ABSTRACT
Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Inositol/metabolism , Mitochondrial Dynamics/physiology , AMP-Activated Protein Kinases/physiology , Animals , Cell Line , Humans , Inositol/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/metabolism , PC-3 Cells , Phosphoric Monoester Hydrolases/metabolism , Phosphorylation , Stress, Physiological/physiologyABSTRACT
Liver cancer, which is well-known to us as one of human most prevalent malignancies across the globe, poses a significant risk to live condition and life safety of individuals in every region of the planet. It has been shown that immune checkpoint treatment may enhance survival benefits and make a significant contribution to patient prognosis, which makes it a promising and popular therapeutic option for treating liver cancer at the current time. However, there are only a very few numbers of patients who can benefit from the treatment and there also exist adverse events such as toxic effects and so on, which is still required further research and discussion. Fortunately, the clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) provides a potential strategy for immunotherapy and immune checkpoint therapy of liver cancer. In this review, we focus on elucidating the fundamentals of the recently developed CRISPR/Cas9 technology as well as the present-day landscape of immune checkpoint treatment which pertains to liver cancer. What's more, we aim to explore the molecular mechanism of immune checkpoint treatment in liver cancer based on CRISPR/Cas9 technology. At last, its encouraging and powerful potential in the future application of the clinic is discussed, along with the issues that already exist and the difficulties that must be overcome. To sum up, our ultimate goal is to create a fresh knowledge that we can utilize this new CRISPR/Cas9 technology for the current popular immune checkpoint therapy to overcome the treatment issues of liver cancer.
Subject(s)
CRISPR-Cas Systems , Gene Editing , Liver Neoplasms , Humans , Liver Neoplasms/therapy , Liver Neoplasms/genetics , Liver Neoplasms/immunology , Gene Editing/methods , Immunotherapy/methods , Immune Checkpoint Inhibitors/therapeutic use , AnimalsABSTRACT
Photodynamic therapy (PDT), as a highly selective, widely applicable, and non-invasive therapeutic modality that is an alternative to radiotherapy and chemotherapy, is extensively applied to cancer therapy. Practically, the efficiency of PDT is severely hindered by the existence of hypoxia in tumor tissue. Hypoxia is a typical hallmark of malignant solid tumors, which remains an essential impediment to many current treatments, thereby leading to poor clinical prognosis after therapy. To address this issue, studies have been focused on modulating tumor hypoxia to augment the therapeutic efficacy. Although nanomaterials to relieve tumor hypoxia for enhanced PDT have been demonstrated in many research articles, a systematical summary of the role of nanomaterials in alleviating tumor hypoxia is scarce. In this review, we introduced the mechanism of PDT, and the involved therapeutic modality of PDT for ablation of tumor cells was specifically summarized. Moreover, current advances in nanomaterials-mediated tumor oxygenation via oxygen-carrying or oxygen-generation tactics to alleviate tumor hypoxia are emphasized. Based on these considerable summaries and analyses, we proposed some feasible perspectives on nanoparticle-based tumor oxygenation to ameliorate the therapeutic outcomes, which may provide some detailed information in designing new oxygenation nanomaterials in this burgeneous field.
Subject(s)
Nanostructures , Photochemotherapy , Humans , Tumor Hypoxia , Photosensitizing Agents/therapeutic use , Oxygen , Hypoxia/drug therapyABSTRACT
Thrombosis initiated by abnormal platelet aggregation is a pivotal pathological event that precedes most cases of cardiovascular diseases (CVD). Recently, growing evidence indicates that platelet could be a potential target for CVD prevention. However, as the conventional antithrombotic management strategy, applications of current antiplatelet agents are somewhat limited by their various side effects, such as bleeding risk and drug resistance. Hence, efforts have been made to search for agents as complementary therapies. Ginsenoside, the principal active component extracted from Panax ginseng, has gained much attention for its regulations on multiple crucial events of platelet aggregation. From structural characteristics to clinical applications, this review anatomized the intrinsic structure-function relationship of antiplatelet potency of ginsenosides, and the involved signal pathways were specifically summarized. Additionally, the emphasis was placed on clinical studies that investigate the antithrombotic efficacy of ginsenosides in the treatment of CVD. Further, a broad overview of approaches for improving the bioavailability of ginsenosides was concluded. Limitations and prospects of current studies were also discussed. This study may provide some new insights into the systematic understanding of ginsenosides in CVD treatment and lay a foundation for future research.
