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Combination therapies have attracted significant attention because they address the limitations of monotherapy while improving overall efficacy. In this study, we designed a novel nanoplatform, named GOx@Fe-DMSN@PDA (GFDP), by integrating Fe2+ into dendritic mesoporous silica nanoparticles (DMSN) and selecting glucose oxidase (GOx) as the model drug loaded into the DMSN pores. Additionally, we coated the surface of the DMSN with polydopamine (PDA) to confer pH/near infrared (NIR) light-responsive controlled-release behavior and photothermal therapy (PTT). The introduction of Fe2+ into the DMSN framework greatly improved biodegradability and enhanced the peroxidase (POD)-like activity of GFDP. In addition, GOx could consume glucose and generate hydrogen peroxide (H2O2) within tumor cells to facilitate starvation therapy and enhance cascade catalysis. The PDA coating provided the DMSN with an intelligent response release ability, promoting efficient photothermal conversion and achieving the PTT effect. Cellular tests showed that under NIR light irradiation, GFDP exhibited a synergistic effect of PTT-enhanced starvation therapy and cascade catalysis, with a half-maximal inhibitory concentration (IC50) of 2.89 µg/mL, which was significantly lower than that of GFDP without NIR light irradiation (18.29 µg/mL). The in vivo anti-tumor effect indicated that GFDP could effectively accumulate at the tumor site for thermal imaging and showed remarkable synergistic therapeutic effects. In summary, GFDP is a promising nanoplatform for multi-modal combination therapy that integrates starvation therapy, PTT, and cascade catalysis.
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The practical application of Na-based solid-state electrolytes (SSEs) is limited by their low level of conduction. To evaluate the impact of tetrahedral anion groups on carrier migration, we designed a set of anti-perovskite SSEs theoretically based on the previously reported Na4OBr2, including Na4O(BH4)2, Na4O(BF4)2, and Na4O(AlH4)2. It is essential to note that the excessive radius of anionic groups inevitably leads to lattice distortion, resulting in asymmetric migration paths and a limited improvement in carrier migration rate. Na4O(AlH4)2 provides a clear example of where Na+ migrates in two distinct environments. In addition, due to different spatial charge distributions, the interaction strength between anionic groups and Na+ is different. Strong interactions can cause carriers to appear on a swing, leading to a decrease in conductivity. The low conductivity of Na4O(BF4)2 is a typical example. This study demonstrates that Na4O(BH4)2 exhibits remarkable mechanical and dynamic stability and shows ionic conductivity of 1.09 × 10-4 S cm-1, two orders of magnitude higher than that of Na4OBr2. This is attributed to the expansion of the carrier migration channels by the anion groups, the moderate interaction between carriers and anionic groups, and the "paddle-wheel" effect generated by the anion groups, indicating that the "paddle-wheel" effect is still effective in low-dimensional anti-perovskite structures, in which atoms are arranged asymmetrically.
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Reactive oxygen species (ROS) generated from photosensitizers exhibit great potential for repolarizing immunosuppressive tumor-associated macrophages (TAMs) toward the anti-tumor M1 phenotype, representing a promising cancer immunotherapy strategy. Nevertheless, their effectiveness in eliminating solid tumors is generally limited by the instability and inadequate TAMs-specific targeting of photosensitizers. Here, a novel core-shell integrated nano platform is proposed to achieve a coordinated strategy of repolarizing TAMs for potentiating cancer immunotherapy. Colloidal mesoporous silica nanoparticles (CMSN) are fabricated to encapsulate photosensitizer-Indocyanine Green (ICG) to improve their stability. Then ginseng-derived exosome (GsE) was coated on the surface of ICG/CMSN for targeting TAMs, as well as repolarizing TAMs concurrently, named ICG/CMSN@GsE. As expected, with the synergism of ICG and GsE, ICG/CMSN@GsE exhibited better stability, mild generation of ROS, favorable specificity toward M2-like macrophages, enhancing drug retention in tumors and superior TAMs repolarization potency, then exerted a potent antitumor effect. In vivo, experiment results also confirm the synergistic suppression of tumor growth accompanied by the increased presence of anti-tumor M1-like macrophages and maximal tumor damage. Taken together, by integrating the superiorities of TAMs targeting specificity and synergistic TAMs repolarization effect into a single nanoplatform, ICG/CMSN@GsE can readily serve as a safe and high-performance nanoplatform for enhanced cancer immunotherapy.
