associations between gut microbiome dysbiosis and diseases. We performed an umbrella review of published meta-analyses to determine the evidence synthesis on the efficacy and safety of FMT in treating various diseases. Our study was registered in PROSPERO (CRD42022301226). Results: Gut microbiome dysbiosis was associated with 117 gastrointestinal and extra-gastrointestinal. Colorectal cancer was associated with 92 dysbiosis. Dysbiosis involving Firmicutes (phylum) was associated with 34 diseases. We identified 62 published meta-analyses of FMT. FMT was found to be effective for 13 diseases, with a 95.56% cure rate (95% CI: 93.88-97.05%) for recurrent Chloridoids difficile infection (rCDI). Evidence was high quality for rCDI and moderate to high quality for ulcerative colitis and Crohn's disease but low to very low quality for other diseases. Conclusion: Gut microbiome dysbiosis may be implicated in numerous diseases. Substantial evidence suggests FMT improves clinical outcomes for certain indications, but evidence quality varies greatly depending on the specific indication, route of administration, frequency of instillation, fecal preparation, and donor type. This variability should inform clinical, policy, and implementation decisions regarding FMT.

A tumor cell exosome-mimicking multifunctional nanozyme for targeted breast cancer radiotherapy.

Radiotherapy (RT) has been extensively used for the treatment of breast cancer. However, the efficacy of RT is reduced by the high content of reducing species within cells (such as glutathione (GSH)). In addition, high-dose radiotherapy is often accompanied by serious side effects. In an attempt to resolve these issues, a tumor cell exosome-mimicking multifunctional nanozyme system (CuPy-Au@EM) was developed as a radiosensitizer, which consists of an internal AuNP-embedded CuPy nanozyme core and an external tumor cell exosome membrane. The exosome membrane protein on the surface of CuPy-Au@EM leads to the accurate localization of nano-materials in the tumor site; simultaneously, the level of H2O2 will be enhanced because of the GOx-like activity of AuNPs. Then CuPy-Au@EM would continue to trigger a rapid decline in cellular GSH content and the production of a large number of hydroxyl radicals (˙OH) through its glutathione peroxidase (GPx) and peroxidase (POD) activities allows for the extension of the radiotherapeutic cascade. Studies conducted in vivo and in vitro demonstrated that the combination of CuPy-Au@EM and moderate dose RT (4 Gy) can significantly reduce tumor proliferation. These findings indicated that CuPy-Au@EM nanospheres could be plausibly developed into promising radio-sensitizers on tumors.

Cu-doped polypyrrole hydrogel with tumor catalyst activity for NIR-II thermo-radiotherapy.

Introduction: Radiotherapy (RT) is one of the key methods for treating breast cancer. However, the effect of single RT is often poor because of insufficient deposition of X-rays in tumor sites and radiation resistance induced by the abnormal tumor microenvironment (overexpression of glutathione (GSH)). The development of multifunctional RT sensitizers and synergetic therapeutic strategies is, therefore, a promising area for enhancing the anticancer effect of RT. Methods: In this study, a multifunctional nanozyme hydrogel based on Cu-doped polypyrrole (CuP) was designed to work concertedly with a second near-infrared thermal RT. The CuP-based hydrogel (CH) reached the tumor site when injected in-situ and achieved long-term storage. Results: Once stimulated with 1064-nm laser irradiation, the heated and softened hydrogel system released CuP nanozyme to provide photothermal therapy, thereby inhibiting the repair of DNA damage caused by RT. In addition, CuP with dual nanozyme activity depleted the intracellular GSH to reduce the antioxidant capacity of the tumor. Moreover, CuP converted H2O2 to produce ·OH to directly kill the tumor cells, thus enhancing the capability of low-dose RT to inhibit tumor growth. In vivo experiments showed that the CH system used in combination with a low-power 1064-nm laser and low-dose RT (4 Gy) exhibited good synergistic anticancer effects and biological safety. Discussion: As a new light-responsive hydrogel system, CH holds immense potential for radio-sensitization.

