Engineering Clinically Relevant Probiotics with Switchable "Nano-Promoter" and "Nano-Effector" for Precision Tumor Therapy.

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.

Nanosecond pulse effectively ablated hepatocellular carcinoma with alterations in the gut microbiome and serum metabolites.

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.

Dynamic ginsenoside-sheltered nanocatalysts for safe ferroptosis-apoptosis combined therapy.

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.

pH-responsive hybrid platelet membrane-coated nanobomb with deep tumor penetration ability and enhanced cancer thermal/chemodynamic therapy.

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.

KRT8 Serves as a Novel Biomarker for LUAD and Promotes Metastasis and EMT via NF-κB Signaling.

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.

Sox15 Methylation Inhibits Cell Proliferation Through Wnt Signaling in Hepatocellular Carcinoma.

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.

An NIR Discrete Metallacycle Constructed from Perylene Bisimide and Tetraphenylethylene Fluorophores for Imaging-Guided Cancer Radio-Chemotherapy.

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.

Multi-Omics Analysis Reveals Disturbance of Nanosecond Pulsed Electric Field in the Serum Metabolic Spectrum and Gut Microbiota.

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.

The synthesis of a nanodrug using metal-based nanozymes conjugated with ginsenoside Rg3 for pancreatic cancer therapy.

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.

3-Bromopyruvate-Conjugated Nanoplatform-Induced Pro-Death Autophagy for Enhanced Photodynamic Therapy against Hypoxic Tumor.

Autophagy triggered by reactive oxygen species (ROS) in photodynamic therapy (PDT) generally exhibits an anti-apoptotic effect to promote cell survival. Herein, an innovative supramolecular nanoplatform was fabricated for enhanced PDT by converting the role of autophagy from pro-survival to pro-death. The respiration inhibitor 3-bromopyruvate (3BP), which can act as an autophagy promoter and hypoxia ameliorator, was integrated into photosensitizer chlorin e6 (Ce6)-encapsulated nanoparticles to combat hypoxic tumor. 3BP could inhibit respiration by down-regulating HK-II and GAPDH expression to significantly reduce intracellular oxygen consumption rate, which could relieve tumor hypoxia for enhanced photodynamic cancer therapy. More importantly, the autophagy level was significantly elevated by the combination of 3BP and PDT determined by Western blot, immunofluorescent imaging, and transmission electron microscopy. It was very surprising that excessively activated autophagy promoted cell apoptosis, leading to the changeover of autophagy from pro-survival to pro-death. Therefore, PDT combined with 3BP could achieve efficient cell proliferation inhibition and tumor regression. Furthermore, hypoxia-inducible factor-1α (HIF-1α) could be down-regulated after tumor hypoxia was relieved by 3BP. Tumor metastasis could then be effectively inhibited by eliminating primary tumors and down-regulating HIF-1α expression. These results provide an inspiration for future innovative approaches of cancer therapy by triggering pro-death autophagy.

Cancer cell membrane-coated gold nanorods for photothermal therapy and radiotherapy on oral squamous cancer.

The combination of different modalities greatly enhances the anticancer efficacy of each treatment by combining their merits, showing promising potential in clinical translation. Herein, we fabricated cancer cell membrane-coated gold nanorods (GNR@Mem) possessing excellent photothermal transfer ability in the second near-infrared window and radiosensitizing ability under X-ray irradiation. The cancer cell membrane coating endowed the nanomedicine with stability in the physiological environment and selective homotypic targeting to specific cancer cells in vitro. Under NIR light and X-ray irradiation, the gold nanorods induced a temperature increase, reactive oxygen generation, and subsequent damage to the DNA helix structure, leading to enhanced cell apoptosis. Benefitting from its relative long circulation time in the blood and homotypic targeting effect, the tumor accumulation of GNR@Mem significantly increased. The in vivo results demonstrate that the combination of photothermal therapy and radiotherapy effectively suppresses tumor growth without noticeable systemic toxicity.

Upregulation of PDGF Mediates Robust Liver Regeneration after Nanosecond Pulsed Electric Field Ablation by Promoting the HGF/c-Met Pathway.

Nanosecond pulsed electric field (nsPEF) has emerged as a promising tool for hepatocellular carcinoma ablation recently. However, little is known about how nsPEF affects liver regeneration while being applied to eliminate liver lesions. Besides, the impact of nsPEF ablation on liver function should also be taken into consideration in the process. In this paper, we study the impact of nsPEF ablation on liver function by the measurement of serum levels of AST and ALT as well as liver regeneration and relevant molecular mechanisms in vivo. We found that mouse liver function exhibited a temporary injury without weight loss after ablation. In addition, local hepatic nsPEF ablation promoted significant proliferation of hepatocytes of the whole liver with an increase in HGF level. Moreover, the proliferation of hepatocytes was dramatically inhibited by the inhibitor of c-Met. Of interest, the periablational area is characterized by high level of PDGF and a large amount of activated hepatic stellate cells. Furthermore, neutralizing PDGF was able to significantly inhibit liver regeneration, the increased HGF level, and the accumulation of activated HSCs. Our findings demonstrated that nsPEF not only was a safe ablation approach but also could stimulate the regeneration of the whole liver through the activation of the HGF/c-Met pathway by upregulation of PDGF within the periablational zone.

