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The excessive reactive oxygen species (ROS) and hypoxia deteriorate the inflammation-related diseases such as myocardial infarction (MI), and thereby deter the normal tissue repair and recovery and further lead to severe fibrosis and malfunction of tissues and organs. In particular, the MI has become one of the leading causes of death nowadays. In this study, a novel type of injectable hydrogel with dual functions of ROS scavenging and O2 generating is fabricated for MI treatment in vivo. The hydrogel is formed within 3 s from the synthetic ROS-cleavable hyperbranched polymers and methacrylate hyaluronic acid (HA-MA) under UV-irradiation. Addition of biocompatible and applicable catalase in vivo enables the further transition of H2 O2 , a major type of ROS, to O2 and H2 O. Results of rat MI model demonstrate that this hydrogel can significantly remove excessive ROS, inhibit cell apoptosis, increase M2/M1 macrophage ratio, promote angiogenesis, reduce infarcted area, and improve cardiac functions. With the appropriate degradation rate, simple structure and composition without cell seeding, and very excellent MI therapeutic effect, this ROS scavenging and O2 generating hydrogel has a great promise to be applied clinically.
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Hidrogéis , Infarto do Miocárdio , Animais , Ácido Hialurônico , Infarto do Miocárdio/tratamento farmacológico , Ratos , Espécies Reativas de Oxigênio , CicatrizaçãoRESUMO
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. The prognosis of HCC remains very poor; thus, an effective treatment remains urgent. Herein, a type of nanomedicine is developed by conjugating Fe@Fe3 O4 nanoparticles with ginsenoside Rg3 (NpRg3), which achieves an excellent coupling effect. In the dimethylnitrosamine-induced HCC model, NpRg3 application significantly prolongs the survival of HCC mice. Further research indicates that NpRg3 application significantly inhibits HCC development and eliminates HCC metastasis to the lung. Notably, NpRg3 application delays HCC-induced ileocecal morphology and gut microbial alterations more than 12 weeks during HCC progression. NpRg3 administration elevates the abundance of Bacteroidetes and Verrucomicrobia, but decreases Firmicutes. Twenty-nine predicted microbial gene functions are enriched, while seven gene functions are reduced after NpRg3 administration. Moreover, the metabolomics profile presents a significant progression during HCC development, but NpRg3 administration corrects tumor-dominant metabolomics. NpRg3 administration decreases 3-indolepropionic acid and urea, but elevates free fatty acids. Importantly, NpRg3 application remodels the unbalanced correlation networks between gut microbiota and metabolism during HCC therapy. In conclusion, nanoparticle conjugation of ginsenoside Rg3 inhibits HCC development and metastasis via the remodeling of unbalanced gut microbiota and metabolism in vivo, providing an antitumor therapy strategy.
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Carcinoma Hepatocelular/patologia , Ginsenosídeos/farmacologia , Neoplasias Hepáticas/patologia , Nanopartículas/química , Animais , Linhagem Celular Tumoral , Ginsenosídeos/química , Humanos , Camundongos , Metástase NeoplásicaRESUMO
Tumor-associated macrophages (TAMs) are recognized as antitumor suppressors, but how TAMs behave in the hypoxic environment of hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrated that hypoxia inducible factor 1α induced increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in TAMs, resulting in immunosuppression. Specifically, TREM-1-positive (TREM-1+ ) TAMs abundant at advanced stages of HCC progression indirectly impaired the cytotoxic functions of CD8+ T cells and induced CD8+ T-cells apoptosis. Biological and functional assays showed that TREM-1+ TAMs had higher expression of programmed cell death ligand 1 (PD-L1) under hypoxic environment. However, TREM-1+ TAMs could abrogate spontaneous and PD-L1-blockade-mediated antitumor effects in vivo, suggesting that TREM-1+ TAM-induced immunosuppression was dependent on a pathway separate from PD-L1/programmed cell death 1 axis. Moreover, TREM-1+ TAM-associated regulatory T cells (Tregs) were crucial for HCC resistance to anti-PD-L1 therapy. Mechanistically, TREM-1+ TAMs elevated chemokine (C-C motif) ligand 20 expression through the extracellular signal-regulated kinase/NF-κß pathway in response to hypoxia and tumor metabolites leading to CCR6+ Foxp3+ Treg accumulation. Blocking the TREM-1 pathway could significantly inhibit tumor progression, reduce CCR6+ Foxp3+ Treg recruitment, and improve the therapeutic efficacy of PD-L1 blockade. Thus, these data demonstrated that CCR6+ Foxp3+ Treg recruitment was crucial for TREM-1+ TAM-mediated anti-PD-L1 resistance and immunosuppression in hypoxic tumor environment. Conclusion: This study highlighted that the hypoxic environment initiated the onset of tumor immunosuppression through TREM-1+ TAMs attracting CCR6+ Foxp3+ Tregs, and TREM-1+ TAMs endowed HCC with anti-PD-L1 therapy resistance.