Dynamic computed tomography manifestations of simulated wooden foreign bodies in blood-saline mixtures with variable concentrations and retention times.

Diagnosing wooden foreign bodies (WFBs) using computed tomography (CT) is often missed, leading to adverse outcomes. This study aims to reduce misdiagnoses by exploring the density variation of blood-saline mixtures in ex vivo models. Twenty Cunninghamia lanceolata sticks, selected as WFB models, were randomly assigned to five groups: a control group (saline) and four experimental groups immersed in blood-saline mixtures with varying concentrations. The samples were then placed in a constant-temperature water bath at 36.8 °C. CT scans were performed in the lowest and highest density areas, and the volume of the low-density areas was measured at the post-processing workstation. Finally, the effects of time and concentration on imaging were analyzed, and fitting curves were generated. The blood-saline mixture concentration and time significantly affected the CT number in the three areas. WFB images changed dynamically over time, with two typical imaging signs: the bull's-eye sign on the short axis images and the tram line sign on the long axis images. Fitting curves of the CT number in the lowest density areas with different concentrations can quantify imaging changes. The CT number of the lowest density areas increased with time, following a logarithmic function type, while the CT number of the highest density areas exhibited a fast-rising platform type. The volume of the low-density areas decreased over time. The time of damage caused by WFBs and the influence of varying blood and tissue fluid contents at the damaged site should be considered in the diagnosis. Imaging changes from multiple CT scans at different times can aid in diagnosis.

Type-I AIE Photosensitizer Loaded Biomimetic System Boosting Cuproptosis to Inhibit Breast Cancer Metastasis and Rechallenge.

Cuproptosis shows good application prospects in tumor therapy. However, the copper efflux mechanism and highly expressed intracellular reducing substances can inhibit the cuproptosis effects. In this study, a platelet vesicle (PV) coated cuprous oxide nanoparticle (Cu2O)/TBP-2 cuproptosis sensitization system (PTC) was constructed for multiple induction of tumor cuproptosis. PTC was prepared by physical extrusion of AIE photosensitizer (TBP-2), Cu2O, and PV. After the biomimetic modification, PTC can enhance its long-term blood circulation and tumor targeting ability. Subsequently, PTC was rapidly degraded to release copper ions under acid conditions and hydrogen peroxides in tumor cells. Then, under light irradiation, TBP-2 quickly enters the cell membrane and generates hydroxyl radicals to consume glutathione and inhibit copper efflux. Accumulated copper can cause lipoylated protein aggregation and iron-sulfur protein loss, which result in proteotoxic stress and ultimately cuproptosis. PTC treatment can target and induce cuproptosis in tumor cells in vitro and in vivo, significantly inhibit lung metastasis of breast cancer, increase the number of central memory T cells in peripheral blood, and prevent tumor rechallenge. It provides an idea for the design of nanomedicine based on cuproptosis.

PLGA Nanoparticles Loaded with Sorafenib Combined with Thermosensitive Hydrogel System and Microwave Hyperthermia for Multiple Sensitized Radiotherapy.

Hypoxia is typically the leading cause of radiotherapy (RT) resistance in solid tumors, and glutathione (GSH) overexpression in tumor cells is a potent antioxidant mechanism that protects tumor cells from radiation damage. Herein, we developed a sorafenib (SFN) loaded-PLGA hydrogel system (SPH) in combination with microwave (MW) hyperthermia for RT sensitization. SPH with stable properties was produced by combining SFN and PLGA in a specific ratio and encapsulating the mixture in agarose hydrogel. Intratumoral injection of SPH to mice combined with MW hyperthermia can not only directly cause thermal damage to tumor cells, but also increase blood oxygen delivery to the tumor site, thus overcoming the problem of intratumoral hypoxia and achieving "first layer" RT sensitization. Moreover, high temperatures can cause the hydrogel to disintegrate and release SFN. Not only can SFN inhibit tumor growth, but it can also achieve the "second layer" of RT sensitization by inhibiting glutathione (GSH) synthesis in cells and increasing reactive oxygen species (ROS) production. Experiments, both in vitro and in vivo, have indicated that SPH and MW hyperthermia can achieve a double RT sensitization effect and a significant tumor inhibition effect. In conclusion, combining our SPH nanosystem and thermoradiotherapy is a promising anti-tumor treatment.