Subject(s)
Blood Platelets/drug effects , Cardiovascular Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Ginsenosides/therapeutic use , Muscle, Smooth, Vascular/drug effects , Neointima , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation/drug effects , Vascular Remodeling/drug effects , Animals , Biological Availability , Blood Platelets/metabolism , Cardiovascular Agents/adverse effects , Cardiovascular Agents/pharmacokinetics , Cardiovascular Diseases/blood , Cardiovascular Diseases/pathology , Ginsenosides/adverse effects , Ginsenosides/pharmacokinetics , Humans , Molecular Structure , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/pharmacokinetics , Signal Transduction , Structure-Activity RelationshipABSTRACT
Reported herein is a unified strategy to generate difluoroalkyl radicals from readily prepared α-difluorinated gem-diols by single electron oxidation. Under microwave irradiation, a catalytic amount of oxidant Cu(OAc)2 succeeds in the formation of transient difluoroalkyl radicals in situ, for the first time. The reaction features a simple protocol, short reaction time, scalability, and high yield. The synthetic utility of this new methodology was also explored for the synthesis of difluoroalkylated spiro-cyclohexadienones, which is an important core structure in natural products and pharmaceuticals.
ABSTRACT
Although the CXCL12-CXCR4/CXCR7 chemokine axis is demonstrated to play an integral role in tumor progression, the controversy exists and the role of CXCL12-CXCR4/CXCR7 signaling axis in epithelial-mesenchymal transition (EMT) of human ovarian cancer has not been explored. Here, we showed that in ovarian cancer CXCL12 induced EMT phenotypes including the spindle-like cell morphology, podia and stress fiber formation, a decrease in E-cadherin expression, and increases in mesenchymal N-cadherin and vimentin expressions. These effects of CXCL12 could be antagonized by the CXCR4 antagonist AMD3100, but not by the anti-CXCR7 antibody. The expressions of the EMT markers were significantly down-regulated by the CXCR4 siRNA, and up-regulated by the pcDNA3.1/CXCR4 plasmid, whereas not affected by the CXCR7 siRNA. Furthermore, intraperitoneal administration of AMD3100 inhibited tumor dissemination and growth in the nude mice inoculated with ovarian IGROV-1 cells with a concomitant reduction in EMT marker expressions. Collectively, these data suggest that CXCR4, rather than CXCR7, plays a key role in CXCL12-activated EMT phenotypes, and targeting the CXCL12-CXCR4 chemokine axis represents a potential therapeutic strategy to prevent ovarian cancer progression.
Subject(s)
Chemokine CXCL12/metabolism , Epithelial-Mesenchymal Transition , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/secondary , Receptors, CXCR4/metabolism , Receptors, CXCR/metabolism , Animals , Apoptosis , Benzylamines , Biomarkers, Tumor/metabolism , Cell Movement , Cell Proliferation , Cyclams , Female , Heterocyclic Compounds , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/metabolism , Receptors, CXCR4/antagonists & inhibitors , Signal Transduction , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Protein arginine methyltransferase 5 (PRMT5) is responsible for the mono-methylation and symmetric dimethylation of arginine, and its expression level and methyl transferring activity have been demonstrated to have a close relationship with tumorigenesis, development and poor clinical outcomes of human cancers. Two PRMT5 small molecule inhibitors (GSK3326595 and JNJ-64619178) have been put forward into clinical trials. Here, we describe the design, synthesis and biological evaluation of a series of novel, potent and selective PRMT5 inhibitors with antiproliferative activity against Z-138 mantle cell lymphoma cell line. Among them, compound C_4 exhibited the highest potency with enzymatic and cellular level IC50 values of 0.72 and 2.6 µM, respectively, and displayed more than 270-fold selectivity toward PRMT5 over several other isoenzymes (PRMT1, PRMT4 and PRMT6). Besides, C_4 demonstrated obvious cell apoptotic effect while reduced the cellular symmetric arginine dimethylation levels of SmD3 protein. The potency, small size, and synthetic accessibility of this compound class provide promising hit scaffold for medicinal chemists to further explore this series of PRMT5 inhibitors.