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Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Animais , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/fisiologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos , Humanos , Hipóxia/metabolismo , Terapia de Imunossupressão , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Microambiente TumoralRESUMO
BACKGROUND/AIMS: The prevalence of hyperlipidemia is increasing rapidly. The role of Coreopsis tinctoria (CT) in amending lipid metabolism in hyperlipidemia patients has not been reported. This study aims to evaluate the role of CT in altering lipid metabolism in hyperlipidemia patients and to explore the possible mechanisms mediated by gut microbiota in hyperlipidemia mice models. METHODS: A retrospective analysis in 40 hyperlipidemia patients was conducted, in which 20 patients took fenofibrate and another 20 patients normatively drank water with CT. Hyperlipidemia mice models were also established. Blood biochemical tests were performed using an automatic biochemical analyzer. Liver histopathology was observed by hematoxylin and eosin staining. Ileocecal samples were collected from mice, and bacterial DNA was extracted and sequenced by MiSeq sequencing. Bacterial composition and differences were analyzed. RESULTS: In hyperlipidemia patients, CT was associated with decreased triglyceride and low-density lipoprotein (LDL) levels without liver injury. The experimental hyperlipidemia model also verified a similar result. Gut microbial richness and diversity were significantly decreased in hyperlipidemic mice, but increased after CT treatment. Bacterial communities were significantly differentiated between normal controls and hyperlipidemic mice. CT administration improved gut microbiota composition to an approximately normal status. Meanwhile, CT administration attenuated bacterial alterations at the class, order, family, and genus levels in hyperlipidemic mice. Importantly, the genera Barnesiella, Lactobacillus, and Helicobacter achieved high discriminatory power in hyperlipidemic mice relative to normal controls. CONCLUSIONS: CT can modulate blood lipid metabolism with improvement of liver function by decreasing LDL and improving gut microbiota compositions. These findings may provide novel therapeutic strategies for patients with hyperlipidemia.
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Coreopsis/química , Microbioma Gastrointestinal/efeitos dos fármacos , Hiperlipidemias/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/sangue , Extratos Vegetais/farmacologia , Adulto , Animais , Bactérias/genética , Bactérias/isolamento & purificação , Coreopsis/metabolismo , DNA Bacteriano/química , DNA Bacteriano/isolamento & purificação , DNA Bacteriano/metabolismo , Modelos Animais de Doenças , Feminino , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Humanos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Intestinos/microbiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Estudos RetrospectivosRESUMO
Probiotics have the potential as biotherapeutic agents for cancer management in preclinical models and human trials by secreting antineoplastic or immunoregulatory agents in the tumor microenvironment (TME). However, current probiotics lack the ability to dynamically respond to unique TME characteristics, leading to limited therapeutic accuracy and efficacy. Although progress has been made in customizing controllable probiotics through synthetic biology, the engineering process is complex and the predictability of production is relatively low. To address this, here, for the first time, this work adopts pH-dependent peroxidase-like (POD-like) artificial enzymes as both an inducible "nano-promoter" and "nano-effector" to engineer clinically relevant probiotics to achieve switchable control of probiotic therapy. The nanozyme initially serves as an inducible "nano-promoter," generating trace amounts of nonlethal reactive oxygen species (ROS) stress to upregulate acidic metabolites in probiotics. Once metabolites acidify the TME to a threshold, the nanozyme switches to a "nano-effector," producing a great deal of lethal ROS to fight cancer. This approach shows promise in subcutaneous, orthotopic, and colitis-associated colorectal cancer tumors, offering a new methodology for modulating probiotic metabolism in a pathological environment.