A type I AIE photosensitiser-loaded biomimetic nanosystem allowing precise depletion of cancer stem cells and prevention of cancer recurrence after radiotherapy.

Radioresistance of Cancer stem cell (CSC) is an important cause of tumor recurrence after radiotherapy (RT). Herein, we designed a type I aggregation-induced emission (AIE) photosensitiser-loaded biomimetic mesoporous organosilicon nanosystem (PMT) for precise depletion of CSC to prevent tumor recurrence after RT. This PMT system is composed of a type I AIE photosensitiser (TBP-2) loaded mesoporous organosilicon nanoparticles (MON) with an outer platelet membrane. The PMT system is able to specifically target CSC. Intracellular glutathione activity leads to MON degradation and the release of TBP-2. Type I photodynamic therapy is activated by exposure to white light, producing a large amount of hydroxyl radicals to promote CSC death. The results of in vivo experiments demonstrated specific removal of CSC following PMT treatment, with no tumor recurrence observed when combined with RT. However, tumor recurrence was observed in mice that received RT only. The expression of CSC markers was significantly reduced following PMT treatment. We demonstrate the development of a system for the precise removal of CSC with good biosafety and high potential for clinical translation. We believe the PMT nanosystem represents a novel idea in the prevention of tumor recurrence.

CuS nanoparticles and camptothecin co-loaded thermosensitive injectable hydrogel with self-supplied H2O2 for enhanced chemodynamic therapy.

Chemodynamic therapy (CDT) is a kind of anti-tumor strategy emerging in recent years, but the concentration of hydrogen peroxide (H2O2) in the tumor microenvironment is insufficient, and it is difficult for a single CDT to completely inhibit tumor growth. Here, we designed a CuS nanoparticles (NPs) and camptothecin (CPT) co-loaded thermosensitive injectable hydrogel (SCH) with self-supplied H2O2 for enhanced CDT. SCH is composed of CuS NPs and CPT loaded into agarose hydrogel according to a certain ratio. We injected SCH into the tumor tissue of mice, and under the irradiation of near-infrared region (NIR) laser at 808 nm, CuS NPs converted the NIR laser into heat to realize photothermal therapy (PTT), and at the same time, the agarose hydrogel was changed into a sol state and CPT was released. CPT activates nicotinamide adenine dinucleotide phosphate oxidase, increases the level of H2O2 inside the tumor, and realizes the self-supply of H2O2. At the same time, CuS can accelerate the release of Cu2+ in an acidic environment and light, combined with H2O2 generated by CPT for CDT treatment, and consume glutathione in tumor and generate hydroxyl radical, thus inducing tumor cell apoptosis. The SCH system we constructed achieved an extremely high tumor inhibition rate in vitro and in vivo, presenting a new idea for designing future chemical kinetic systems.

Cancer cell membrane-coated C-TiO2 hollow nanoshells for combined sonodynamic and hypoxia-activated chemotherapy.

