ABSTRACT
The abnormal estrogens levels in human body can cause many side effects and diseases, but the quantitative detection of the trace estrogens in complex biological samples still remains great challenge. Here we reported the fabrication of a novel core-shell structured magnetic cyclodextrin microporous organic network (Fe3O4@CD-MON) for rapid magnetic solid phase extraction (MSPE) of four estrogens in human serum and urine samples prior to HPLC-UV determination. The uniform spherical core-shell Fe3O4@CD-MONs was successfully regulated by altering the reactive monomers and solvents. The Fe3O4@CD-MONs owned high specific surface area, good hydrophobicity, large superparamagnetism, and abundant extraction sites for estrogens. Under optimal conditions, the proposed MSPE-HPLC-UV method provided wide linearity range (2.0-400 µg L-1), low limits of detection (0.5-1.0 µg L-1), large enrichment factors (183-198), less adsorbent consumption (3 mg), short extraction time (3 min), and good stability and reusability (at least 8 cycles). The established method had also been successfully applied to the enrichment and detection of four estrogens in serum and urine samples with a recovery of 88.4-105.1 % and a relative standard deviation of 1.0-5.9 %. This work confirmed the feasibility of solvent and monomer regulation synthesis of Fe3O4@CD-MON composites, and revealed the great prospects of magnetic CD-MONs for efficient enrichment of trace estrogens in complex biological samples.
Subject(s)
Estrogens , Limit of Detection , Solid Phase Extraction , beta-Cyclodextrins , Humans , Chromatography, High Pressure Liquid/methods , Estrogens/urine , Estrogens/blood , Estrogens/isolation & purification , Estrogens/analysis , Estrogens/chemistry , Solid Phase Extraction/methods , beta-Cyclodextrins/chemistry , Solvents/chemistry , Porosity , Magnetite Nanoparticles/chemistry , AdsorptionABSTRACT
This study explore the molecular mechanism of the synergistic effect of Chinese Yam polysaccharides and nucleoside analogues(NAs) on hepatitis B virus(HBV) resistance. Different concentrations of Chinese Yam polysaccharide and entecavir were ad-ded to HepG2.2.15 cells. After the cytotoxicity was detected by cell counting kit-8(CCK-8), the optimal concentration and time of the two drugs to inhibit HepG2.2.15 cells were screened out. They were divided into control group, Chinese Yam polysaccharide group, entecavir group and combination drug group(Chinese Yam polysaccharide + entecavir). The drugs were added to HepG2.2.15 cells, ELISA was used to detect the effects of each group of drugs on the secretion of hepatitis B virus surface antigen(HBsAg) and hepatitis B virus e antigen(HBeAg) in cell supernatant, probe quantitative real-time PCR(probe qRT-PCR) was used to detect the effects of drugs on HBV-DNA in HepG2.2.15 cells, and Western blot was used to detect the effects of each group of drugs on the expression of p38 MAPK, p-p38 MAPK, NTCP proteins in HepG2.2.15 cells. The qRT-PCR was used to detect the effect of drugs on the expression of p38 MAPK and NTCP mRNA in HepG2.2.15 cells. The results showed that compared with control group, the concentrations of HBeAg and HBsAg in Chinese Yam polysaccharide group, entecavir group and combination group decreased(P<0.01 or P<0.001), and both of them inhibited HBV-DNA in HepG2.2.15 cells(P<0.01), and the HBV-DNA inhibition of HepG2.2.15 cells in the combination group was more obvious(P<0.001), and the protein expression levels of p-p38 MAPK and NTCP were significantly decreased(P<0.05 or P<0.01), the mRNA expression level of p38 MAPK increased, and the mRNA expression level of NTCP decreased(P<0.05 or P<0.01). To sum up, Chinese Yam polysaccharide can reduce the expression of NTCP protein and mRNA through p38 MAPK signaling pathway and cooperate with entecavir in anti-HBV.