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Antineoplásicos , Neoplasias , Probióticos , Humanos , Espécies Reativas de Oxigênio , Probióticos/uso terapêutico , Neoplasias/terapia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Microambiente TumoralRESUMO
Ischemic stroke is an acute and serious cerebral vascular disease, which greatly affects people's health and brings huge economic burden to society. Microglia, as important innate immune components in central nervous system (CNS), are double-edged swords in the battle of nerve injury, considering their polarization between pro-inflammatory M1 or anti-inflammatory M2 phenotypes. High mobility group box 1 (HMGB1) is one of the potent pro-inflammatory mediators that promotes the M1 polarization of microglia. 18ß-glycyrrhetinic acid (GA) is an effective intracellular inhibitor of HMGB1, but of poor water solubility and dose-dependent toxicity. To overcome the shortcomings of GA delivery and to improve the efficacy of cerebral ischemia therapy, herein, we designed reactive oxygen species (ROS) responsive polymer-drug conjugate nanoparticles (DGA) to manipulate microglia polarization by suppressing the translocation of nuclear HMGB1. DGA presented excellent therapeutic efficacy in stroke mice, as evidenced by the reduction of infarct volume, recovery of motor function, suppressed of M1 microglia activation and enhanced M2 activation, and induction of neurogenesis. Altogether, our work demonstrates a close association between HMGB1 and microglia polarization, suggesting potential strategies for coping with inflammatory microglia-related diseases.
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PFA uses short-duration, high-voltage electrical pulses to induce transient or irreversible electroporation on cell membranes, causing cell death. Selective inhibition of chaotic electrical signals in morbid cardiomyocytes significantly aids the treatment of atrial fibrillation, ventricular tachycardia, and other heart arrhythmias. Recent preclinical and clinical studies have only investigated physical changes, such as lesion size and myocardial scar. Compared to radiofrequency ablation and cryoballoon ablation, PFA causes less postoperative myocardial cell fibrosis and inflammatory reaction and does not result in myocardial necrosis or tissue scar formation. However, the regulatory mechanism of cellular stress following PFA treatment remains unknown. This study aimed to analyze the transcriptome of the mouse ventricle after PFA treatment. The animals were subjected to a 225-V electric pulse with a 1.5-mm gap between the positive and negative electrodes. Hearts were harvested at 3, 6, 12, 24 h, and 2, 5 days for myocardial zymogram testing. PFA-treated ventricular regions were selected for single-nucleus sequencing. We discovered that PFA remodeled the cardiac microenvironment as a whole. Further, we discussed the possible stress response and wound-healing mechanism in non-targeted cells. In conclusion, PFA allowed effective and selective ventricular myocardium ablation with controllable inflammation.