Subject(s)
Enzyme Inhibitors/chemistry , Neoplasms/drug therapy , Protein-Arginine N-Methyltransferases/ultrastructure , Triazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Methylation/drug effects , Molecular Docking Simulation , Neoplasms/genetics , Neoplasms/pathology , Protein Binding/drug effects , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Protein-Arginine N-Methyltransferases/genetics , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship , Triazoles/pharmacologyABSTRACT
The nanocarrier-based delivery system has emerged as a promising candidate for cancer therapy; nevertheless, their quality problems, variation between batches, and carrier-related toxicity issues have restricted their clinical utilization. Compared with traditional carrier-based nanoparticles, carrier-free nanodrug delivery systems preferred to overcome all these drawbacks and will have a wide range of applications in biomedicine and nanotechnology. Herein, we developed a novel carrier-free nanodrug Asp-UA consisted of the classical drug aspirin and the natural plant drug UA via a green and simple approach. The Asp-UA NPs were investigated for shape, particle size, zeta potential, stability, and UV-vis spectroscopy absorption. Cellular uptake study showed that Asp-UA NPs could be easily internalized by HepG2 cells; cellular study demonstrated that Asp-UA NPs held better inhibitory efficiency on tumor metastasis with low toxicity in vitro and in vivo. Moreover, Asp-UA NPs could obviously suppress the progress of cancer metastasis by H22 cells in vivo. Overall, Asp-UA NPs possess a variety of advantages and hold promise to become an alternative to the treatment of cancer metastasis.
Subject(s)
Antineoplastic Agents/therapeutic use , Nanoparticles , Neoplasm Metastasis/drug therapy , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Aspirin/administration & dosage , Cell Line, Tumor , Drug Carriers , Drug Screening Assays, Antitumor , Drug Stability , Humans , Male , Mice , Phytochemicals/administration & dosageABSTRACT
Ursolic acid (UA) is a food-plant-derived natural product which has good anticancer activities and low toxicity. However, the poor water solubility of UA limits its application in clinic. To address this issue, we developed a carrier-free nanodrug by self-assembly of UA. Here, we showed that UA nanoparticles (NPs) have a near-spherical shape with a diameter of â¼150 nm. UA NPs exhibited higher antiproliferative activity; significantly caused apoptosis; decreased the expression of COX-2/VEGFR2/VEGFA; and increased the immunostimulatory activity of TNF-α, IL-6, and IFN-ß and decreased the activity of STAT-3 in A549 cells in vitro. Furthermore, UA NPs could inhibit tumor growth and have the ability of liver protection in vivo. More importantly, UA NPs could significantly improve the activation of CD4+ T-cells, which indicated that UA NPs have the potential for immunotherapy. Overall, a carrier-free UA nanodrug may be a promising drug to further enhance their anticancer efficacy and immune function.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Immunotherapy/methods , Nanoparticles/administration & dosage , Neoplasms/drug therapy , Triterpenes/administration & dosage , A549 Cells , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis/drug effects , Drug Design , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Neoplasms/immunology , Neoplasms/pathology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Triterpenes/chemistry , Triterpenes/therapeutic use , Xenograft Model Antitumor Assays , Ursolic AcidABSTRACT
Ursolic acid (UA), a natural triterpene acid, is a promising anti-cancer drug due to its inhibitory effect on tumor growth and metastasis. However, clinical translation of UA is limited by its poor water solubility and low bioavailability. To overcome these problems, herein an amphiphilic self-assembly nanodrug composed of UA, lactobionic acid (LA) and low-polyamidoamine (low-PAMAM) dendrimers is developed. This near-spherical nanodrug with a uniform size (~180 nm) demonstrated to have an enhanced cytotoxicity against liver cancer SMMC7721 cells, and could attenuate the migration and adhesion of SMMC7721 cells at non-toxic concentrations by suppressing metastasis-related protein MMP-9 expression. Furthermore, in vivo study indicates that the nanodrug exhibited prolonged circulation time in blood as well as increased AUC, MRT and Cmax, and could effectively inhibit the tumor growth in H22 mice model. Overall, the UA-based nanodrug delivery system reported in the present work represents a novel strategy for targeted tumor therapy.