Sonodynamic therapy (SDT) is a promising strategy for tumor treatment that satisfies all requirements of penetrating deep-seated tissues without causing additional trauma. However, the hypoxic tumor microenvironment impairs the therapeutic effect of SDT. The synergistic treatment of oxygen concentration-dependent SDT and bio-reductive therapy has been proven to be an effective approach to improve the therapeutic efficiency of SDT by exploiting tumor hypoxia. Herein, a biomimetic drug delivery system (C-TiO2/TPZ@CM) was successfully synthesized for combined SDT and hypoxia-activated chemotherapy, which was composed of tirapazamine (TPZ)-loaded C-TiO2 hollow nanoshells (HNSs) as the inner cores and cancer cell membrane (CM) as the outer shells. C-TiO2 HNSs coated with CM achieved tumor targeting via homologous binding. C-TiO2@CM as a nanocarrier loaded with TPZ in the presence of the trapping ability of CM and the special cavity structure of C-TiO2 HNSs. Moreover, C-TiO2 HNSs as sonosensitizers killed cancer cells under ultrasound (US) irradiation. Oxygen depletion during SDT induced a hypoxic environment in the tumor to activate the killing effect of co-delivered TPZ, thereby obtaining satisfactory synergistic therapeutic effects. In addition, C-TiO2@CM exhibited remarkable biocompatibility without manifest damage and toxicity to the blood and major organs of the mice. The study highlighted that C-TiO2/TPZ@CM served as a powerful biomimetic drug delivery system for effective SDT by exploiting tumor hypoxia. STATEMENT OF SIGNIFICANCE: • C-TiO2@CM achieved tumor targeting via homologous binding. • C-TiO2 hollow nanoshells could be used as a sonosensitizer and drug carrier for synergistic SDT and hypoxia-activated chemotherapy. • C-TiO2/TPZ@CM showed no obvious toxicity under the injection dose.

Nanozyme hydrogel for enhanced alkyl radical generation and potent antitumor therapy.

Alkyl radicals (R˙), which do not rely on oxygen generation for causing cellular stress, have been applied in tumor treatment, but a large amount of glutathione (GSH) in the tumor cells reacts with alkyl radicals, thereby reducing their antitumor effect. In this study, an enhanced alkyl radical generation system responsive to near-infrared light was designed. The alkyl radical trigger 2,2'-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH) and nanozyme pyrite (FeS2) were encapsulated in agarose hydrogel to prepare the AIPH-FeS2-hydrogel (AFH) system. FeS2 can be used as a photothermal agent to convert near-infrared light energy into heat energy, leading to the dissolution of the hydrogel. AIPH is simultaneously induced to produce alkyl radicals. FeS2 can also be used as an oxidative stress amplifier to reduce intracellular GSH content, thereby boosting the therapeutic effect of alkyl radicals. Eventually, the oxygen-independent free radicals generated by the AFH system under near-infrared laser irradiation and photothermal treatment can kill cancer cells through the synergistic oxidation/photothermal effect. The AFH system developed herein provides new insights into enhancing the therapeutic effect of alkyl radicals.

Boosting the photodynamic therapy of near-infrared AIE-active photosensitizers by precise manipulation of the molecular structure and aggregate-state packing.

Organic functional materials have emerged as a promising class of emissive materials with potential application in cancer phototheranostics, whose molecular structures and solid-state packing in the microenvironment play an important role in reactive oxygen species (ROS) generation and the photodynamic therapy (PDT) effect. Clarifying the guidelines to precisely modulate PDT performance from molecular and aggregate levels is desired but remains challenging. In this work, two compounds, TCP-PF6 and TTCP-PF6, with similar skeletons are strategically synthesized, in which a thiophene segment is ingeniously introduced into the molecular backbone of TCP-PF6 to adjust the intrinsic molecular characteristics and packing in the aggregate state. The experimental and theoretical results demonstrate that TTCP-PF6 can form tight packing mode in comparison with TCP-PF6, resulting in efficient cell imaging and enhanced ROS generation ability in vitro and in vivo. The promising features make TTCP-PF6 a superior photosensitizer for PDT treatment against cancer cells by targeting mitochondria. These findings can provide a feasible molecular design for modulating the biological activity and developing photosensitizers with high ROS generation and PDT effect.

Nanosensitizers for sonodynamic therapy for glioblastoma multiforme: current progress and future perspectives.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, and it is associated with poor prognosis. Its characteristics of being highly invasive and undergoing heterogeneous genetic mutation, as well as the presence of the blood-brain barrier (BBB), have reduced the efficacy of GBM treatment. The emergence of a novel therapeutic method, namely, sonodynamic therapy (SDT), provides a promising strategy for eradicating tumors via activated sonosensitizers coupled with low-intensity ultrasound. SDT can provide tumor killing effects for deep-seated tumors, such as brain tumors. However, conventional sonosensitizers cannot effectively reach the tumor region and kill additional tumor cells, especially brain tumor cells. Efforts should be made to develop a method to help therapeutic agents pass through the BBB and accumulate in brain tumors. With the development of novel multifunctional nanosensitizers and newly emerging combination strategies, the killing ability and selectivity of SDT have greatly improved and are accompanied with fewer side effects. In this review, we systematically summarize the findings of previous studies on SDT for GBM, with a focus on recent developments and promising directions for future research.