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Fibrilação Atrial , Ablação por Cateter , Animais , Camundongos , Cicatriz/cirurgia , Coração , Fibrilação Atrial/cirurgia , MiocárdioRESUMO
Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the world. Nanosecond pulsed electric fields (nsPEFs) have emerged as a new treatment for cancer. This study aims to identify the effectiveness of nsPEFs in the treatment of HCC and analyze the alterations in the gut microbiome and serum metabonomics after ablation. Methods: C57BL/6 mice were randomly divided into three groups: healthy control mice (n = 10), HCC mice (n = 10), and nsPEF-treated HCC mice (n = 23). Hep1-6 cell lines were used to establish the HCC model in situ. Histopathological staining was performed on tumor tissues. The gut microbiome was analyzed by 16S rRNA sequencing. Serum metabolites were analyzed by liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis. Spearman's correlation analysis was carried out to analyze the correlation between the gut microbiome and serum metabonomics. Results: The fluorescence image showed that nsPEFs were significantly effective. Histopathological staining identified nuclear pyknosis and cell necrosis in the nsPEF group. The expression of CD34, PCNA, and VEGF decreased significantly in the nsPEF group. Compared with normal mice, the gut microbiome diversity of HCC mice was increased. Eight genera including Alistipes and Muribaculaceae were enriched in the HCC group. Inversely, these genera decreased in the nsPEF group. LC-MS analysis confirmed that there were significant differences in serum metabolism among the three groups. Correlation analysis showed crucial relationships between the gut microbiome and serum metabolites that are involved in nsPEF ablation of HCC. Conclusion: As a new minimally invasive treatment for tumor ablation, nsPEFs have an excellent ablation effect. The alterations in the gut microbiome and serum metabolites may participate in the prognosis of HCC ablation.
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Inflammatory bowel disease can be caused by the dysfunction of the intestinal mucosal barrier and dysregulation of gut microbiota. Traditional treatments use drugs to manage inflammation with possible probiotic therapy as an adjuvant. However, current standard practices often suffer from metabolic instability, limited targeting and result in unsatisfactory therapeutic outcomes. Here we report on artificial-enzyme-modified Bifidobacterium longum probiotics for reshaping a healthy immune system in inflammatory bowel disease. Probiotics can promote the targeting and retention of the biocompatible artificial enzymes to persistently scavenge elevated reactive oxygen species and alleviate inflammatory factors. The reduced inflammation caused by artificial enzymes improves bacterial viability to rapidly reshape the intestinal barrier functions and restore the gut microbiota. The therapeutic effects are demonstrated in murine and canine models and show superior outcomes to traditional clinical drugs.
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Bifidobacterium longum , Doenças Inflamatórias Intestinais , Microbiota , Probióticos , Animais , Cães , Camundongos , Disbiose/terapia , Inflamação/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Probióticos/farmacologia , Probióticos/uso terapêuticoRESUMO
OBJECTIVE: The purpose of this study is to evaluate the preliminary safety and effect of a pulsed electric field (PEF) ablation system. METHODS: The pulmonary veins (PVs) and superior vena cava (SVC) were isolated with the pulsed field ablation (PFA) system, which included a PEF generator and an electrode. The effects of PFA were investigated in six porcines using a novel circular catheter with combined functions (mapping/ablation) designed to work with a cardiac mapping system. The PEF generator delivered a train of biphasic pulsed electric pulses with a high amplitude (800-2000 V) and short pulse duration. The voltage mapping, PVs and SVC potentials, ostial diameters, and phrenic nerve and esophagus viability data were collected 4 weeks later, after which the animals were subsequently euthanized for gross histopathology analysis. RESULTS: PFA 100% isolated the PVs and SVC with four applications with a mean pulse number of 100-150 pulses, causing no muscle convulsion. PFA does not cause PV stenosis or phrenic nerve dysfunction. Histological analysis confirmed 100% transmurally without any venous stenoses or phrenic injuries. Pathology follow-up showed that PFA had selectively ablated cardiomyocytes but spared blood vessels, the esophagus, and phrenic nerves; after ablation, the myocardial tissue showed homogeneous fibrosis. CONCLUSION: The PFA system is safe and feasible in the preliminary porcine model, which can effectively isolate PVs and SVCs. Transmural tissue damage can be achieved without phrenic palsy or stenosis.