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Hepatocellular/drug therapy , Dendrimers/chemistry , Drug Delivery Systems , Liver Neoplasms, Experimental/drug therapy , Nanoparticles/administration & dosage , Triterpenes/chemistry , Animals , Antineoplastic Agents/chemistry , Cell Adhesion/drug effects , Cell Proliferation/drug effects , Disaccharides/chemistry , Drug Carriers , Liver Neoplasms, Experimental/pathology , Matrix Metalloproteinase 9/metabolism , Mice , Nanoparticles/chemistry , Neoplasm Metastasis , Rats , Rats, Sprague-Dawley , Tumor Cells, Cultured , Ursolic AcidABSTRACT
Fibroblast growth factor receptors (FGFRs) are important oncology targets due to the dysregulation of this signaling pathway in a wide variety of human cancers. We identified a series of pyrazolylaminoquinazoline derivatives as potent FGFR inhibitors with low nanomolar potency. The representative compound 29 strongly inhibited FGFR1-3 kinase activity and suppressed FGFR signaling transduction in FGFR-addicted cancer cells; FGFRs-driven cell proliferation was also strongly inhibited regardless of mechanistic complexity implicated in FGFR activation, which further confirmed that 29 was a potent pan-FGFR inhibitor. The flexibility of our structure offered the potential to preserve good affinity for mutant FGFR, which is important for developing TKIs with long-term efficacy.
Subject(s)
Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Drug Design , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity RelationshipABSTRACT
BACKGROUND: This study was aimed at establishing a sensitive and specific isolation, characterization, and enumeration method for living circulating tumor cells (CTCs) in patients with colorectal carcinoma. METHODS: Quantitative isolation and characterization of CTCs were performed through a combination of immunomagnetic negative enrichment and fluorescence-activated cell sorting. Isolated CTCs were identified by immunofluorescence staining. The viability and purity of the sorted cells were determined by flow cytometry. Blood samples spiked with HCT116 cells (range, 3-250 cells) were used to determine specificity, recovery, and sensitivity. The method was used to enumerate, characterize, and isolate living CTCs in 10 mL of blood from patients with colorectal carcinoma. RESULTS: The average recovery of HCT116 cells was 61% or more at each spiking level, and the correlation coefficient was 0.992. An analysis of samples from all 18 patients with colorectal carcinoma revealed that 94.4% were positive for CTCs with an average of 33 ± 24 CTCs per 10 mL of blood and with a diameter of 14 to 20 µm (vs 8-12 µm for lymphoma). All patients were CD47(+) , with only 4.3% to 61.2% being CD44(+) . The number of CTCs was well correlated with the patient TNM stage and could be detected in patients at an early cancer stage. The sorted cells could be recultured, and their viability was preserved. CONCLUSIONS: This method provides a novel technique for highly sensitive and specific detection and isolation of CTCs in patients with colorectal carcinoma. This method complements the existing approaches for the de novo functional identification of a wide variety of CTC types. It is likely to help in predicting a patient's disease progression and potentially in selecting the appropriate treatment.