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Mucosal immunization is a powerful weapon against viral infection. In this paper, large pore mesoporous silica nanoparticles (LMSN) with different particle sizes were synthesized for loading influenza split vaccine (SV) to explore the effect of nanoparticle sizes on mucosal immunization and adjuvant efficacy. Interestingly, it was found that among the three particle sizes of nanoparticles, only LMSN-M with around 250â¯nm could significantly enhance the mucosal immune effect of SV, possessing adjuvant effect. The results indicated that particle size affected the adjuvant effect of LMSN. There was no apparent difference in vaccine loading capacity of LMSN with different particle sizes, but the release of SV depended on the pore length of LMSN. The adjuvant effect of LMSN-M was attributed to its higher cellular uptake performance, intestine absorption and transport efficiency, and the ability to stimulate the maturation of dendritic cells. Simultaneously, compared with LMSN-S and LMSN-L, the more retention of LMSN-M in mesenteric lymph nodes increased the chance of interaction between vaccine and immune system, resulting in the enhanced immunity. This is the first time to study the impact of particle size of LMSN adjuvant on improving mucosal immunity of oral influenza vaccine, and the present work provides a scientific reference for adjuvant design of oral vaccine.
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Vacunas contra la Influenza , Nanopartículas , Tamaño de la Partícula , Dióxido de Silicio , Dióxido de Silicio/química , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/química , Vacunas contra la Influenza/administración & dosificación , Nanopartículas/química , Animales , Administración Oral , Porosidad , Ratones , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Ratones Endogámicos BALB C , Femenino , Inmunidad Mucosa/efectos de los fármacos , Propiedades de SuperficieRESUMEN
[This corrects the article DOI: 10.1016/j.apsb.2022.04.018.].
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Photodynamic therapy (PDT) is limited in tumor therapy due to the mature antioxidant barrier of tumor microenvironment (TME) and phototoxicity/easy-degradation characteristics of photosensitizers. Therefore, we prepared Cu2+-doped hollow carbon nanoparticles (CHC) to protect the loaded photosensitizers and sensitize TME by glutathione-depletion and peroxidase (POD)-like activity for enhanced PDT. CHC significantly increased the maximum speed of POD-like reaction (Vm) of 8.4 times. By coating with hyaluronic acid (HA), the active sites on CHC were temporarily masked with low catalytic property, and restored in response to the overexpressed hyaluronidase in TME. Meanwhile, due to the excellent photothermal conversion efficiency (32.5 %) and hollow structure of CHC, the loaded photosensitizers were well protected from sunlight activation-induced unwanted phototoxicity and rapid degradation under the near-infrared light irradiation. In-vivo anti-tumor experiments demonstrated that the combination of photothermal-photodynamic effect achieved the best anti-tumor effect (tumor inhibition rate at 87.8 %) compared with any monotherapy. In addition, the combination of photothermal and photodynamic effect could efficiently suppress the cell migration, manifesting the reduced number of lung metastasized nodules by 74 %. This work provides an integrated platform for photosensitizers protection and TME sensitization for enhanced PDT.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotosensibilizantes/química , Carbono/farmacología , Microambiente Tumoral , Neoplasias/tratamiento farmacológico , Catálisis , Línea Celular Tumoral , Nanopartículas/química , Peróxido de HidrógenoRESUMEN
Limited drug loading and incomplete drug release are two major obstacles that traditional polymeric microneedles (MNs) have to overcome. For smart controlled-release MNs, since drug release duration is uncertain, a clear indication of the finish of drug release is also important for patient guidance on the timing of the next dose. In this study, MN with a triple structure of a glucose-responsive shell, loaded insulin powders and a colored propelling inner core (inspired by the mechanism of osmotic pump) was innovatively constructed. The MN patch could release insulin according to blood glucose levels (BGLs) and had excellent drug loading, more complete drug release, and good drug stability, which significantly prolonged the normoglycemic time. An approximately 0.3 cm2 patch has a hypoglycemic effect on diabetic mice for up to 24 h. Moreover, the fading of the inner core could indicate the release process of the loaded drug and can help to facilitate uninterrupted closed loop therapy for patients. The designed triple MN structure is also suitable, and can be used in the design of other smart MN drug delivery systems to further improve their drug loading capacity and simultaneously achieve more complete, smart controlled and visualized drug release.