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Objective: We investigate the characteristics of histological damage to myocardial cells in the ablation region and surrounding areas of the left ventricular epicardium in rabbits using our self-developed cardiac pulsed electric field (PEF) ablation instrument and ablation catheter. Methods: Forty eight New Zealand rabbits underwent ablation on the left ventricular myocardium after open-heart exposure with a cardiac arrhythmia PEF ablation device and ablation catheter developed by the Medical Translation Laboratory of Pulsed Electric Field Technology in Zhejiang Province. The ablation parameters were set as biphasic electrical pulses; voltage, ±800 V; pulse width, 10 µs; interphase delay, 500 us. Six rabbits were included in the sham group and 42 other rabbits were randomly divided into immediately, 6-h, 1-, 3-day, 1-, 2-, and 4-week post-ablation groups, with six rabbits in each group. Creatine kinase- (CK)-MB isoenzyme (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels were measured before and at different time points after PEF ablation to analyze their dynamic evolution. Masson staining of tissue block sections of left ventricular myocardial ablation and adjacent tissue heart specimens was performed, and the occurrence of TUNEL apoptosis in myocardium tissue was analyzed. Results: All rabbits completed the PEF ablation procedure and the follow-up process. After PEF ablation, the levels of cardiac enzymes, including CK-MB, CK, and AST, increased significantly, peaking 1-3 days after the procedure. In particular, those of CK and CK-MB increased by 15-20 times but returned to the preoperative level after 2 weeks. Based on general observation, it was found that the myocardium in the ablation area was swollen immediately after PEF ablation. Masson staining analysis revealed that cardiomyocytes were broken and infiltrated by erythrocytes after 6 h. After 1 day, the cells started to experience atrophy and necrosis; after 3 days, fibrotic replacement of the necrotic area became obvious. Then, by 4 weeks, the myocardial cells were completely replaced by hyperplasia. Apoptosis occurred significantly at 6 h and peaked at 24 h post-ablation, demonstrating a 37.7-fold increase; apoptotic cell counts decreased significantly at 3 days post-ablation, and no significant apoptotic cardiomyocytes were seen after 1 week. Conclusion: After PEF ablation, cardiomyocytes showed apoptotic process and dyed, at least partially, through a secondary necrosis, the ablation boundary was clear, the ablation area was replaced by structurally intact fibroblasts, no island myocardium tissue were seen, and the ablation area vessels and nerves were not affected.
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The expression of the SRY-Box Transcription Factor 15 (Sox15) is reduced by DNA methylation, and its progression is suppressed within numerous tumors. However, its effect on hepatocellular carcinoma (HCC) remains unknown. In the present work, the clinical importance and function of Sox15, as well as the underlying molecular mechanism, were explored within HCC. The expression of Sox15 is reduced and positively correlated with prognosis in HCC as analyzed by GEPIA (Gene Expression Profiling Interactive Analysis) and OncoLnc. Meanwhile, the hypermethylated Sox15 promoter CpG-site predicted a dismal HCC prognosis. Besides, ectopic Sox15 expression within the HCC cells (LM3, HUH7, SK-hep-1) remarkably inhibited in vitro cell growth and inhibited xenograft tumorigenesis in the nude mice. Moreover, Sox15 inactivated the Wnt pathway under both in vivo and in vitro conditions. To summarize, Sox15 played a tumor suppressor role within the HCC via the inactivated Wnt pathway. Sox15 and CpG-site methylation of its promoter are the factors that independently predict the prognosis of HCC.
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Keratin 8 (KRT8) is the major component of the intermediate filament cytoskeleton and aberrant expression in multiple tumors. However, the role of KRT8 in lung adenocarcinoma (LUAD) remains unclear. In the present study, KRT8 expression was found to be upregulated along with prognosis and metastasis in LUAD. Kaplan-Meier analysis presented that the 5-year OS and DSS rates were significantly better among patients with low KRT8 expression compared to those with high expression. Correlation analysis showed that KRT8 expression was significantly associated with gender (P = 0.027), advanced T stage (P = 0.001), advanced N stage (P = 0.048), and advanced pathologic stage (P = 0.025). Univariate Cox analysis demonstrated that KRT8 was a predictor of OS [hazard ratio (HR) = 1.526; 95% confidence interval (CI) 1.141-2.040; P = 0.004] and DSS (HR = 1.625; 95% CI 1.123-2.353; P = 0.010) in the TCGA database. Importantly, downregulation of KRT8 obviously suppressed cell proliferation, cell migration, invasion, and EMT as well as induced cell apoptosis. KRT8 knockdown significantly inhibited NF-κB signaling, suggesting a potential mechanism. Overall, our results indicated that KRT8 could regulate lung carcinogenesis and may serve as a potential target for antineoplastic therapies.