Subject(s)
Antiviral Agents , Dioscorea , Hepatitis B virus , Polysaccharides , p38 Mitogen-Activated Protein Kinases , Humans , Hepatitis B virus/drug effects , Hepatitis B virus/genetics , Polysaccharides/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism , p38 Mitogen-Activated Protein Kinases/genetics , Hep G2 Cells , Antiviral Agents/pharmacology , Dioscorea/chemistry , Drug Synergism , Nucleosides/pharmacology , MAP Kinase Signaling System/drug effects , Hepatitis B Surface Antigens/metabolism , Hepatitis B Surface Antigens/genetics , Hepatitis B e Antigens/metabolism , Hepatitis B/drug therapy , Hepatitis B/virology , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Guanine/analogs & derivatives , Guanine/pharmacologyABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality. The Food and Drug Administration-approved drugs, nintedanib and pirfenidone, could delay progressive fibrosis by inhibiting the overactivation of fibroblast, however, there was no significant improvement in patient survival due to low levels of drug accumulation and remodeling of honeycomb cyst and interstitium surrounding the alveoli. Herein, we constructed a dual drug (verteporfin and pirfenidone)-loaded nanoparticle (Lip@VP) with the function of inhibiting airway epithelium fluidization and fibroblast overactivation to prevent honeycomb cyst and interstitium remodeling. Specifically, Lip@VP extensively accumulated in lung tissues via atomized inhalation. Released verteporfin inhibited the fluidization of airway epithelium and the formation of honeycomb cyst, and pirfenidone inhibited fibroblast overactivation and reduced cytokine secretion that promoted the fluidization of airway epithelium. Our results indicated that Lip@VP successfully rescued lung function through inhibiting honeycomb cyst and interstitium remodeling. This study provided a promising strategy to improve the therapeutic efficacy for IPF.
Subject(s)
Cysts , Idiopathic Pulmonary Fibrosis , Nanoparticles , Humans , Verteporfin , Idiopathic Pulmonary Fibrosis/drug therapy , LungABSTRACT
Triacylglycerols (TAG) from microalgae can be used as feedstocks for biofuel production to address fuel shortages. Most of the current research has focused on the enzymes involved in TAG biosynthesis. In this study, the effects of malic enzyme (ME), which provides precursor and reducing power for TAG biosynthesis, on biomass and lipid accumulation and its response to salt stress in Dunaliella salina were investigated. The overexpression of DsME1 and DsME2 improved the lipid production, which reached 0.243 and 0.253 g/L and were 30.5 and 36.3% higher than wild type, respectively. The transcript levels of DsME1 and DsME2 increased with increasing salt concentration (0, 1, 2, 3, and 4.5 mol/L NaCl), indicating that DsMEs participated in the salt stress response in D. salina. It was found that cis-acting elements associated with the salt stress response were present on the promoters of two DsMEs. The deletion of the MYB binding site (MBS) on the DsME2 promoter confirmed that MBS drives the expression of DsME2 to participate in osmotic regulation in D. salina. In conclusion, MEs are the critical enzymes that play pivotal roles in lipid accumulation and osmotic regulation.
ABSTRACT
Despite the rapid development of versatile metal-organic frameworks (MOFs), the synthesis of water-stable MOFs remains challenging, which significantly limits their practical applications. Herein, a novel engineering strategy was developed to prepare superhydrophobic MOFs by an in situ fluorinated microporous organic network (FMON) coating. Through controllable modification, the resulting MOF@FMON retained the porosity and crystallinity of the pristine MOFs. Owing to the superhydrophobicity of the FMON and the feasibility of MOF synthesis, the FMON coating could be in situ integrated with various water-sensitive MOFs to provide superhydrophobicity. The coating thickness and hydrophobicity of the MOF@FMON composites were easily regulated by changing the FMON monomer concentration. The MOF@FMON composites exhibited excellent oil/water separation and catalytic activities and enhanced durability in aqueous solutions. This study provides a general approach for the synthesis of superhydrophobic MOFs, expanding the application scope of MOFs.