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Diabetes Mellitus Experimental , Humanos , Ratones , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Agujas , Sistemas de Liberación de Medicamentos , Insulina , Glucosa , Administración CutáneaRESUMEN
Phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), has been considered an elegant solution to eradicate tumors due to its minimal invasiveness and low systemic toxicity. Nevertheless, it is still challenging for phototherapy to achieve ideal outcomes and clinical translation due to its inherent drawbacks. Owing to the unique biological functions, diverse gases have attracted growing attention in combining with phototherapy to achieve super-additive therapeutic effects. Specifically, gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) have been proven to kill tumor cells by inducing mitochondrial damage in synergy with phototherapy. Additionally, several gases not only enhance the thermal damage in PTT and the reactive oxygen species (ROS) production in PDT but also improve the tumor accumulation of photoactive agents. The inflammatory responses triggered by hyperthermia in PTT are also suppressed by the combination of gases. Herein, we comprehensively review the latest studies on gas-synergized phototherapy for cancer therapy, including (1) synergistic mechanisms of combining gases with phototherapy; (2) design of nanoplatforms for gas-synergized phototherapy; (3) multimodal therapy based on gas-synergized phototherapy; (4) imaging-guided gas-synergized phototherapy. Finally, the current challenges and future opportunities of gas-synergized phototherapy for tumor treatment are discussed. STATEMENT OF SIGNIFICANCE: 1. The novelty and significance of the work with respect to the existing literature. (1) Strategies to design nanoplatforms for gas-synergized anti-tumor phototherapy have been summarized for the first time. Meanwhile, the integration of various imaging technologies and therapy modalities which endow these nanoplatforms with advanced theranostic capabilities has been summarized. (2) The mechanisms by which gases synergize with phototherapy to eradicate tumors are innovatively and comprehensively summarized. 2. The scientific impact and interest. This review elaborates current trends in gas-synergized anti-tumor phototherapy, with special emphases on synergistic anti-tumor mechanisms and rational design of therapeutic nanoplatforms to achieve this synergistic therapy. It aims to provide valuable guidance for researchers in this field.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Medicina de Precisión , Fototerapia/métodos , Gases/uso terapéutico , Neoplasias/patología , Terapia Combinada , Nanopartículas/uso terapéutico , Línea Celular TumoralRESUMEN
Reactive oxygen species (ROS) play a crucial role in regulating the metabolism of tumor growth, metastasis, death and other biological processes. ROS-based nanodynamic therapies (NDTs) are becoming attractive due to non-invasive, low side effects and tumor-specific advantages. NDTs have rapidly developed into numerous branches, such as photodynamic therapy, chemodynamic therapy, sonodynamic therapy and so on. However, the complexity of the tumor microenvironment and the limitations of existing sensitizers have greatly restricted the therapeutic effects of NDTs, which heavily rely on ROS levels. To address the limitations of NDTs, various strategies have been developed to increase ROS yield, which is an urgent aspect for the positive development of NDTs. In this review, the nanodynamic potentiation strategies in terms of unique properties and universalities of NDTs are comprehensively outlined. We mainly summarize the current dilemmas faced by each NDT and the respective solutions. Meanwhile, the NDTs universalities-based potentiation strategies and NDTs-based combined treatments are elaborated. Finally, we conclude with a discussion of the key issues and challenges faced in the development and clinical transformation of NDTs.
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Neoplasias , Fotoquimioterapia , Humanos , Especies Reactivas de Oxígeno/metabolismo , Medicina de Precisión , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fotoquimioterapia/métodos , Terapia Combinada , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Wound healing is a crucial process that restores the integrity and function of the skin and other tissues after injury. However, external factors, such as infection and inflammation, can impair wound healing and cause severe tissue damage. Therefore, developing new drugs or methods to promote wound healing is of great significance. Photothermal therapy (PTT) is a promising technique that uses photothermal agents (PTAs) to convert near-infrared radiation into heat, which can eliminate bacteria and stimulate tissue regeneration. PTT has the advantages of high efficiency, controllability, and low drug resistance. Hence, nanomaterial-based PTT and its related strategies have been widely explored for wound healing applications. However, a comprehensive review of PTT-related strategies for wound healing is still lacking. In this review, we introduce the physiological mechanisms and influencing factors of wound healing, and summarize the types of PTAs commonly used for wound healing. Then, we discuss the strategies for designing nanocomposites for multimodal combination treatment of wounds. Moreover, we review methods to improve the therapeutic efficacy of PTT for wound healing, such as selecting the appropriate wound dressing form, controlling drug release, and changing the infrared irradiation window. Finally, we address the challenges of PTT in wound healing and suggest future directions.