Subject(s)
Colorectal Neoplasms/pathology , Neoplastic Cells, Circulating/pathology , CD47 Antigen/metabolism , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Flow Cytometry , Humans , Hyaluronan Receptors/metabolism , Immunomagnetic Separation , Neoplasm Staging , Neoplastic Cells, Circulating/metabolism , Sensitivity and SpecificityABSTRACT
Boldine is a potential anti-inflammatory agent found in several different plants. Published bioanalytical methods using HPLC with ultraviolet and fluorescent detection lacked enough sensitivity and required tedious sample preparation procedures. Herein, we describe the development of a novel ultra-high performance LC with MS/MS for determination of boldine in plasma. Boldine in plasma was recovered by liquid-liquid extraction using 1 mL of methyl tert-butyl ether. Chromatographic separation was performed on a C18 column at 45°C, with a gradient elution consisting of acetonitrile and water containing 0.1% (v/v) formic acid at a flow rate of 0.3 mL/min. The detection was performed on an electrospray triple-quadrupole MS/MS by positive ion multiple reaction monitoring mode. Good linearity (r(2) > 0.9926) was achieved in a concentration range of 2.555-2555 ng/mL with a lower limit of quantification of 2.555 ng/mL for boldine. The intra- and inter-day precisions of the assay were 1.2-6.0 and 1.8-7.4% relative standard deviation with an accuracy of -6.0-8.0% relative error. This newly developed method was successfully applied to a single low-dose pharmacokinetic study in rats and was demonstrated to be simpler and more sensitive than the published methods, allowing boldine quantification in reduced plasma volume.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Aporphines/blood , Aporphines/pharmacokinetics , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/analysis , Aporphines/administration & dosage , Calibration , Chromatography, High Pressure Liquid/instrumentation , Drug Stability , Injections, Intravenous , Limit of Detection , Male , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and Specificity , Spectrometry, Mass, Electrospray Ionization/methodsABSTRACT
Mifepristone (RU486) is a born-for-woman molecule discovered three decades ago. Unlike those antihypertensive and antipsychotic pharmaceutical blockbusters, this abortifacient offers relatively low profit potential. Current understanding of mechanism of action of mifepristone and its on-going clinical trials are changing our views on the drug beyond its abortifacient scope. Here we briefly review its metabolism and pharmacokinetic properties including its unique enterohepatic circulation, its mechanisms of actions involving antiprogesterone and antiglucocorticoid, growth inhibition of various cancer cell lines, suppression of invasive and metastatic cancer potential, downregulation of Cdk2, Bcl-2, and NF-kappa B, interference of heterotypic cell adhesion to basement membrane, and cell migration. We comprehensively analyze recent results from preclinical and clinical studies using mifepristone as an anticancer drug for breast, meningioma, and gliomas tumors in the central nervous system, prostate cancer, ovarian and endometrial cancer, and gastric adenocarcinoma. Although mifepristone has more benefits for global public health than we originally thought, its effect as a postmetastatic chemotherapeutic agent is limited. Nonetheless, owing to its unique safe, metabolism and other pharmacological properties, metapristone (the primary metabolite of mifepristone) may have potential for cancer metastatic chemoprevention.
Subject(s)
Abortifacient Agents, Steroidal/administration & dosage , Abortion, Therapeutic , Mifepristone/administration & dosage , Neoplasm Metastasis/prevention & control , Pregnancy Complications, Neoplastic/pathology , Abortifacient Agents, Steroidal/pharmacokinetics , Female , Humans , Liver/metabolism , Mifepristone/pharmacokinetics , PregnancyABSTRACT
In this study, a hyperbranched rolling circle amplification (HRCA)-based colorimetric biosensor for carcinoembryonic antigen (CEA) is developed with high sensitivity and specificity. A CEA aptamer can bind with its target (CEA) to form a complex due to their high affinity, and the introduced CDNA cannot hybridize with the aptamer. Thus, free CDNA can propagate the HRCA reaction to form a large number of single-stranded DNA (ss-DNA). ss-DNA can be easily adsorbed onto AuNPs and prevent salt-induced AuNPs aggregation, which causes the change in the color of the system. It is found that the absorbance intensity ratio (A520/A660) has a linear relationship with the concentration of the target in the range of 5 pM-0.5 nM, and the detection limit is as low as 2 pM (S/N = 3).