ABSTRACT
This study explored the molecular mechanism of acteoside against hepatoma 22(H22) tumor in mice through c-Jun N-terminal kinase(JNK) signaling pathway. H22 cells were subcutaneously inoculated in 50 male BALB/c mice, and then the model mice were classified into model group, low-dose, medium-dose, and high-dose acteoside groups, and cisplatin group. The administration lasted 2 weeks for each group(5 consecutive days/week). The general conditions of mice in each group, such as mental status, diet intake, water intake, activity, and fur were observed. The body weight, tumor volume, tumor weight, and tumor-inhibiting rate were compared before and after administration. Morphological changes of liver cancer tissues were observed based on hematoxylin and eosin(HE) staining, and the expression of phosphorylated(p)-JNK, JNK, B-cell lymphoma-2(Bcl-2), Beclin-1, and light chain 3(LC3) in each tissue was detected by immunohistochemistry and Western blot. qRT-PCR was performed to detect the mRNA expression of JNK, Bcl-2, Beclin-1, and LC3. The general conditions of mice in model and low-dose acteoside groups were poor, while the general conditions of mice in the remaining three groups were improved. The body weight of mice in medium-dose acteoside group, high-dose acteoside group, and cisplatin group was smaller than that in model group(P<0.01). The tumor volume in model group was insignificantly different from that in low-dose acteoside group, and the volume in cisplatin group showed no significant difference from that in high-dose acteoside group. Tumor volume and weight in medium-dose and high-dose acteoside groups and cisplatin group were lower than those in the model group(P<0.001). The tumor-inhibiting rates were 10.72%, 40.32%, 53.79%, and 56.44% in the low-dose, medium-dose, and high-dose acteoside groups and cisplatin group, respectively. HE staining showed gradual decrease in the count of hepatoma cells and increasing sign of cell necrosis in the acteoside and cisplatin groups, and the necrosis was particularly obvious in the high-dose acteoside group and cisplatin group. Immunohistochemical results suggested that the expression of Beclin-1, LC3, p-JNK, and JNK was up-regulated in acteoside and cisplatin groups(P<0.05). The results of immunohistochemistry, Western blot, and qRT-PCR indicated that the expression of Bcl-2 was down-regulated in the medium-dose and high-dose acteoside groups and cisplatin group(P<0.01). Western blot showed that the expression of Beclin-1, LC3, and p-JNK was up-regulated in acteoside and cisplatin groups(P<0.01), and there was no difference in the expression of JNK among groups. qRT-PCR results showed that the levels of Beclin-1 and LC3 mRNA were up-regulated in the acteoside and cisplatin groups(P<0.05), and the level of JNK mRNA was up-regulated in medium-dose and high-dose acteoside groups and cisplatin group(P<0.001). Acteoside promotes apoptosis and autophagy of H22 cells in mice hepatoma cells by up-regulating the JNK signaling pathway, thus inhibiting tumor growth.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Male , Animals , Mice , Cisplatin/pharmacology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , MAP Kinase Signaling System , Beclin-1 , Apoptosis , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Necrosis , Proto-Oncogene Proteins c-bcl-2/metabolism , Cell Line, Tumor , RNA, Messenger/metabolism , AutophagyABSTRACT
Circulating tumor cells (CTCs) as important biomarkers for noninvasive clinical diagnosis and prognostic evaluation are significant in predicting the overall survival and progression-free survival of cancer patients. However, the current typical CTCs separation and enrichment techniques were limited to a single collection of small-volume blood samples, which was inadequate to comprehensively profile the distribution of CTCs in the systemic blood. In addition, those techniques cannot reduce metastasis of CTCs unless adjuvant chemotherapy. Herein, inspired by hemodialysis, we designed a whole blood purifier (WBP) composed of a functionalized special spiral-like glass tube modified by anti-epithelial cell adhesion molecule (anti-EpCAM). The WBP allowed real-time capture, enrichment and removal of CTCs from systemic blood circulation, and the purified blood was immediately returned to the body. Furthermore, the WBP did not cause any organic damages in vivo. This approach achieves the high accuracy of liquid biopsy technology and is expected to become an effective clinical adjuvant therapy for tumor metastasis.
