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Microwave thermotherapy (MWTT), as a treatment for tumors, lacks specificity and requires sensitizers. Most reported microwave sensitizers are single metal-organic frameworks (MOFs), which must be loaded with ionic liquids to enhance the performance in MWTT. Meanwhile, MWTT is rarely combined with other treatment modalities. Here, we synthesized a novel Fe-Cu bimetallic organic framework FeCuMOF (FCM) by applying a hydrothermal method and further modified it with methyl polyethylene glycol (mPEG). The obtained FCM@PEG (FCMP) showed remarkable heating performance under low-power microwave irradiation; it also acted as a novel nanospheres enzyme to catalyze H2O2 decomposition, producing abundant reactive oxygen species (ROS) to deplete glutathione (GSH) and prevent ROS clearance from tumor cells during chemodynamic treatment. The FCMP was biodegradable and demonstrated excellent biocompatibility, allowing it to be readily metabolized without causing toxic effects. Finally, it was shown to act as a suitable agent for T2 magnetic resonance imaging (MRI) in vitro and in vivo. This new bimetallic nanostructure could successfully realize two tumor treatment modalities (MWTT and chemodynamic therapy) and dual imaging modes (T2 MRI and microwave thermal imaging). Our findings represent a breakthrough for integrating the diagnosis and treatment of tumors and provides a reference for developing new microwave sensitizers.
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Unavoidable damage to normal tissues and tumor microenvironment (TME) resistance make it challenging to eradicate breast carcinoma through radiotherapy. Therefore, it is urgent to develop radiotherapy sensitizers that can effectively reduce radiation doses and reverse the suppressive TME. Here, a novel biomimetic PEGylated Cu2WS4 nanozyme (CWP) with multiple enzymatic activities is synthesized by the sacrificing template method to have physical radiosensitization and biocatalyzer-responsive effects on the TME. Experiment results show that CWP can improve the damage efficiency of radiotherapy on breast cancer cell 4T1 through its large X-ray attenuation coefficient of tungsten and nucleus-penetrating capacity. CWP also exhibit strong Fenton-like reactions that produced abundant ROS and GSH oxidase-like activity decreasing GSH. This destruction of redox balance further promotes the effectiveness of radiotherapy. Transcriptome sequencing reveals that CWP induced ferroptosis by regulating the KEAP1/NRF2/HMOX1/GPX4 molecules. Therefore, owing to its multiple enzymatic activities, high-atomic W elements, nucleus-penetrating, and ferroptosis-inducing capacities, CWP effectively improves the efficiency of radiotherapy for breast carcinoma in vitro and in vivo. Furthermore, CWP-mediated radiosensitization can trigger immunogenic cell death (ICD) to improve the anti-PD-L1 treatments to inhibit the growth of primary and distant tumors effectively. These results indicate that CWP is a multifunctional nano-sensitizers for radiotherapy and immunotherapy.
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Ferroptosis , Polietilenglicoles , Ferroptosis/efectos de los fármacos , Polietilenglicoles/química , Animales , Línea Celular Tumoral , Ratones , Cobre/química , Cobre/farmacología , Femenino , Inmunoterapia/métodos , Microambiente Tumoral/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/química , Neoplasias de la Mama/patología , Humanos , Ratones Endogámicos BALB CRESUMEN
Microwave hyperthermia (MH) is an emerging treatment for solid tumors, such as breast cancer, due to its advantages of minimally invasive and deep tissue penetration. However, MH induced tumor hypoxia is still an obstacle to breast tumor treatment failure. Therefore, an original nanoengineering strategy was proposed to exacerbate hypoxia in two stages, thereby amplifying the efficiency of activating tirapazamine (TPZ). And a novel microwave-sensitized nanomaterial (GdEuMOF@TPZ, GEMT) is designed. GdEuMOF (GEM) nanoparticles are certified excellent microwave (MW) sensitization performance, thus improving tumor selectivity to achieve MH. Meanwhile MW can aggravate the generation of thrombus and caused local circulatory disturbance of tumor, resulting in the Stage I exacerbated hypoxia environment passively. Due to tumor heterogeneity and uneven hypoxia, GEMT nanoparticles under microwave could actively deplete residual oxygen through the chemical reaction, exacerbating hypoxia level more evenly, thus forming the Stage II of exacerbated hypoxia environment. Consequently, a two-stage exacerbated hypoxia GEMT nanoparticles realize amplifying activation of TPZ, significantly enhance the efficacy of microwave hyperthermia and chemotherapy, and effectively inhibit breast cancer. This research provides insights into the development of progressive nanoengineering strategies for effective breast tumor therapy.