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Both of the surface topographical features and distribution of biochemical cues can influence the cell-substrate interactions and thereby tissue regeneration in vivo. However, they have not been combined simultaneously onto a biodegradable scaffold to demonstrate the synergistic role so far. In this study, a proof-of-concept study is performed to prepare micropatterns and peptide gradient on the inner wall of a poly (D,L-lactide-co-caprolactone) (PLCL) guidance conduit and its advantages in regeneration of peripheral nerve in vivo. After linear ridges/grooves of 20/40 µm in width are created on the PLCL film, its surface is aminolyzed in a kinetically controlled manner to obtain the continuous gradient of amino groups, which are then transferred to CQAASIKVAV peptide density gradient via covalent coupling of glutaraldehyde. The Schwann cells are better aligned along with the stripes, and show a faster migration rate toward the region of higher peptide density. Implantation of the nerve guidance conduit made of the PLCL film having both the micropatterns and peptide gradient can significantly accelerate the regeneration of sciatic nerve in terms of rate, function recovery and microstructures, and reduction of fibrosis in muscle tissues. Moreover, this nerve conduit can also benefit the M2 polarization of macrophages and promote vascularization in vivo.
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To promote the clinical theranostic performances of platinum-based anticancer drugs, imaging capability is urgently desired, and their chemotherapeutic efficacy needs to be upgraded. Herein, a theranostic metallacycle (M) is developed for imaging-guided cancer radio-chemotherapy using perylene bisimide fluorophore (PPy) and tetraphenylethylene-based di-Pt(II) organometallic precursor (TPE-Pt) as building blocks. The formation of this discrete supramolecular coordination complex facilitates the encapsulation of M by a glutathione (GSH)-responsive amphiphilic block copolymer to prepare M-loaded nanoparticles (MNPs). TPE-Pt acts as a chemotherapeutic drug and also an excellent radiosensitizer, thus incorporating radiotherapy into the nanomedicine to accelerate the therapeutic efficacy and overcome drug resistance. The NIR-emission of PPy is employed to detect the intracellular delivery and tissue distribution of MNPs in real time. In vitro and in vivo investigations demonstrate the excellent anticancer efficacy combining chemotherapy and radiotherapy; the administration of this nanomedicine effectively inhibits the tumor growth and greatly extends the survival rate of cisplatin-resistant A2780CIS-tumor-bearing mice. Guided by in vivo fluorescence imaging, radio-chemotherapy is precisely carried out, which facilitates boosting of the therapeutic outcomes and minimizing undesired side effects. The success of this theranostic system brings new hope to supramolecular nanomedicines for their potential clinical translations.