Subject(s)
Biosensing Techniques , Neoplastic Cells, Circulating , Humans , Neoplastic Cells, Circulating/pathology , Cell Line, Tumor , Epithelial-Mesenchymal Transition , Cell Separation/methods , Biomarkers, TumorABSTRACT
BACKGROUND: Eosinophilic gastroenteritis is a rare gastrointestinal disease that is characterized by diffuse or localized eosinophil infiltration in the gastrointestinal tract, and is accompanied by increased peripheral blood eosinophils. Herein, a case of plasma membrane lesion-type total intestinal eosinophil enteritis is reported. CASE PRESENTATION: We report on a 20-year-old male patient who was admitted to the hospital with "abdominal distension for 15 days". The infiltration of a large number of eosinophils was found by conducting an intestinal biopsy, routine ascites examination, blood routine, smear test, and a bone marrow puncture. A special feature of this patient was that a large number of eosinophils were found in the duodenum, small intestine, and colon. The final diagnosis was plasma membrane lesion type total intestinal eosinophilic enteritis. After four weeks of prednisone treatment, the symptoms disappeared completely and the entire intestinal mucosa was endoscopically observed as smooth. CONCLUSION: Clinical practitioners must pay attention to gastrointestinal endoscopy and biopsy pathology results for patients presenting with abdominal distention and ascites. Combined with an abnormal increase of eosinophils in ascites, bone marrow, and peripheral blood, clinical practitioners must be highly vigilant against plasma membrane lesion type total intestinal eosinophilic enteritis.
Subject(s)
Enteritis , Eosinophilia , Adult , Ascites/complications , Cell Membrane/pathology , Enteritis/complications , Enteritis/diagnosis , Enteritis/drug therapy , Eosinophilia/complications , Eosinophilia/pathology , Gastritis , Humans , Male , Young AdultABSTRACT
Dunaliella salina can accumulate a large amount of ß-carotene which is generally considered to be its terminal product of carotenoid metabolism. In this study, it was proved that D. salina has the ketolase (DsBKT) of catalyzing the synthesis of astaxanthin, the downstream products of ß-carotene. Therefore, the reason why D. salina does not synthesize astaxanthin is the purpose of this study. The enzymatic activity of DsBKT was detected by functional complementation assays in Escherichia coli, results showed that DsBKT had efficient ketolase activity toward ß-carotene and zeaxanthin to produce astaxanthin, indicating that there were complete astaxanthin-producing genes in Dunaliella. Unlike the induced expression of Lycopene cyclase (catalyzing ß-carotene synthesis) under salt stress, the expression of DsBKT was very low under both normal and stress conditions, which may be the main reason why D. salina cannot accumulate astaxanthin. On the contrary, with the astaxanthin-rich Haematococcus pluvialis as a control, its BKT gene was significantly upregulated under salt stress. Further study showed that DsBKT promoter had strong promoter ability and could stably drive the expression of ble-egfp in D. salina. Obviously, DsBKT promoter is not the reason of DsBKT not being expressed which may be caused by Noncoding RNA.