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Nanocompuestos , Fototerapia , Fototerapia/métodos , Cicatrización de Heridas , Calor , Antibacterianos/farmacología , Antibacterianos/uso terapéuticoRESUMEN
Junctional adhesion molecule 3 (JAM3) can be used as a prognostic marker in multiple cancer types. However, the potential prognostic role of JAM3 in gastric cancer (GC) remains unclear. The purpose of this research was to gauge JAM3 expression and methylation as potential biomarkers for GC patient survival. Through bioinformatics research, we analyzed JAM3 expression, methylation, prognosis, and immune cell infiltrations. JAM3 methylation acts as a negative regulator of JAM3, leading to reduced expression of JAM3 in GC tissues relative to normal tissues. Patients with GC who expressed little JAM3 have a better chance of living a long time free of the disease, according to the Cancer Genome Atlas (TCGA) database. Through univariate and multivariate Cox regression analysis, inadequate JAM3 expression was labeled as an isolated indicator for overall survival (OS). The GSE84437 dataset was also used to confirm JAM3 prognostic role in GC, with consistent findings. A meta-analysis also found that low levels of JAM3 expression were significantly associated with longer OS. Finally, there was a strong correlation between JAM3 expression and a subset of immune cells. According to the TCGA database, low JAM3 expression could predict favorable OS and progression-free-survival (PFS) in GC patients (P < .05). The univariate and multivariate Cox regression demonstrated that low JAM3 expression was independent biomarker for OS (P < .05). Moreover, GSE84437 dataset was utilized to verify the prognostic role of JAM3 in GC, and the similar results were reached (P < .05). A meta-analysis revealed that low JAM3 expression was closely relevant to better OS. Finally, JAM3 expression exhibited a close correlation with some immune cells (P < .05). JAM3 might be a viable predictive biomarker and likely plays a crucial part in immune cell infiltration in individuals with GC.
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Neoplasias Gástricas , Humanos , Biología Computacional , Bases de Datos Factuales , Análisis Multivariante , Estudios Observacionales como Asunto , Pronóstico , Neoplasias Gástricas/genéticaRESUMEN
Glutathione (GSH) is a crucial factor in limiting the effects of chemodynamic therapy (CDT) and ferroptosis, an iron-based cell death pathway. Based on this, we constructed iron-rich mesoporous dopamine (MPDA@Fe) nanovehicles with a dual-GSH depletion function by combining MPDA and Fe. Poly (ethylene glycol) (PEG) was further modified to provide desirable stability (PM@Fe) and glucose oxidase (GOx) was grafted onto PM@Fe (GPM@Fe) to address the limitation of hydrogen peroxide (H2O2). After the nanoparticles reached the tumor site, the weakly acidic microenvironment promoted the release of Fe. Then FeII reacted with H2O2 to generate hydroxyl radical (OH) and FeIII. The generated FeIII was reduced to FeII by GSH, which circularly participated in the Fenton reaction and continuously produced tumor inhibitory free radicals. Meanwhile, GOx consumed glucose to provide H2O2 for the reaction. MPDA had also been reported to deplete GSH. Therefore, dual consumption of GSH led to the destruction of intracellular redox balance and inhibition of glutathione-dependent peroxidase 4 (GPX4) expression, resulting in an increase in lipid peroxides (LPO) and further induction of ferroptosis. Additionally, MPDA-mediated photothermal therapy (PTT) raised the temperature of tumor area and produced photothermal-enhanced cascade effects. Hence, the synergistic strategy that combined dual-GSH depletion-induced ferroptosis, enhanced CDT and photothermal cascade enhancement based on MPDA@Fe could provide more directions for designing nanomedicines for cancer treatment.