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Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Corantes Fluorescentes/uso terapêutico , Imidas , Camundongos , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Perileno/análogos & derivados , Estilbenos , Nanomedicina Teranóstica/métodosRESUMO
Background: Despite their outstanding properties in high surface-to-volume ratio and deep penetration, the application of ultrasmall nanoparticles for tumor theranostics remains limited because of their dissatisfied targeting performance and short blood circulation lifetime. Various synthetic materials with complex structures have been prepared as a multifunctional platform for loading ultrasmall nanoparticles. However, their use in nanomedicine is restricted because of unknown metabolic processes and potential physiological toxicity. Therefore, versatile and biocompatible nanoplatforms need to be designed through a simple yet effective method for realizing specific delivery and responsible release of ultrasmall nanoparticles. Methods: Iron-gallic acid coordination polymer nanodots (FeCNDs) exhibits outstanding photothermal ability and Fenton catalytic performance, which can be applied for tumor inhibition via hyperthermia and reactive oxygen species. A pH-responsive platelet-based hybrid membrane (pH-HCM) was prepared via co-extrusion and acted as a safe nanoplatform to load FeCNDs (pH-HCM@FeCNDs). Subsequently, their responsive performance and penetration ability were valued considering the multicellular sphere (MCS) model in an acidic or neutral environment. Thereafter, in vivo fluorescence image was performed to assess targeting capability of pH-HCM@FeCNDs. Finally, the corresponding antitumor and antimetastatic effects on orthotropic breast cancer were investigated. Results: In 4T1 MCS model, pH-HCM@FeCNDs group exhibited higher penetration efficiency (72.84%) than its non-responsive counterparts (17.77%) under an acidic environment. Moreover, the fluorescence intensity in pH-HCM@FeCNDs group was 3.18 times higher than that in group without targeting performance in the in vivo fluorescence image experiment. Finally, through in vivo experiments, pH-HCM@FeCNDs was confirmed to exhibit the best antitumor effect (90.33% tumor reduction) and antimetastatic effects (only 0.29% tumor coverage) on orthotropic breast cancer. Conclusions: Hybrid cell membrane was an ideal nanoplatform to deliver nanodots because of its good responsibility, satisfactory targeting ability, and excellent biocompatibility. Consequently, this study provides novel insights into the delivery and release of nanodots in a simple but effect method.
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Neoplasias da Mama , Hipertermia Induzida , Nanopartículas , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas/químicaRESUMO
Chemodynamic therapy (CDT)-activated apoptosis is a potential anticancer strategy. However, CDT encounters a bottleneck in clinical translation due to its serious side effects and low efficacy. Here, we first reveal that surface engineering of ginsenoside Rg3 dramatically alters the organ distribution and tumor enrichment of systematically administered nanocatalysts using the orthotopic pancreatic tumor model while avoiding toxicity and increasing efficacy in vivo to address the key and universal toxicity problems encountered in nanomedicine. Compared with nanocatalysts alone, Rg3-sheltered dynamic nanocatalysts form hydrophilic nanoclusters, prolonging their circulation lifespan in the blood, protecting the internal nanocatalysts from leakage while allowing their specific release at the tumor site. Moreover, the nanoclusters provide a drug-loading platform for Rg3 so that more Rg3 reaches the tumor site to achieve obvious synergistic effect with nanocatalysts. Rg3-sheltered dynamic nanocatalysts can simultaneously activate ferroptosis and apoptosis to significantly improve anticancer efficacy. Systematic administration of ginsenoside Rg3-sheltered nanocatalysts inhibited 86.6% of tumor growth without toxicity and prolonged the survival time of mice. This study provides a promising approach of nanomedicine with high biosafety and a new outlook for catalytic ferroptosis-apoptosis combined antitumor therapies. STATEMENT OF SIGNIFICANCE: Chemodynamic therapy (CDT) has limited clinical efficacy in cancer. In this study, we developed Rg3-sheltered dynamic nanocatalysts, which could simultaneously activate ferroptosis based on CDT-activated apoptosis, and ultimately form a combined therapy of ferroptosis-apoptosis to kill tumors. Studies have shown that the nanocatalysts after Rg3 surface engineering dramatically alters the pharmacokinetics and organ distribution of the nanocatalysts after being systematically administered, resulting in avoiding the toxicity of the nanocatalysts. Nanocatalysts also act as a drug-loading platform, guiding more Rg3 into the tumor site. This study emphasizes that nanocatalysts after Rg3 surface engineering improve the safety and effectiveness of ferroptosis-apoptosis combined therapy, providing an effective idea for clinical practices.