Subject(s)
Chlorophyta , Oxygenases , beta Carotene , Escherichia coli/genetics , Escherichia coli/metabolism , Oxygenases/genetics , Salt Stress/genetics , Xanthophylls , beta Carotene/metabolismABSTRACT
Carotenoids are important precursors of a wide range of apocarotenoids with their functions including: hormones, pigments, retinoids, volatiles, and signals, which can be used in the food, flavors, fragrances, cosmetics, and pharmaceutical industries. This article focuses on the formation of these multifaceted apocarotenoids and their diverse biological roles in all living systems. Carotenoid degradation pathways include: enzymatic oxidation by specific carotenoid cleavage oxygenases (CCOs) or nonspecific enzymes such as lipoxygenases and peroxidases and non-enzymatic oxidation by reactive oxygen species. Recent advances in the regulation of carotenoid cleavage genes and the biotechnological production of multiple apocarotenoids are also covered. It is suggested that different developmental stages and environmental stresses can influence both the expression of carotenoid cleavage genes and the formation of apocarotenoids at multiple levels of regulation including: transcriptional, transcription factors, posttranscriptional, posttranslational, and epigenetic modification. Regarding the biotechnological production of apocarotenoids especially: crocins, retinoids, and ionones, enzymatic biocatalysis and metabolically engineered microorganisms have been a promising alternative route. New substrates, carotenoid cleavage enzymes, biosynthetic pathways for apocarotenoids, and new biological functions of apocarotenoids will be discussed with the improvement of our understanding of apocarotenoid biology, biochemistry, function, and formation from different organisms.
Subject(s)
Biosynthetic Pathways , Carotenoids , Carotenoids/metabolismABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous and fatal disease. However, IPF treatment has been limited by the low drug delivery efficiency to lungs and dysfunctional "injured" type II alveolar epithelial cell (AEC II). Here, we present surface-engineered nanoparticles (PER NPs) loading astaxanthin (AST) and trametinib (TRA) adhered to monocyte-derived multipotent cell (MOMC) forming programmed therapeutics (MOMC/PER). Specifically, the cell surface is designed to backpack plenty of PER NPs that reach directly to the lungs due to the homing characteristic of the MOMC and released PER NPs retarget injured AEC II after responding to the matrix metalloproteinase-2 (MMP-2) in IPF tissues. Then, released AST can enhance synergetic effect of TRA for inhibiting myofibroblast activation, and MOMC can also repair injured AEC II to promote damaged lung regeneration. Our findings provide proof of concept for developing a strategy for cell-mediated lung-targeted delivery platform carrying dual combined therapies to reverse IPF.
Subject(s)
Idiopathic Pulmonary Fibrosis , Alveolar Epithelial Cells/metabolism , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Lung/metabolism , Matrix Metalloproteinase 2/metabolism , Monocytes/metabolismABSTRACT
Ferroptosis, a newfound non-apoptotic cell death pathway, results from the accumulation of iron-dependent lipid peroxide (LPO). Recently, emerging iron-based nanomaterials have been extensively developed to induce Fenton reaction-dependent ferroptosis for cancer therapy. However, insufficient amount of H2O2 and limited acidity of tumor could not satisfy the optimal conditions for Fenton reaction, which extremely limited the efficacy of ferroptosis therapy. Herein, we report a novel glutathione (GSH) and iron redox couple sequentially triggered LPO generator (LPOgener) which can directly supply the Fenton reaction-independent downstream executioner of ferroptosis for cancer therapy. By harnessing GSH-mediated Fe3+ reduction and the well-established iron redox couple-mediated lipid peroxidation, LPOgener was constructed by complete ferric ammonium citrate (FAC) and unsaturated lipids-rich phosphatidylcholine, and formed as FAC loaded liposome. The Fe3+ encapsulated in LPOgener could be efficiently reduced to Fe2+ under high GSH level in tumor cells. Subsequently, the formed iron redox couple could trigger overwhelming lipid peroxidation for Fenton reaction-independent ferroptosis. Superior anticancer therapeutic effect with little systemic toxicity demonstrated that LPOgener was a potent ferroptosis-inducing agent for cancer therapy. Therefore, to directly supply the druglike, easily prepared, GSH and iron redox couple sequentially triggered LPOgener would provide a new direction in designing strategies for ferroptosis therapy.