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Ferroptosis , Neoplasias , Humanos , Dopamina , Compuestos Férricos , Peróxido de Hidrógeno , Glucosa Oxidasa , Glutatión , Hierro , Compuestos Ferrosos , Línea Celular Tumoral , Microambiente TumoralRESUMEN
The over-expressed GSH in tumor microenvironment significantly weakens the lethal reactive oxygen species (ROS) generated by photodynamic therapy (PDT) and catalysis of nanoenzyme. Hence, it is necessary to excavate a versatile and effective vehicle with oxidative stress-enhancement and GSH-depletion capacity to break the redox homeostasis in tumor microenvironment. GO has been reported to possess GSH-depletion and peroxidase (POD)-like capacity. Based on this, PEGylated mesoporous carbon (MC-PEG) was prepared as ICG vehicle to compare with PEGylated graphene oxide (GO-PEG). Excitingly, MC-PEG was found to exhibit three times higher oxidative capacity by POD-like process than GO-PEG, and owned more effective and continuous GSH-depletion capacity to further amplify the oxidative stress. Meanwhile, MC-PEG exhibited better protective effect on the loaded ICG against unwanted light excitation than GO-PEG. Together with the higher photothermal conversion effect, under the NIR light irradiation, MC-PEG could markedly improve the temperature of tumor cells and produce more hydroxyl radical, continuously consume GSH and provide more better protection for ICG compared with GO-PEG, thus further boosting the combination of photothermal and photodynamic effects. The anti-tumor experiment in cell and in-vivo level both validated that ICG/MC-PEG showed better synergistic effect with lower IC50 value and higher tumor suppression rate than ICG/GO-PEG.
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Fotoquimioterapia , Fototerapia , Carbono , Colorantes , Polietilenglicoles , Línea Celular TumoralRESUMEN
Glycolysis plays a vital role in the development and progression of tumors. Inhibiting glycolysis via smart and safe methods serves as a promising target for cancer therapy. Here, an oral "sugar-coated bullet" aiming at intervening Warburg effect is designed by coating colloidal mesoporous silica nanoparticles (CMS) encapsulating glycolysis inhibitor shikonin (SHK) with dextran, namely DCMS/SHK. The solubility and drug-loading capacity of SHK were enhanced by the special structure of CMS. Besides, the tempting bullets possess the spatial-to-point cascade targeting ability in delivering SHK from the colonic lumen to colon cancer cells and finally to PKM2. After DCMS/SHK reaches the colon, the dextran is hydrolyzed by dextranase especially existing in the colon site to glucose and the carriers become glucose-coated nanoparticles. The glucose-cloak nanoparticles would be largely endocytosed by tumor cells and complete the efficient delivery of SHK. The encapsulated SHK can prevent the glycolysis of cancer cells and thus inhibit tumor growth effectively. This work presents an ingenious cascade colon-targeting strategy to treat colon cancer by destroying cell energy metabolism.
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Neoplasias del Colon , Nanopartículas , Humanos , Azúcares , Dextranos , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Glucosa , Neoplasias del Colon/tratamiento farmacológico , Línea Celular TumoralRESUMEN
To assess carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), platelet distribution width (PDW), neutrophil-to-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) for gastric cancer's (GC) diagnostic efficiency, and the use of receiver operating characteristic curves (ROC) combined with logistic regression to evaluate multi-index combination's diagnostic value of GC. 773 GC patients' clinical data were retrospectively collected in the Weihai Municipal Hospital, affiliated hospital of Shandong University from April 2018 to May 2021, and selected 2368 healthy physical examination patients during the same period as the control group. A total of 3141 samples was included in this study, including 773 cases in the GC group and 2368 cases in the healthy physical examination group. The results of the overall comparison between groups showed that apart from gender, the age differences, CEA, CA19-9, PDW, NLR, and PLR were statistically significant (Pâ <â .001). Spearman ranks correlation analysis's results showed that CA19-9, CEA, PLR, and NLR were correlated with GC patients' clinical-stage positively, and the correlation coefficients r was 0.249, 0.280, 0.252, 0.262 (all Pâ <â .001), and PDW was correlated with the clinical stage negatively (râ =â -0.186, Pâ <â .001). The ROC curve analysis results of CEA, CA19-9, PDW, NLR and PLR showed that CEA's diagnostic cutoff value for GC was 3.175 (area under the curve [AUC]â =â 0.631, 95% CI: 0.606-0.655, Pâ <â .001), the CA19-9's diagnostic cutoff value is 19.640 (AUCâ =â 0.589, 95% CI: 0.563-0.615, Pâ <â .001), PDW's diagnostic cutoff value is 15.750 (AUCâ =â 0.799, 95% CI: 0.778-0.820, Pâ <â .001), NLR's diagnostic cutoff value was 2.162 (AUCâ =â 0.699, 95% CI: 0.675-0.721, Pâ <â .001), and PLR's diagnostic cutoff value was 149.540 (AUCâ =â 0.709, 95% CI: 0.688-0.732, Pâ <â .001). The area under the ROC curve for the combined diagnosis of GC with 5 indicators was 0.877 (95% CI: 0.860-0.894, Pâ <â .001), which was better than a single indicator (Pâ <â .05). The diagnostic efficiency of combined detection of CEA, CA19-9, PDW, NLR, and PLR is better than that of single index detection alone, which can reduce the misdiagnosis rate of GC effectively.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Antígeno Carcinoembrionario , Estudios Retrospectivos , Antígeno CA-19-9 , Biomarcadores AmbientalesRESUMEN