Activation of aldehyde dehydrogenase 2 protects ethanol-induced osteonecrosis of the femoral head in rat model.

OBJECTIVES: Osteonecrosis of the femoral head (ONFH) is a devastating disease characterized by destructive bone structures, enlarged adipocyte accumulation and impaired vascularization. The aldehyde dehydrogenase 2 (ALDH 2) is the limiting enzyme for ethanol metabolism with many physiological functions. The aim was investigated the potential protective role of activated ALDH 2 by Alda-1 for ethanol-induced ONFH. MATERIALS AND METHODS: The ethanol-induced ONFH in rat was performed to explore the protective of Alda-1 by various experimental methods. Subsequently, the effect of Alda-1 and ethanol on the osteogenic and adipogenic differentiation was investigated via multiple cellular and molecular methods. Finally, the effect of Alda-1 and ethanol on the neo-vascularization was detected in Human umbilical vein endothelial cells (HUVECs) and ONFH model. RESULTS: Firstly, radiographical and pathological measurements indicated that alda-1 protected ethanol-induced ONFH. Moreover, ethanol significantly inhibited the proliferation and osteogenic differentiation of BMSCs, whereas Alda-1 could distinctly rescue it by PI3K/AKT signalling. Secondly, ethanol remarkably promoted the lipid vacuoles formation of BMSCs, while Alda-1 significantly retarded it on BMSCs by AMPK signalling pathway. Finally, ethanol significantly inhibited proliferation and growth factor level resulting in reduced angiogenesis, whereas Alda-1 could rescue the effect of ethanol. Additionally, Alda-1 significantly reduced the occurrence of ONFH and promoted vessel number and distribution in alcoholic ONFH. CONCLUSIONS: Alda-1 activation of ALDH 2 was highly demonstrated to protect ethanol-induced ONFH by triggering new bone formation, reducing adipogenesis and stimulating vascularization.

AIEgen-Based Bionic Nanozymes for the Interventional Photodynamic Therapy-Based Treatment of Orthotopic Colon Cancer.

Relative to traditional photosensitizer (PS) agents, those that exhibit aggregation-induced emission (AIE) properties offer key advantages in the context of photodynamic therapy (PDT). At present, PDT efficacy is markedly constrained by the hypoxic microenvironment within tumors and the limited depth to which lasers can penetrate in a therapeutic context. Herein, we developed platelet-mimicking MnO2 nanozyme/AIEgen composites (PMD) for use in the interventional PDT treatment of hypoxic tumors. The resultant biomimetic nanoparticles (NPs) exhibited excellent stability and were able to efficiently target tumors. Moreover, they were able to generate O2 within the tumor microenvironment owing to their catalase-like activity. Notably, through an interventional approach in which an optical fiber was introduced into the abdominal cavity of mice harboring orthotopic colon tumors, good PDT efficacy was achieved. We thus propose that a novel strategy consisting of a combination of an AIEgen-based bionic nanozyme and a biomimetic cell membrane coating represents an ideal therapeutic platform for targeted antitumor PDT. This study is the first to have combined interventional therapy and AIEgen-based PDT, thereby overcoming the limited light penetration that typically constrains the therapeutic efficacy of this technique, highlighting a promising new AIEgen-based PDT treatment strategy.

Tumor-derived exosomes co-delivering aggregation-induced emission luminogens and proton pump inhibitors for tumor glutamine starvation therapy and enhanced type-I photodynamic therapy.