Subject(s)
Ferroptosis , Glutathione/metabolism , Hydrogen Peroxide , Iron , Lipid Peroxides , Oxidation-ReductionABSTRACT
Oxaliplatin is a chemotherapeutic agent widely used in cancer treatment whereas its immunosuppressive effect hinders the progress of immunotherapy. Here we have synthesized a new compound NLGplatin constructed by combining oxaliplatin (OXA) and indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919. The NLGplatin acquires chemotherapeutic properties of OXA and can activate the immune system, and also retains the ability to inhibit IDO enzyme activity without affecting the proliferation of immune cells. This difunctional drug has a great potential to achieve effective cancer chemoimmunotherapy.
Subject(s)
Imidazoles/administration & dosage , Immunotherapy/methods , Isoindoles/administration & dosage , Neoplasms/drug therapy , Oxaliplatin/administration & dosage , Animals , Antigens, Neoplasm/immunology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Female , Humans , Imidazoles/pharmacology , Isoindoles/pharmacology , Mice , Mice, Inbred BALB C , Neoplasms/immunology , Oxaliplatin/pharmacologyABSTRACT
Cationic polymeric vectors attracted plenty of attentions in gene therapy due to nonimmunogenicity, easy to synthesis and flexible properties. However, biocompatibility challenge such as nonspecific interactions with blood cells and serum proteins, may affect the delivery efficiency of cationic vectors; besides, inefficient endosomal escape causes low transfection efficiency. Herein, we synthesized an anionic coating polymer dextran-g-aconic anhydride (Dex-Aco, DA) through a simple esterification reaction, which can protect cationic polymer poly(cystamine-bis-acrylamide)-agmatine-histamine (PCAH, PC) constructed nanomedicine against interactions with blood cells and serum proteins, improving biocompatibility. Interestingly, DA coating significantly increased the transfection efficiency of cationic PCï¼not due to the increase of cellular uptake, nor functioning as a receptor ligand, but was associated to the change of endocytosis pathway. Finally, using programmed cell death protein 4 (PDCD4) as a functional gene, DA coating PC NPs showed improved therapeutic effect and biocompatibility on tumor bearing mice. We believe that this DA coating PC NPs provides a facile method to improve the performance of cationic polymer vectors in gene therapy and has great potential for clinical applications.
Subject(s)
Apoptosis Regulatory Proteins/genetics , DNA/administration & dosage , Genetic Vectors , Neoplasms/therapy , Polymers/administration & dosage , RNA-Binding Proteins/genetics , Animals , Cell Line, Tumor , Cell Survival/drug effects , Female , Mice, Inbred BALB C , TransfectionABSTRACT
Multi-drug resistance (MDR) of tumor cells has greatly hindered the therapeutic efficacy of chemotherapeutic drugs, resulting in chemotherapy failure, while overexpression of ATP-binding cassette (ABC) transporters in cell membranes is the leading cause of MDR. In this study, we reported novel self-assembled triphenylphosphine-quercetin-polyethylene glycol-monoclonal antibody nanoparticles (TQ-PEG-mAb NPs) for overcoming MDR primarily through mitochondrial damage to block ATP supply to ABC transporters both in vitro and in vivo. The doxorubicin (DOX)-loaded NPs (TQ/DOX-PEG-mAb) were composed of two drugs (TQ and DOX) and an outer shielding shell of the PEG-mAb conjugate. Besides, the outer shell could be acid-responsively detached to expose the positive charge of TQ inside the NPs to enhance cellular uptake. TQ was proved to effectively induce mitochondrial damage with increased ROS levels and depolarization of mitochondrial membrane potential (MMP), leading to prominently reduced ATP supply to ABC transporters. Moreover, the involvement of the anti-vascular endothelial growth factor (VEGF) mAb was not only for efficient targeting but also for combined therapy. Consequently, TQ/DOX-PEG-mAb showed that the internalized amount of DOX was largely improved while the efflux amount was dramatically inhibited on MCF-7/ADR cells, indicating excellent reversal of DOX resistance. Importantly, the growth of DOX-resistant breast tumors was significantly inhibited with no evident systemic toxicity. Therefore, the employment of TQ-PEG-mAb is believed to be a new approach to improve the efficacy of chemotherapeutic drugs in MDR tumors.