Subject(s)
Aptamers, Nucleotide/chemistry , Biosensing Techniques/methods , Carcinoembryonic Antigen/analysis , Nucleic Acid Amplification Techniques/methods , Biomarkers, Tumor/analysis , Colorimetry/methods , DNA, Single-Stranded/chemistry , Gold/chemistry , Humans , Limit of Detection , Metal Nanoparticles/chemistryABSTRACT
Combination immunotherapy has shown promising potential for enhancing the objective response rate compared to immune checkpoint blockade (ICB) monotherapy. However, combination therapy with multi-drugs is limited by the different properties of the agents and inconsistent synergistic targeted delivery. Herein, based on a universal triterpene template and the anticancer active agent ursolic acid (UA), a cytomembrane-coated biomimetic delivery nanoplatform (UR@M) prepared by the self-assembly of a PD-L1 targeted CRISPR/Cas9 system and UA was designed for hepatocellular carcinoma (HCC) treatment. UR@M showed enhanced tumor accumulation in vivo with homologous tumor targeting, and CRISPR in the nanosystem exhibited potent gene-editing efficiency of 76.53% in vitro and 62.42% in vivo with no off-target effects. UA activated the natural immune system through the TLR-2-MyD88-TRAF6 pathway, which synergistically enhanced the proliferation of natural killer cells and dendritic cells and realized excellent immune cytotoxic T cell infiltration by combining with the ICB of PD-L1. The strategy of work along both lines based on innate immune and adaptive immunity displayed a significant effect in tumor regression. Overall, the UA-templated strategy "killed three birds with one stone" by establishing a self-assembly nanosystem, inducing tumor cell death, and promoting synergistic immunostimulation for HCC treatment.
ABSTRACT
The existing therapies for cancer are not remote satisfactory due to drug-resistance in tumors that are malignant. There is a pressing necessity to take a step forward to develop innovative therapies that can complement current ones. Multiple investigations have demonstrated that ferroptosis therapy, a non-apoptotic modality of programmed cell death, has tremendous potential in face of multiple crucial events, such as drug resistance and toxicity in aggressive malignancies. Recently, ferroptosis at the crosswalk of chemotherapy, materials science, immunotherapy, tumor microenvironment, and bionanotechnology has been presented to elucidate its therapeutic feasibility. Given the burgeoning progression of ferroptosis-based nanomedicine, the newest advancements in this field at the confluence of ferroptosis-inducers, nanotherapeutics, along with tumor microenvironment are given an overview. Here, the signaling pathways of ferroptosis-related were first talked about briefly. The emphasis discussion was placed on the pharmacological mechanisms and the nanodrugs design of ferroptosis inducing agents based on multiple distinct metabolism pathways. Additionally, a comprehensive overview of the action mechanisms by which the tumor microenvironment influences ferroptosis was elaborately descripted. Finally, some limitations of current researches and future research directions were also deliberately discussed to provide details about therapeutic avenues for ferroptosis-related diseases along with the design of anti-drugs.