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Antineoplásicos , Neoplasias de la Mama , Hipertermia Inducida , Neoplasias , Humanos , Femenino , Tirapazamina/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Microondas , Neoplasias/terapia , Hipoxia/terapia , Línea Celular TumoralRESUMEN
Microwave thermotherapy (MWT) has shown great potential in cancer treatment due to its deep tissue penetration and minimally invasive nature. However, the poor microwave absorption (MA) properties of the microwave thermal sensitizer in the medical frequency band significantly limit the thermal effect of MWT and then weaken the therapeutic efficacy. In this paper, a Ni-based multilayer heterointerface nanomissile of MOFs-Ni-Ru@COFs (MNRC) with improved MA performance in the desired frequency band via introducing magnetic loss and dielectric loss is developed for MWT-based treatment. The loading of the Ni nanoparticle in MNRC mediates the magnetic loss, introducing the MA in the medical frequency band. The heterointerface formed in the MNRC by nanoengineering induces significant interfacial polarization, increasing the dielectric loss and then enhancing the generated MA performance. Moreover, MNRC with the strong MA performance in the desired frequency range not only enhances the MW thermal effect of MWT but also facilitates the electron and energy transfer, generating reactive oxygen species (ROS) at tumor sites to mediate microwave dynamic therapy (MDT). The strategy of strengthening the MA performance of the sensitizer in the medical frequency band to improve MWT-MDT provides a direction for expanding the clinical application of MWT in tumor treatment.
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Síndrome de Cockayne , Neoplasias , Humanos , Microondas , Transferencia de EnergíaRESUMEN
The adaptive control of sunlight through photochromic smart windows could have a huge impact on the energy efficiency and daylight comfort in buildings. However, the fabrication of inorganic nanoparticle and polymer composite photochromic films with a high contrast ratio and high transparency/low haze remains a challenge. Here, a solution method is presented for the in situ growth of copper-doped tungsten trioxide nanoparticles in polymethyl methacrylate, which allows a low-cost preparation of photochromic films with a high luminous transparency (luminous transmittance Tlum = 91%) and scalability (30 × 350 cm2 ). High modulation of visible light (ΔTlum = 73%) and solar heat (modulation of solar transmittance ΔTsol = 73%, modulation of solar heat gain coefficient ΔSHGC = 0.5) of the film improves the indoor daylight comfort and energy efficiency. Simulation results show that low-e windows with the photochromic film applied can greatly enhance the energy efficiency and daylight comfort. This photochromic film presents an attractive strategy for achieving more energy-efficient buildings and carbon neutrality to combat global climate change.
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Microwave thermotherapy (MWTT) has limited its application in the clinic due to its high rate of metastasis and recurrence after treatment. Nitric oxide (NO) is a gaseous molecule that can address the high metastasis and recurrence rates after MWTT by increasing thermal sensitivity, down-regulating the expression of hypoxia-inducible factor-1 (HIF-1), and inducing the immunogenic cell death (ICD). Therefore, GaMOF-Arg is designed, a gallium-based organic skeleton material derivative loaded with L-arginine (L-Arg), and coupled the mitochondria-targeting drug of triphenylphosphine (TPP) on its surface to obtain GaMOF-Arg-TPP (GAT) MW-immunosensitizers. When GAT MW-immunosensitizers are introduced into mice through the tail vein, reactive oxygen species (ROS) are generated and L-Arg is released under MW action. Then, L-Arg reacts with ROS to generate NO, which not only downregulates HIF-1 expression to improve tumor hypoxia exacerbated by MW, but also enhances immune responses by augment calreticulin (CRT) exposure, high mobility group box 1 (HMGB1) release, and T-cell proliferation to achieve prevention of tumor metastasis and recurrence. In addition, NO can induce mitochondria damage to increase their sensitivity to MWTT. This study provides a unique insight into the use of metal-organic framework MW-immunosensitizers to enhance tumor therapy and offers a new way to treat cancer efficiently.