Although promising, the efficiency of aggregation-induced emission luminogens (AIEgens)-based photodynamic therapy (PDT) is limited by cellular glutathione (GSH). GSH is not a terminal reducing agent but it can be oxidized and subsequently reduced to its original state by reductases to further participate in antioxidant activity. It is therefore imperative to control GSH for effectively inducing oxidation within tumor cells. Recent studies showed that tumor cell metabolism depends mainly on glutamine, which is also the nitrogen and ATP source for GSH synthesis. Therefore, glutamine-based starvation therapy may be effective in enhancing photodynamic therapy. In this work, tumor-derived exosomes were developed for co-delivering AIEgens and proton pump inhibitors (PPI) for tumor combination therapy. Tumor-derived exosomes could specifically deliver drugs to the tumor sites, where PPI inhibited cell glutamine metabolism, suppressed tumor cell GSH and ATP production, and improved the effect of type-I PDT from AIEgens. When used in the treatment of MGC803 gastric cancer subcutaneous model, our system shows a high tumor growth inhibition rate, and even promoting tumor immunogenic death. This is the first work which combine inhibition of glutamine metabolism with PDT, and it has the potential to be applied for future designs of new tumor metabolic therapies and photodynamic systems.

Effective Combination of Isoniazid and Core-Shell Magnetic Nanoradiotherapy Against Gastrointestinal Tumor Cell Types.

Introduction: Radiotherapy is a conventional treatment for gastrointestinal tumors. However, its therapeutic effect might not be satisfactory because of factors such as radio-resistance of tumor cells and dose reduction applied to avoid damage to normal tissues. We developed a novel combination therapy involving the use of isoniazid (INH) and core-shell magnetic nanospheres (NPs) to enhance the efficacy of radiotherapy. Methods: Magnetic core-shell NPs were synthesized. The shell manganese dioxide (MnO2) reacted with intracellular glutathione to produce Mn2+, which decomposed hydrogen peroxide (H2O2) to hydroxyl radicals (·OH) in the presence of INH to produce sufficient amount of reactive oxygen species. In addition to this chemodynamic therapy, MnO2 catalyzed H2O2 to O2, which alleviated hypoxia in tumors and thus enhanced the effect of radiotherapy. In addition, iron oxide (Fe3O4) and reduced Mn2+ were potential candidates for T1-T2 dual-mode magnetic resonance imaging (MRI) with remarkable magnetic targeting ability. Results: NPs exhibited efficient tumor targeting performance under the magnetic field and improved T1/T2 dual-mode MRI, which elevated oxygen levels without toxicity to the mice to achieve remarkable therapeutic outcomes, reaching a tumor inhibition rate of 93.2%. Moreover, chemodynamic therapy mediated by INH and NPs enhanced the therapeutic effect of radiotherapy both in vivo and in vitro. Conclusion: The results demonstrated that the combination of INH and NPs could be a novel strategy for radiosensitization with clinical potential.

An Injectable Hydrogel for Enhanced FeGA-Based Chemodynamic Therapy by Increasing Intracellular Acidity.

Hydroxyl radical (•OH)-mediated chemodynamic therapy (CDT) is an emerging antitumor strategy, however, acid deficiency in the tumor microenvironment (TME) hampers its efficacy. In this study, a new injectable hydrogel was developed as an acid-enhanced CDT system (AES) for improving tumor therapy. The AES contains iron-gallic acid nanoparticles (FeGA) and α-cyano-4-hydroxycinnamic acid (α-CHCA). FeGA converts near-infrared laser into heat, which results in agarose degradation and consequent α-CHCA release. Then, as a monocarboxylic acid transporter inhibitor, α-CHCA can raise the acidity in TME, thus contributing to an increase in ·OH-production in FeGA-based CDT. This approach was found effective for killing tumor cells both in vitro and in vivo, demonstrating good therapeutic efficacy. In vivo investigations also revealed that AES had outstanding biocompatibility and stability. This is the first study to improve FeGA-based CDT by increasing intracellular acidity. The AES system developed here opens new opportunities for effective tumor treatment.