ABSTRACT
We report a novel and easy-to-fabricate polynuclear nanoparticle based on the collaborative re-assembly of nanoparticles as a robust chemogene co-delivery platform. Specifically, the polynuclear nanoparticle carrying DOX and siBcl-2 exerts remarkable co-delivery efficiency, increases tumour cell apoptosis and inhibits tumour cell proliferation in vitro and in vivo.
Subject(s)
Antineoplastic Agents/pharmacology , Doxorubicin/pharmacology , Drug Delivery Systems , Drug Design , Nanoparticles/chemistry , Polymers/chemistry , RNA, Small Interfering/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Doxorubicin/chemistry , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Particle Size , RNA, Small Interfering/chemistry , Structure-Activity Relationship , Surface PropertiesABSTRACT
A highly hydrophilic polymer equipped with guanidinium groups was used to load aromatic ring-containing hydrophobic agent doxorubicin (DOX) via π-π interaction. The results have shown that the delivery system exhibited enhanced cellular uptake and antitumor efficiency compared with free drugs. This study opens new avenues for the application of hydrophilic polymers in drug delivery.
Subject(s)
Antineoplastic Agents/pharmacology , Doxorubicin/pharmacology , Drug Carriers/chemistry , Guanidines/chemistry , Polymers/chemistry , Animals , Antineoplastic Agents/chemistry , Doxorubicin/chemistry , Drug Carriers/chemical synthesis , Drug Liberation , Female , Fluorescence , Humans , Hydrophobic and Hydrophilic Interactions , MCF-7 Cells , Mice, Inbred BALB C , Polymers/chemical synthesisABSTRACT
Finding a cure for breast cancer currently remains a medical challenge in due to the failure of common treatment methods to inhibit invasion and metastasis of cancer cells, which eventually leads to recurrence of breast cancer. Many secreted proteins are overexpressed and play crucial roles in tumorigenesis and development. The Golgi apparatus is a key protein processing and secretion factory in which metastasis-associated proteins are modified, transported and secreted; thus, regulating the Golgi apparatus of tumor cells is a viable strategy to inhibit tumor metastasis. Herein, celecoxib (CLX) and Brefeldin A (BFA) were encapsulated into the biocompatible polymer PLGA-PEG to form nanoparticles that act on the Golgi apparatus to treat metastatic breast cancer; CLX is a specific COX-2 inhibitor which accumulates in the Golgi apparatus, and BFA is a protein transport inhibitor fusing the Golgi apparatus into endoplasmic reticulum. The optimized CLX and BFA co-loaded nanoparticles (CBNPs) possessed good physicochemical properties. CBNPs efficiently damaged the Golgi apparatus within 30 min and showed enhanced cytotoxicity of CLX and BFA toward murine metastatic breast cancer 4T1 cells. The migration and invasion abilities of the cells were dramatically suppressed by the CBNPs. Further, the expression and secretion of metastasis-associated proteins such as matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) were remarkably decreased. Our findings showed that co-delivering CLX and BFA to regulate the Golgi apparatus may be an efficient strategy to inhibit breast cancer growth and suppress tumor cell metastasis.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Brefeldin A/pharmacology , Celecoxib/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Delivery Systems , Golgi Apparatus/drug effects , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Biocompatible Materials/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Brefeldin A/administration & dosage , Brefeldin A/chemistry , Celecoxib/administration & dosage , Celecoxib/chemistry , Cell Movement/drug effects , Cell Proliferation/drug effects , Cyclooxygenase 2 Inhibitors/administration & dosage , Cyclooxygenase 2 Inhibitors/chemistry , Drug Screening Assays, Antitumor , Female , Golgi Apparatus/metabolism , HeLa Cells , Humans , Mice , Nanoparticles/chemistry , Particle Size , Polyethylene Glycols/chemistry , Polyglactin 910/chemistry , Tumor Cells, CulturedABSTRACT