Surface-Anchored Graphene Oxide Nanosheets on Cell-Scale Micropatterned Poly(d,l-lactide-co-caprolactone) Conduits Promote Peripheral Nerve Regeneration.

Regeneration and functional recovery of peripheral nerves remain formidable due to the inefficient physical and chemical cues in the available nerve guidance conduits (NGCs). Introducing micropatterns and bioactive substances into the inner wall of NGCs can effectively regulate the behavior of Schwann cells, the elongation of axons, and the phenotype of macrophages, thereby aiding the regeneration of injured nerve. In this study, linear micropatterns with ridges and grooves of 3/3, 5/5, 10/10, and 30/30 µm were created on poly(d,l-lactide-co-caprolactone) (PLCL) films following with surface aminolysis and electrostatic adsorption of graphene oxide (GO) nanosheets. The GO-modified micropatterns could significantly accelerate the collective migration of Schwann cells (SCs) and migration of SCs from their spheroids in vitro. Moreover, the SCs migrated directionally along the stripes with a fastest rate on the 3/3-GO film that had the largest cell adhesion force. The neurites of N2a cells were oriented along the micropatterns, and the macrophages tended to differentiate into the M2 type on the 3/3-GO film judged by the higher expression of Arg 1 and IL-10. The systematic histological and functional assessments of the regenerated nerves at 4 and 8 weeks post-surgery in vivo confirmed that the 3/3-GO NGCs had better performance to promote the nerve regeneration, and the CMAP, NCV, wet weight of gastrocnemius muscle, positive S100ß and NF200 area percentages, and average myelinated axon diameter were more close to those of the autograft group at 8 weeks. This type of NGCs thus has a great potential for nerve regeneration.

A Metal-Polyphenol-Coordinated Nanomedicine for Synergistic Cascade Cancer Chemotherapy and Chemodynamic Therapy.

The clinical application of chemotherapy is impeded by the unsatisfactory efficacy and severe side effects. Chemodynamic therapy (CDT) has emerged as an efficient strategy for cancer treatment utilizing Fenton chemistry to destroy cancer cells by converting endogenous H2 O2 into highly toxic reactive oxygen species. Apart from the chemotherapeutic effect, cisplatin is able to act as an artificial enzyme to produce H2 O2 for CDT through cascade reactions, thus remarkably improving the anti-tumor outcomes. Herein, an organic theranostic nanomedicine (PTCG NPs) is constructed with high loading capability using epigallocatechin-3-gallate (EGCG), phenolic platinum(IV) prodrug (Pt-OH), and polyphenol modified block copolymer (PEG-b-PPOH) as the building blocks. The high stability of PTCG NPs during circulation stems from their strong metal-polyphenol coordination interactions, and efficient drug release is realized after cellular internalization. The activated cisplatin elevates the intracellular H2 O2 level through cascade reactions. This is further utilized to produce highly toxic reactive oxygen species catalyzed by an iron-based Fenton reaction. In vitro and in vivo investigations demonstrate that the combination of chemotherapy and chemodynamic therapy achieves excellent anticancer efficacy. Meanwhile, systemic toxicity faced by platinum-based drugs is avoided through this nanoformulation. This work provides a promising strategy to develop advanced nanomedicine for cascade cancer therapy.

Nanoparticle Conjugation of Ginsenoside Rg3 Inhibits Hepatocellular Carcinoma Development and Metastasis.

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.

Multiple novel hepatocellular carcinoma signature genes are commonly controlled by the master pluripotency factor OCT4.

BACKGROUND: Worldwide, hepatocellular carcinoma (HCC) is a common solid tumor with a poor prognosis. HCC is often due to hepatitis B virus (HBV) infection. As yet, efficacious HCC treatment regimens for late-stage HCC patients are lacking. Therefore, the identification of more specific and sensitive biomarkers for its early diagnosis and treatment remains an urgent need. METHODS: Total RNAs from paired HBV-derived HCC tumors and adjacent peritumor tissues (APTs) were subjected to RNA sequencing (RNA-seq), and differentially expressed genes (DEGs) between HCC tumors and APTs were selected and verified. RESULTS: We identified 166 DEGs and found that eight top-ranked and verified DEGs (TK1, CTTN, CEP72, TRIP13, FTH1, FLAD1, CHRM2, AMBP) all contained putative OCT4 binding motifs in their promoter regions. TK1, TRIP13 and OCT4 were found to exhibit concurrent higher expression levels in HCC tumors than in APTs. The mRNA levels of TK1, TRIP13 and OCT4 in a cohort of 384 HCC samples from the TCGA database were all found to be negatively correlated with patient overall survival, relapse-free survival and progression-free survival, underscoring the HCC biomarker status of TK1 and TRIP13 on one hand, and implicating their association with OCT4 on the other hand. Furthermore, OCT4 proteins were found to bind to the promoters of both genes in vitro and in vivo. Knocking out OCT4 in HCC-derived cell lines reduced the expression of TK1 and TRIP13 and significantly decreased their tumorigenicity. CONCLUSIONS: Using RNA-seq, we identified several novel HCC signature genes that may serve as biomarkers for its diagnosis and prognosis. Their common transcriptional regulation by OCT4 suggests key roles in the development of HCC, and indicates that OCT4 may serve as a potential therapeutic target.