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Aiming at the clinical problems of high recurrence and metastasis rate of triple-negative breast cancer, a divide-and-conquer tactic is developed. The designed nanoactivators enhance microwave thermo-dynamic-chemotherapy to efficiently kill primary tumors, simultaneously ameliorate the immunosuppressive microenvironment, activate the tumor infiltration of T lymphocytes, and enhance the accumulation and penetration of PD-1/PD-L1 immune agents, ultimately boosting the efficacy of immune checkpoint blocking therapy to achieve efficient inhibition of distal tumors and metastases. Metal-organic framework (MOF)-based MPPT nano-activator is synthesized by packaging chemotherapeutic drug Pyrotinib and immunosuppressant PD-1/PD-L1 inhibitor 2 into MnCa-MOF and then coupling target molecule triphenylphosphine, which significantly improved the accumulation and penetration of Pyrotinib and immunosuppressant in tumors. In addition to the combined treatment of microwave thermo-dynamic-chemotherapy under microwave irradiation, Mn2+ in the nano-activator comprehensively promotes the cGAS-STING pathway to activate innate immunity, microwave therapy, and hypoxia relief are combined to ameliorate the tumor immunosuppressive microenvironment. The released Pyrotinib down-regulates epidermal growth factor receptor and its downstream pathways PI3K/AKT/mTOR and MAPK/ERK signaling pathways to maximize the therapeutic effect of immune checkpoint blocking, which helps to enhance the antitumor efficacy and promote long-term memory immunity. This nano-activator offers a generally promising paradigm for existing clinical triple-negative breast cancer treatment through a divide-and-conquer strategy.
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Estructuras Metalorgánicas , Neoplasias de la Mama Triple Negativas , Humanos , Estructuras Metalorgánicas/farmacología , Estructuras Metalorgánicas/uso terapéutico , Microondas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Receptor de Muerte Celular Programada 1 , Fosfatidilinositol 3-Quinasas , Inmunosupresores/farmacología , Microambiente Tumoral , Inmunoterapia , Línea Celular TumoralRESUMEN
BACKGROUNDS: The novel concept of microwave dynamic therapy (MDT) solves the problem of incomplete tumor eradication caused by non-selective heating and uneven temperature distribution of microwave thermal therapy (MWTT) in clinic, but the poor delivery of microwave sensitizer and the obstacle of tumor hypoxic microenvironment limit the effectiveness of MDT. RESULTS: Herein, we engineer a liquid metal-based nanozyme LM@ZIF@HA (LZH) with eutectic Gallium Indium (EGaIn) as the core, which is coated with CoNi-bimetallic zeolite imidazole framework (ZIF) and hyaluronic acid (HA). The flexibility of the liquid metal and the targeting of HA enable the nanozyme to be effectively endocytosed by tumor cells, solving the problem of poor delivery of microwave sensitizers. Due to the catalase-like activity, the nanozyme catalyze excess H2O2 in the tumor microenvironment to generate O2, alleviating the restriction of the tumor hypoxic microenvironment and promoting the production of ROS under microwave irradiation. In vitro cell experiments, the nanozyme has remarkable targeting effect, oxygen production capacity, and microwave dynamic effect, which effectively solves the defects of MDT. In the constructed patient-derived xenograft (PDX) model, the nanozyme achieves excellent MDT effect, despite the heterogeneity and complexity of the tumor model that is similar to the histological and pathological features of the patient. The tumor volume in the LZH + MW group is only about 1/20 of that in the control group, and the tumor inhibition rate is as high as 95%. CONCLUSION: The synthesized nanozyme effectively solves the defects of MDT, improves the targeted delivery of microwave sensitizers while regulating the hypoxic microenvironment of tumors, and achieves excellent MDT effect in the constructed PDX model, providing a new strategy for clinical cancer treatment.