Liver fibrosis refers to excessive accumulation of hepatic collagen, which is primarily produced by activated hepatic stellate cells (HSCs). No effective drugs are clinically available to treat this condition, reflecting the fact that antifibrotic drugs do not specifically target activated HSCs. Here, we report the synthesis and evaluation of poly (lactide-co-glycolide)-polyspermine-poly (ethylene glycol)-vitamin A (PLGA-PSPE-PEG-VA), and activated HSC-targeted, biocompatible amphiphilic polymers for co-delivery of chemical (silibinin) and genetic (siCol1α1) drugs that synergistically suppress collagen I accumulation in fibrogenesis. PLGA-PSPE-PEG-VA self-assembled into core-shell polymeric micelles (PVMs) at low concentrations. After loading with silibinin and siCol1α1, the resulting chemical/genetic drug-loaded PVMs (CGPVMs) exhibited a small particle size and a slightly positive surface. CGPVMs had very low cytotoxicity and hemolytic activity in vitro and were well tolerated in mice, with no liver toxicity or inflammation. Importantly, CGPVMs effectively accumulated in fibrotic livers and specifically targeted activated HSCs. As expected CGPVMs more efficiently decreased collagen I production and ameliorated liver fibrosis compared with chemical drug (silibinin)-loaded PVMs (CPVMs) or genetic drug (siCol1α1)-loaded PVMs (GPVMs) only. These results indicate that CGPVMs are a promising tool for targeted delivery of chemogenes to activated HSCs in the treatment of liver fibrosis.
Subject(s)
Collagen Type I/genetics , Liver Cirrhosis/therapy , Micelles , RNA, Small Interfering/administration & dosage , Silybin/administration & dosage , Vitamin A/administration & dosage , Vitamins/administration & dosage , Animals , Biocompatible Materials , Cell Line , Cell Survival/drug effects , Collagen Type I/metabolism , Drug Carriers/administration & dosage , Gene Transfer Techniques , Genetic Therapy , Hemolysis/drug effects , Humans , Male , Mice, Inbred C57BL , Polymers/administration & dosage , Rabbits , RatsABSTRACT
Sepsis associated encephalopathy (SAE), appears often indicates the deterioration of the sepsis disease and which have high risk of death. Although several mechanism and hypotheses have been proposed and studied, there is no breakthrough in the treatment of SAE. We performed a systematic research to evaluate the effect of intraperitoneal pressure on SAE. A mice model of sepsis was established by intraperitoneal injection of endotoxin. A total of 48 female BALB/c mouse (30 days old) were randomly divided into a control group (n = 12) and an injection of endotoxin referred to bacterial lipopolysaccharide (LPS) group (n = 12). Intraperitoneal hypertension (IAH) referred to IAH group (n = 12), and LPS + IAH group (n = 12). Following sepsis induction, diagnosis, the brains were analyzed for both function and ultrastructural morphology.We determined that IAH exacerbated sepsis induces sepsis-associated encephalopathy when examining low score of neurological function and more delta wave in EEG, increased neuronal edema in LPS + IAH group, as well as an escalation of Bax and Cleaved-caspase-3, Cleaved-parp, and reduction of Bcl-2 and Mfsd2a in LPS + IAH group. Therefore, IAH can exacerbate and increase incident rate of sepsis-related encephalopathy in sepsis mice by promoting neuronal apoptosis and destruction of the blood-brain barrier.