Utilization of the intestinal lymphatic pathway will allow extraordinary gains in lymph and tumors cascade-targeted delivery of oral drugs and awakening the innate/adaptive immunity of the body and the lesion microenvironment, in addition to improving oral bioavailability relative to other means of delivery of oral drugs. Here, inspired by the specific invasion route of intestinal microorganisms, we pioneered an immune-awakening Saccharomyces-inspired mesoporous silicon nanoparticle (yMSN) for the ingenious cascade-targeted delivery of therapeutic cancer vaccines and antitumor drugs to lymph and tumors via the intestinal lymphatic pathway. Encouragingly, yMSN high-loaded tumor-specific antigens (OVA, 11.9%) and anti-tumor drugs (Len, 28.6%) with high stability, namely Len/OVA/yMSN, efficiently co-delivered OVA and Len to their desired target sites. Moreover, yMSN concomitantly awakened the innate antitumor immunity of dendritic cells and macrophages, strengthening vaccine-induced adaptive immune responses and reversing macrophage-associated immunosuppression in the tumor microenvironment. Surprisingly, Len/OVA/yMSN treatment resulted in excellent synergistic antitumor efficacy and long-term antitumor memory in OVA-Hepa1-6-bearing mice. This high-performance nanocarrier provides a novel approach for lesion-targeting delivery of oral drugs accompanied with awakening of the innate/adaptive immunity of the lesion environment, and also represents a novel path for the oral delivery of diverse therapeutic agents targeting other lymph-mediated diseases.
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Photodynamic therapy (PDT) has been thriving in the theranostics of cancer in recent years. However, due to a series of problems such as high concentration of GSH and insufficient O2 partial pressure in the tumor micro-environment, it is difficult to achieve the desired therapeutic effects with single PDT. Mesoporous carbon (MC-COOH) has been widely used in photothermal therapy (PTT) due to its high photothermal conversion efficiency and drug loading. In addition, we have discovered that MC-COOH owned high-efficiency glutathione oxidase-like activity for intracellular lasting GSH consumption. Hence, a smart mesoporous carbon nanozyme (CCM) was designed as a dual-GSH depletion agent and O2 generator combined with PTT to overcome the dilemma of PDT. MnO2-doped carbon nanozyme (MC-Mn) was developed as the photothermal vehicles for the efficient loading of photosensitizer (Ce6). Subsequently, 4T1 membrane-coated nanozyme (Ce6/CCM) was constructed to achieve homologous targeting capability. The carbon nanozyme owned the sustained dual-GSH depletion function through MC-COOH and MnO2, which greatly destroyed the antioxidant system of the tumor. Meanwhile, MnO2 could produce affluent O2 in the presence of H2O2, thereby alleviating the hypoxic state of tumor tissues and further promoting the generation of ROS. In addition, the novel carbon nanozyme was designed as photoacoustic imaging (PAI) agent and magnetic resonance imaging (MRI) contrast for real-time imaging during tumor therapy. In summary, this work showed that the biomimetic carbon nanozyme could be used as dual-GSH depletion agent and O2 generator for dual-mode imaging-guided PTT-PDT. STATEMENT OF SIGNIFICANCE: - MC-COOH with highly efficient GSH-OXD activity was first discovered and applied in PDT. - MnO2 acted as an O2 generator and GSH depletion agent to enhance PDT. - The tumor-targeting ability of the nanozyme was improved by cell membrane camouflage. - CCM nanozyme possesses both PAI and MRI dual-mode imaging modalities to guide PDT/PTT.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Biomimética , Carbono/farmacología , Línea Celular Tumoral , Humanos , Peróxido de Hidrógeno/farmacología , Compuestos de Manganeso/farmacología , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Óxidos/farmacología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Microambiente TumoralRESUMEN
The intracellular delivery of proteins is of great significance. For diseases such as cancer, heart disease and neurodegenerative diseases, many important pharmacological targets are located inside cells. For genetic engineering and cell engineering, various functional proteins need to be delivered into cells for gene editing or cell state regulation. However, most existing protein delivery strategies involve endosomal escape (endocytosis-dependent), resulting in inefficient delivery due to endosome trapping. In contrast, endocytosis-independent intracellular delivery, which refers to the directly delivery of proteins across the cell membrane to the cytoplasm, will bypass the low efficiency of early endosomal escape, avoid protein inactivation caused by late endosome/lysosome, fundamentally improve the intracellular delivery efficiency, and open up a new way for intracellular protein delivery. In this review, the latest advances in direct intracellular delivery of proteins through membrane perforation, membrane translocation, and membrane fusion were summarized. The mechanisms, related materials and potential therapeutic in living cells/in vivo for each approach were discussed in detail, and the future development in this promising field was briefly presented.