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Neoplasias de la Mama , Neoplasias , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Microondas , Peróxido de Hidrógeno , Neoplasias/tratamiento farmacológico , Metales/uso terapéutico , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Microwave thermal therapy (MWTT) is one of the most potent ablative treatments known, with advantages like deep penetration, minimal invasion, repeatable operation, and low interference from bone and gas. However, microwave (MW) is not selective against tumors, and residual tumors after incomplete ablation will generate immunosuppression, ultimately making tumors prone to recurrence and metastasis. Herein, a nano-immunomodulator (Bi-MOF-l-Cys@PEG@HA, BMCPH) is proposed to reverse the immunosuppression and reactivate the antitumor immune effect through responsively releasing H2S in tumor cells for improving MWTT. Under MW irradiation, BMCPH will mediate MWTT to ablate tumors and release l-cysteine (l-Cys) to react with the highly expressed cystathionine ß-synthase in tumor to generate H2S. The generated H2S can inhibit the accumulation of myeloid-derived suppressor cells (MDSCs) and promote the expression of cytotoxic T lymphocytes (CTLs). Moreover, Bi-MOF can also scavenge reactive oxygen species (ROS), a major means of MDSCs-mediated immunosuppression, to further weaken the immunosuppressive effect. Simultaneously, the surface-covered HA will gather CTLs around the tumor to enhance the immune response. This nano gas immunomodulator provides an idea for the sensitive and tunable release of unstable gas molecules at tumor sites. The strategy of H2S gas to reverse immunosuppression and reactivate antitumor immune response introduces a direction to reduce the risk of tumor recurrence and metastasis after thermal ablation.
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Microondas , Neoplasias , Humanos , Microondas/uso terapéutico , Terapia de Inmunosupresión , Neoplasias/terapia , Inmunidad , Tolerancia Inmunológica , Microambiente TumoralRESUMEN
In vivo monitoring of treatment response is of great significance for tumor therapy in clinical trials, but it remains a formidable challenge. Herein, we demonstrate a logic AND gate theranostic nanoagent that responds to the coexistence of endogenous and exogenous stimuli, namely HAuCl4@1-Tetradecanol@Gd-based metal-organic framework@SiO2 nanocomposites (APGS NCs). Upon microwave (MW) irradiation, HAuCl4 in the inner part of APGS NCs reacts with the tumor-associated glutathione (GSH). Subsequently, it transforms into an active luminescent form of Au@1-Tetradecanol@Gd-MOF@SiO2 nanocomposites (AuPGS NCs). The intensity of generated fluorescence is correlated with the tumor thermal-injury status. Thus, the generation of AuPGS NCs with high intensity fluorescence under the co-activation of MW and GSH can visualize the treatment effects during MW thermal therapy and instantly modulate the irradiation time and range for optimal outcomes. Hence, this logic gate controlled APGS NCs makes MW thermal therapy eliminate tumor cells completely. This research offers an effective strategy for the design and preparation of activatable theranostic nanoagents for precise tumor imaging and therapy.
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Neoplasias , Medicina de Precisión , Humanos , Microondas , Dióxido de Silicio , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Neoplasias/patología , Nanomedicina Teranóstica/métodos , Línea Celular TumoralRESUMEN
Microwave (MW) dynamic therapy (MDT) can efficiently eliminate tumor residue resulting from MW thermal therapy. However, MDT is currently in its infancy, and luck of effective MDT sensiters severely limits its clinical therapeutic effect. Herein, based on TiMOF (TM), a high-efficiency MW sensitizer is designed for MW thermo-dynamic therapy. TM can generate heat and cytotoxic reacyive oxygen species (ROS) under MW irradiation and has the potential to be used as an MW sensitizer, while the suboptimal MW dynamic sensitization effect of TM limits its application. Inorder to improve the MW dynamic sensitization performance, a covalent organic framework (COF) with good stability and a large conjugate system is used to cover TM, which is conductive to electron and energy transfer, thus increasing the ROS generation rate and prolonging the ROS lifetime. In addition, loading Ni NPs endow nanomaterials with magnetic resonance imaging capabilities. Therefore, this work develops an MW sensitizer based on TM for the first time, and the mechanism of COF coating to enhance the MW dynamic sensitization of TM is preliminarily explored, which provides a new idea for the further development of MW sensitizer with great potential.