Subject(s)
Ferroptosis , Neoplasms , Humans , Tumor Microenvironment , Apoptosis , Immunotherapy , Nanomedicine , Neoplasms/drug therapyABSTRACT
As a sort of fluorescent carbon nanomaterial with a particle size of less than 10 nm, carbon dots (CDs) have their own merits of good dispersibility in water, stable optical properties, strong chemical inertness, stable optical properties, and good biosecurity. These excellent peculiarities facilitated them like sensing, imaging, medicine, catalysis, and optoelectronics, making them a new star in the field of nanotechnology. In particular, the development of CDs in the fields of chemical probes, imaging, cancer therapy, antibacterial and drug delivery has become a hot topic in current research. Although the biomedical applications in CDs have been demonstrated in many research articles, a systematic summary of their role in biomedical applications is scarce. In this review, we introduced the basic information of CDs in detail, including synthesis approaches of CDs as well as their favorable properties including photoluminescence and low cytotoxicity. Subsequently, the application of CDs in the field of biomedicine was emphasized. Finally, the main challenges and research prospects of CDs in this field were proposed, which might provide some detailed information in designing new CDs in this promising biomedical field.
Subject(s)
Carbon , Quantum Dots , Carbon/chemistry , Quantum Dots/chemistry , Quantum Dots/toxicity , Humans , AnimalsABSTRACT
The effectiveness of chemotherapeutic agents for hepatocellular carcinoma (HCC) is unsatisfactory because of tumor heterogeneity, multidrug resistance, and poor target accumulation. Therefore, multimodality-treatment with accurate drug delivery has become increasingly popular. Herein, a cell penetrating peptide-aptamer dual modified-nanocomposite (USILA NPs) was successfully constructed by coating a cell penetrating peptide and aptamer onto the surface of sorafenib (Sora), ursolic acid (UA) and indocyanine green (ICG) condensed nanodrug (USI NPs) via one-pot assembly for targeted and synergistic HCC treatment. USILA NPs showed higher cellular uptake and cytotoxicity in HepG2 and H22 cells, with a high expression of epithelial cell adhesion molecule (EpCAM). Furthermore, these NPs caused more significant mitochondrial membrane potential reduction and cell apoptosis. These NPs could selectively accumulate at the tumor site of H22 tumor-bearing mice and were detected with the help of ICG fluorescence; moreover, they retarded tumor growth better than monotherapy. Thus, USILA NPs can realize the targeted delivery of dual drugs and the integration of diagnosis and treatment. Moreover, the effects were more significant after co-administration of iRGD peptide, a tumor-penetrating peptide with better penetration promoting ability or programmed cell death ligand 1 (PD-L1) antibody for the reversal of the immunosuppressive state in the tumor microenvironment. The tumor inhibition rates of USILA NPs + iRGD peptide or USILA NPs + PD-L1 antibody with good therapeutic safety were 72.38 % and 67.91 % compared with control, respectively. Overall, this composite nanosystem could act as a promising targeted tool and provide an effective intervention strategy for enhanced HCC synergistic treatment.
Subject(s)
Carcinoma, Hepatocellular , Cell-Penetrating Peptides , Liver Neoplasms , Nanoparticles , Mice , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Pharmaceutical Preparations , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Cell-Penetrating Peptides/chemistry , B7-H1 Antigen/therapeutic use , Nanoparticles/chemistry , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
Both ursolic acid (UA) and sorafenib (Sora) have been generally utilized in cancer treatment, and the combination of the two has also shown a good anti-tumor effect. However, single-agent therapy for Hepatocellular carcinoma (HCC) has the disadvantages of multi-drug resistance, poor water solubility and low bioavailability, and the application of traditional nanocarrier materials is limited due to their low drug loading and low carrier-related toxicity. Therefore, we prepared US NPs with different proportions of UA and Sora by solvent exchange method for achieving synergistic HCC therapy. US NPs had suitable particle size, good dispersibility and storage stability, which synergistically inhibited the proliferation of HepG2 cells, SMMC7721 cells and H22 cells. In addition, we also proved that US NPs were able to suppress the migration of HepG2 cells and SMMC7721 cells and reduce the adhesion ability and colony formation ability of these cells. According to the results, US NPs could degrade the membrane potential of mitochondrial, participate in cell apoptosis, and synergistically induce autophagy. Collectively, the carrier-free US NPs provide new strategies for HCC treatment and new ideas for the development of novel nano-drug delivery systems containing UA and Sora.