Tumor-Targeting Polycaprolactone Nanoparticles with Codelivery of Paclitaxel and IR780 for Combinational Therapy of Drug-Resistant Ovarian Cancer.

Synergetic treatments that combine chemotherapy with photothermal/photodynamic therapy have been developed as promising new strategies for cancer therapy, especially for drug-resistant cancers. To achieve optimized synergetic outcomes for cancer therapy, it is highly desirable to selectively and simultaneously deliver both chemotherapeutics and near-infrared photosensitizers to the cancer tissues and cells, enhancing local accumulation. Here we report the preparation of poly-ε-caprolactone nanoparticles (PCL NPs) using bovine albumin as a stabilizer; the nanoparticles are loaded with IR780 and paclitaxel (PTX) for combinational phototherapy and chemotherapy. Moreover, in order to enable active targeting toward ovarian cancer, a specific peptide recognizing luteinizing hormone-releasing hormone receptors (LHRH) on ovarian cancer cells was covalently grafted onto the surface of the as-prepared NPs. As a result, LHRH peptide modified PCL (PCL-LHRH) NPs demonstrated increased internalization in ovarian tumor cells in vitro and selective targeting in tumor xenografts in vivo. PTX and IR780 can be efficiently encapsulated into PCL-LHRH NPs by an oil-in-water emulsion and solvent evaporation method. The systematic administration of ovarian tumor targeting PCL-LHRH/IR780-PTX can efficiently hinder the growth of drug-resistant xenografts in vivo with the assistance of an 808 nm near-infrared laser. These findings indicate that peptide mediated tumor targeting multifunctional nanomaterials may have remarkable profits in controlled drug delivery and synergistic therapy on drug-resistant cancer.

CDCA5, Transcribed by E2F1, Promotes Oncogenesis by Enhancing Cell Proliferation and Inhibiting Apoptosis via the AKT Pathway in Hepatocellular Carcinoma.

Cell division cycle associated 5 (CDCA5) is an important element for the interaction between cohesin and chromatin in interphase. It is abnormally expressed in many types of cancer and works as an indicator of poor prognosis, but little is known about its activity in hepatocellular carcinoma (HCC). In the present study, we found that the expression of CDCA5 was upregulated in HCC tissues compared to paracancerous tissues and had a negative correlation with patient survival. Cell proliferation and tumorigenesis were inhibited and cell apoptosis was induced with the knockdown of CDCA5, suggesting an oncogenic role of CDCA5 in liver cancer. Luciferase reporter assay and chromatin immunoprecipitation showed that CDCA5 was transcribed by E2F1. Furthermore, we confirmed that CDCA5 interrupted cell behavior via the AKT pathway. These findings demonstrated that CDCA5 plays an important role in HCC progression.

Blocking Triggering Receptor Expressed on Myeloid Cells-1-Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver Cancer.

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.

Comprehensive analysis of common safety profiles and their predictive factors in 520 records of liver cancer patients treated by drug-eluting beads transarterial chemoembolization.

This study aimed to investigate the difference of common adverse events (AEs) between patients experienced first drug-eluting beads transarterial chemoembolization (DEB-TACE; FD) and second or higher DEB-TACE (SHD), and the factors influencing AEs.Five hundred twenty DEB-TACE records were retrospectively reviewed in this cohort study, among which 284 and 236 records were in FD and SHD groups, respectively. The incidence and/or severity of pain, fever, vomiting, and increased blood pressure (BP) were collected.Pain numerical rating scale (NRS) score, pain severity, body temperature, fever severity, and fever lasting days were higher in FD group than in SHD group, while no difference of vomiting and increased BP between 2 groups were disclosed. Age ≥65 years was associated with decreased high fever and less possibility of vomiting in FD group, and lower pain and fever severity in SHD group; Male decreased the possibility of vomiting in both the groups, and reduced increased BP incidence in SHD group; diabetes history correlated with decreased pain degree and less fever in FD group.In conclusion, SHD was better tolerated compared with FD in liver cancer patients, and older age as well as male were correlated with less occurrence or severity of common AEs in DEB-TACE operation.