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Estructuras Metalorgánicas , Nanoestructuras , Neoplasias , Humanos , Estructuras Metalorgánicas/química , Microondas , Especies Reactivas de Oxígeno , Neoplasias/tratamiento farmacológicoRESUMEN
Microwave thermal dynamic therapy (MTDT), which combines thermal effects and reactive oxygen species (ROS) by microwave activation, seems to be a promising anticancer therapeutic method. A multifunctional agent for achieving synergistic localized cancer treatment is the key to exploit the strategy to inhibit tumor cell recurrence and metastasis. In the study, a ZIF-67 based theranostic agent loaded with metal-chalcogenide open framework 3 (MCOF3) and heat shock protein 70 (HSP70) as the inner component was studied, coupled with targeting cancer cell membrane (TCM) as the biomimetic outer shell. We found that metal ions in MCOF3 enabled the composite agents to show peroxide-like activity to produce â¢OH and destroy cancer cells. And then, the microwave (MW) thermal sensitizer of ZIF-67 was used to specifically convert the MW energy into thermal energy and selectively heat the tumor via the cell's targeting. Additionally, the effect of continuous MW thermal therapy has been shown to promote the expression of HSP70, and further activate the effector of CD4 T cell and CD8α T cell. As such, the agents effectively inhibit the tumor cell growth under MW irradiation in vitro and in vivo due to the synergistic effects of MTDT and immune cell activation. The study provides an emerging strategy to ablation cancer effectively.
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Biomimética , Neoplasias , Microondas , Presentación de Antígeno , Linfocitos T CD4-Positivos , Ciclo Celular , Proteínas HSP70 de Choque Térmico , Metales , Neoplasias/tratamiento farmacológicoRESUMEN
Janus particles have been considered suitable for biomedicine owing to their asymmetric structure and unique properties. Although Janus particles have been applied in biosensing for dual-mode sensing, there are almost no reports for the detection of multiple indicators. In fact, many patients require different diagnoses, such as the examination of hepatogenic diseases in diabetics. Here, a Janus particle based on SiO2 was synthesized using a Pickering emulsion method. A novel strategy for detecting glucose and alpha-fetoprotein (AFP) based on different principles using this Janus particle was then constructed as a detection platform. Composed of adjustable dendritic silica loaded with gold nanoclusters (Au NCs) and glucose oxidase (GOx) and spherical SiO2 coupled with AFP antibody, this Janus fluorescent probe achieved the double detection of glucose and AFP. With the protection of dendritic silica, the enzyme temperature stability was enhanced. Moreover, the low limit of detection for glucose (0.5 µM in PBS and 2.5 µM in serum) and AFP (0.5 ng mL-1) illustrated the feasibility of the application of the Janus material in integrated detection. This work not only supported the use of a Janus fluorescent probe as a detection platform toward glucose and AFP but also showed the potential of Janus particles in integrated detection in the future.
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Glucosa , alfa-Fetoproteínas , Humanos , Colorantes Fluorescentes , Dióxido de Silicio/químicaRESUMEN
A compact millimeter-wave on-chip sensor for dielectric detection is presented using gallium arsenide technology based on spoof surface plasmon polaritons (SSPPs). The proposed structure is developed from traditional half-mode substrate integrated waveguide (HMSIW) and its dispersion characteristics is analyzed through electromagnetic simulations. Consequently, the operating frequency and bandwidth of the on-chip sensor can be easily adjusted, which provides more flexibility for the practical application of the sensor. The linear sensing for relative dielectric constant of the film materials is acquired, with thickness-insensitive property. Moreover, the low coupling to the nearby components can be achieved due to the strong field confinement characteristics of the SSPPs, which is of great significance in the application scenarios of on-chip integrated circuits for the suppression of electromagnetic interference.