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Ferroptose , Ginsenosídeos , Animais , Apoptose , Linhagem Celular Tumoral , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , CamundongosRESUMO
Emergent and long-term hemorrhage control is requisite and beneficial for reducing global mortality and postoperative complications (e.g., second bleeding and adverse tissue adhesion). Despite recent advance in injectable hydrogels for hemostasis, achieving rapid gelation, strong tissue-adhesive property and stable mechanical strength under fluid physiological environment is still challenging. Herein, we developed a novel chitosan hydrogel (CCS@gel) via dynamic Schiff base reaction and mussel-inspired catechol chemistry. The hydrogel possessed high gelation rate (<10 s), strong wet adhesiveness, excellent self-healing performance and biocompatibility. More importantly, the CCS@gel exhibited saline-induced contractile performance and mechanical enhancement, promoting its mechanical property in moist internal conditions. In vivo studies demonstrated its superior hemostatic efficacy for diverse anticoagulated visceral and carotid bleeding scenarios, compared to commercialized fibrin glue. The hydrogel-treated rats survived for 8 weeks with minimal inflammation and postoperative adhesion. These results revealed that the promising CCS@gel would be a facile, efficient and safe sealant for clinical hemorrhage control.
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Quitosana/farmacologia , Hemorragia/terapia , Hemostáticos/farmacologia , Hidrogéis/farmacologia , Adesivos Teciduais/farmacologia , Cicatrização/efeitos dos fármacos , Adesividade , Animais , Bandagens , Lesões das Artérias Carótidas/terapia , Quitosana/síntese química , Técnicas Hemostáticas/instrumentação , Hemostáticos/síntese química , Hidrogéis/síntese química , Fígado/lesões , Masculino , Polietilenoglicóis/síntese química , Polietilenoglicóis/farmacologia , Ratos Sprague-Dawley , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Baço/lesões , Adesivos Teciduais/síntese química , Técnicas de Fechamento de Ferimentos/instrumentaçãoRESUMO
Nanozymes have limited applications in clinical practice due to issues relating to their safety, stability, biocompatibility, and relatively low catalytic activity in the tumor microenvironment (TME) in vivo. Herein, we report a synergistic enhancement strategy involving the conjugation of metal-based nanozymes (Fe@Fe3O4) with natural bioactive organic molecules (ginsenoside Rg3) to establish a new nanodrug. Importantly, this metal-organic nanocomposite drug ensured the stability and biosafety of the nanozyme cores and the cellular uptake efficiency of the whole nanodrug entity. This nanodrug is based on integrating the biological characteristics and intrinsic physicochemical properties of bionics. The glycoside chain of Rg3 forms a hydrophilic layer on the outermost layer of the nanodrug to improve the biocompatibility and pharmacokinetics. Additionally, Rg3 can activate apoptosis and optimize the activity and status of normal cells. Internal nanozymes enter the TME and release Fe3+ and Fe2+, and the central metal Fe(0) continuously generates highly active Fe2+ under the conditions of the TME and in the presence of Fe3+, maintaining the catalytic activity. Therefore, these nanozymes can effectively produce reactive oxygen species and oxygen in the TME, thereby promoting the apoptosis of cancer cells. Thus, we propose the use of a new type of metal-organic nanocomposite material as a synergistic strategy against cancer.
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Nanosecond pulsed electric field (nsPEF) is a novel ablation technique that is based on high-intensity electric voltage to achieve tumour-killing effect in the target region, and increasingly considered for treating tumours of the liver, kidneys and other organs with rich blood supply. This study aims to observe effect of nsPFE treatment on serum metabolites and gut microbiota. The serum and faecal specimens of the pigs were collected pre- and post-treatment. The gut microbiota of pigs was sequenced by Illumina Miseq platform for analysing the diversity and alterations of gut microbiota. Liquid chromatography-mass spectrometry (LC-MS)-based metabonomic analysis and Pearson coefficient method were also used to construct the interaction system of different metabolites, metabolic pathways and flora. A total of 1,477 differential metabolites from the serum were identified by four cross-comparisons of different post-operative groups with the control group. In addition, an average of 636 OTUs per sample was detected. Correlation analysis also revealed the strong correlation between intestinal bacteria and differential metabolites. The nsPEF ablation of the liver results in a degree of liver damage that affects various metabolic pathways, mainly lipid metabolism, as well as gut microbiota. In conclusion, our study provided a good point for the safety and feasibility of applying nsPEF on liver through the integrated analysis of metabolomics and microbiomes, which is beneficial for the improvement of nsPEF in clinical use.