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Endocitosis , Endosomas , Membrana Celular/metabolismo , Endocitosis/fisiología , Endosomas/metabolismo , Proteínas/metabolismoRESUMEN
The accumulation of nanomedicines in tumor tissues determines their therapeutic efficacy. We herein exploit the tropism of macrophages to improve the accumulation and retention time of nanomedicine at tumors. Interestingly, macrophages are not merely as transporters, but killers activated by nanomedicine. The system(M@C-HA/ICG) was established by decorating macrophages with hyaluronic acid-modified hollow mesoporous carbon (C) nanoparticles loading indocyanine green (ICG). Notably, C nanoparticles with superior photothermal conversion capability not merely guarantee the efficient delivery of ICG through high drug loading efficiency and inhibiting the premature leaky, but effectually activate the polarization of macrophages. The results exhibited that those activated macrophages could release pro-inflammatory cytokines (NO, TNF-α, IL-12), while M@C-HA/ICG afforded about 2-fold higher tumor accumulation compared with pure nanoparticle C-HA/ICG and produced heat and singlet oxygen (1O2) under irradiation of an 808 nm laser, realizing the combination of photodynamic therapy (PDT), photothermal therapy (PTT) and cytokines-mediated immunotherapy. Specially, we also investigated the relationship of singlet oxygen (1O2) or temperature and tumor-killing activity for understanding the specific effectual procedure of PDT/PTT synergistic therapy. Overall, we firstly established an "all active" delivery system integrating the features of nanomedicine with biological functions of macrophages, providing a novel insight for cell-mediated delivery platform and tumor targeted multimodality anti-cancer therapy.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Línea Celular Tumoral , Citocinas , Humanos , Verde de Indocianina/uso terapéutico , Macrófagos , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Fototerapia/métodos , Oxígeno SingleteRESUMEN
Polyvinylidene fluoride (PVDF) is an advanced functional polymer which exhibits excellent chemical and thermal stability, and good mechanical, piezoelectric and ferroelectic properties. This work opens a new strategy for the fabrication of nanocomposites, combining the functional properties of PVDF and advanced inorganic nanomaterials. Electrophoretic deposition (EPD) has been developed for the fabrication of films containing PVDF and nanoparticles of TiO2, MnO2 and NiFe2O4. An important finding was the feasibility of EPD of electrically neutral PVDF and inorganic nanoparticles using caffeic acid (CA) and catechol violet (CV) as co-dispersants. The experiments revealed strong adsorption of CA and CV on PVDF and inorganic nanoparticles, which involved different mechanisms and facilitated particle dispersion, charging and deposition. The analysis of the deposition yield data, chemical structure of the dispersants and the microstructure and composition of the films provided an insight into the adsorption and dispersion mechanisms and the influence of deposition conditions on the deposition rate, film microstructure and composition. PVDF films provided the corrosion protection of stainless steel. Overcoming the limitations of other techniques, this investigation demonstrates a conceptually new approach for the fabrication of PVDF-NiFe2O4 films, which showed superparamagnetic properties. The approach developed in this investigation offers versatile strategies for the EPD of advanced organic-inorganic nanocomposites.