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BACKGROUNDS: Reversing the immunosuppressive tumor microenvironment (TME) in the tumor is widely deemed to be an effective strategy to improve immune therapy. In particular, the redox balance in TME needs to be well controlled due to its critical role in mediating the functions of various cells, including cancer cells and immune-suppressive cells. RESULTS: Here, we propose an efficient strategy to reshape the redox homeostasis to reverse immunosuppressive TME. Specifically, we developed a microwave-chemo-immunostimulant CMMCP to promote the infiltration of the tumor-T cells by simultaneously reducing the reactive oxygen species (ROS) and glutathione (GSH) and improving the oxygen (O2) levels in TME. The CMMCP was designed by loading chemotherapy drugs cisplatin into the bimetallic Ce-Mn MOF nanoparticles coated with polydopamine. The Ce-Mn MOF nanoparticles can effectively improve the catalytic decomposition of ROS into O2 under microwave irradiation, resulting in overcoming hypoxia and limited ROS generation. Besides, the activity of intracellular GSH in TME was reduced by the redox reaction with Ce-Mn MOF nanoparticles. The reprogrammed TME not only boosts the immunogenic cell death (ICD) induced by cisplatin and microwave hyperthermia but also gives rise to the polarization of pro-tumor M2-type macrophages to the anti-tumor M1-type ones. CONCLUSION: Our in vivo experimental results demonstrate that the microwave-chemo-immunostimulant CMMCP significantly enhances the T cell infiltration and thus improves the antitumor effect. This study presents an easy, safe, and effective strategy for a whole-body antitumor effect after local treatment.
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Adyuvantes Inmunológicos , Microondas , Cisplatino , Especies Reactivas de Oxígeno , Factores Inmunológicos , Inmunosupresores , Inmunoterapia , Oxidación-Reducción , Glutatión , OxígenoRESUMEN
Hollow materials derived from metal-organic frameworks (MOFs) have emerged in the biomedical field due to their unique properties, and different synthesis methods have been proposed. However, so far, the large-scale use of hollow MOFs is mostly limited by the timeliness of synthesis methods. Herein, we propose a new ultrasonic aerosol flow strategy for the instantaneous synthesis of a Zr-MOF-derived hollow sphere complex (ZC-HSC) in only one step. Through rapid transient heating, the coordination between metal salts and organic ligands occurs along with prompt evaporation of the solvent. The whole process lasts for only about 21 s, compared with several steps that take hours or even days for conventional synthesis methods. Based on the ZC-HSC, we designed a nanodrug with the functions of manipulating the tumor microenvironment, which can reshape the tumor microenvironment by improving tumor hypoxia and inflammatory microenvironment and promoting antiangiogenic therapy. Combined with microwave thermo-chemotherapy, the nanodrugs effectively treat triple-negative breast cancer (the tumor cell survival rate was only 34.76 and 31.05% in normoxic and hypoxic states, respectively, and the tumor inhibition rate reached 87.9% at the animal level), providing a new theoretical basis for the treatment of triple-negative breast cancer. This rapid, one-step, and continuous ultrasonic aerosol flow strategy has bright prospects in the synthesis of MOF-derived hollow materials and promotes the further development of large-scale applications of biological nanomaterials.
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Estructuras Metalorgánicas , Nanopartículas , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Microondas , Estructuras Metalorgánicas/farmacología , Microambiente Tumoral , Nanopartículas/uso terapéuticoRESUMEN
Despite being a common therapy for hepatocellular carcinoma (HCC), insufficient thermal ablation can leave behind tumor residues that can cause recurrence. This is believed to augment M2 inflammatory macrophages that usually play a pro-tumorigenic role. To address this problem, we designed d-mannose-chelated iron oxide nanoparticles (man-IONPs) to polarize M2-like macrophages into the antitumor M1 phenotype. In vitro and in vivo experiments demonstrated that man-IONPs specifically targeted M2-like macrophages and accumulated in peri-ablation zones after macrophage infiltration was augmented under insufficient microwave ablation (MWA). The nanoparticles simultaneously induced polarization of pro-tumorigenic M2 macrophages into antitumor M1 phenotypes, enabling the transformation of the immunosuppressive microenvironment into an immunoactivating one. Post-MWA macrophage polarization exerted robust inhibitory effects on HCC progression in a well-established orthotopic liver cancer mouse model. Thus, combining thermal ablation with man-IONPs can salvage residual tumors after insufficient MWA. These results have strong potential for clinical translation.
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Thermotherapy can directly kill tumor cells whilst being accompanied by immune-enhancing effects. However, this immune-enhancing effect suffers from insufficient expression of immune response factors (e.g., heat shock protein 70, HSP70), resulting in no patient benefiting due to the recurrence of tumor cells after thermotherapy. Herein, a nanoengineered strategy of programmed upregulating of the immune response factors for amplifying synergistic therapy is explored. Metal-organic frameworks nanoamplifiers (teprenone/nitrocysteine@ZrMOF-NH2 @L-menthol@triphenylphosphine, GGA/CSNO@ZrMOF-NH2 -LM-TPP nanoamplifier, and GCZMT nanoamplifier) achieve excellent microwave (MW) thermal-immunotherapy by programmed induction of HSP70 expression. After intravenous administration, GCZMT nanoamplifiers target the mitochondria, and then release nitric oxide (NO) under MW irradiation. NO inhibits the growth of tumor cells by interfering with the energy supply of cells. Subsequently, under the combination of MW, NO, and GGA, HSP70 expression can be programmed upregulated, which can induce the response of cytotoxic CD4+ T cells and CD8+ T cells, and effectively activate antitumor immunotherapy. Hence, GCZMT nanoamplifier-mediated MW therapy can achieve a satisfactory therapeutic effect with the tumor inhibition of 97%. This research offers a distinctive insight into the exploitation of metal-organic frameworks nanoamplifiers for enhanced tumor therapy, which provides a new approach for highly effective cancer treatment.
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Estructuras Metalorgánicas , Linfocitos T CD8-positivos , Proteínas HSP70 de Choque TérmicoRESUMEN
Microwave hyperthermia is an emerging minimally invasive therapy in which thermal damage and apoptosis of tumor cells are induced by local heating of tissues with microwave radiation. Recently, microwave hyperthermia has been widely used in clinical practice; however, uneven aggregation and dispersion of malignant tumors after microwave hyperthermia are the main problems associated with this method. In this work, a microridged waveguide tumor hyperthermia antenna with an operating frequency of 915 MHz was designed. Although its volume is only 6.6 cm3, it exhibited a highly focused heating effect, achieving rapid heating in a small area. However, microwave hyperthermia has several shortcomings. Microwaves cannot specifically identify and target tumors; this decreases the efficiency of the treatment if the temperature of the tumor site is not sufficiently high for its size and location. Therefore, Zr metal-organic framework (ZrMOF)-derived composite ZCNC was synthesized using the ultrasonic aerosol flow method, which has good microwave sensitization and biosafety. ZCNC reduced the damage to normal cells and greatly improved the tumor treatment effect of microwave hyperthermia (tumor inhibition rate reached 78.01%). Thus, the proposed strategy effectively improves the current clinical microwave hyperthermia treatment method.
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Microwave (MW) hyperthermia is one of the safest and most efficient minimally invasive tumor treatment methods, it is restricted by the bottlenecks of the heat sink effect and ineffective immune activation. Herein, a multifunctional nano platform with the load of nano immune modulator bimetallic metal-organic framework (BM), tumor vessel destructive agent and prodrug for gas production is developed for improving MW hyperthermia. Specifically, the combretastatin A4 phosphate (CA4P) was a vessel destructive agent to reduce MW heat loss by destructing the tumor blood vessel. Moreover, the as designed BM can scavenge the endogenic reactive oxygen species, which is conducive to hydrogen sulfide gas (H2S) that produced by bismuth sulfide (Bi2S3) to activate immune cells. Our in vivo experimental results demonstrate the destruction of tumor blood vessels coupled with the activated immune system results in the remarkable antitumor effect. This study provides an efficient strategy to improve MW hyperthermia by a combination of vasculature-targeting therapy with systemic immunity.