ABSTRACT
GABA (Gamma-aminobutyric acid), a crucial neurotransmitter in the central nervous system, has gained significant attention in recent years due to its extensive benefits for human health. The review focused on recent advances in the biosynthesis and production of GABA. To begin with, the investigation evaluates GABA-producing strains and metabolic pathways, focusing on microbial sources such as Lactic Acid Bacteria, Escherichia coli, and Corynebacterium glutamicum. The metabolic pathways of GABA are elaborated upon, including the GABA shunt and critical enzymes involved in its synthesis. Next, strategies to enhance microbial GABA production are discussed, including optimization of fermentation factors, different fermentation methods such as co-culture strategy and two-step fermentation, and modification of the GABA metabolic pathway. The review also explores methods for determining glutamate (Glu) and GABA levels, emphasizing the importance of accurate quantification. Furthermore, a comprehensive market analysis and prospects are provided, highlighting current trends, potential applications, and challenges in the GABA industry. Overall, this review serves as a valuable resource for researchers and industrialists working on GABA advancements, focusing on its efficient synthesis processes and various applications, and providing novel ideas and approaches to improve GABA yield and quality.
ABSTRACT
As a first-line drug for breast cancer chemotherapy, the effectiveness of doxorubicin (DOX) is challenged by high doses and high toxicity. Studies showed the combination of Tanshinone IIA (TSIIA) and DOX could enhance the efficacy of DOX for cancer and reduce the toxic effects to normal tissues. Unfortunately, free drugs are easily metabolized in the systemic circulation, which are less prone to aggregation at the tumor site to exert anticancer efficacy. In present study, we prepared a carboxymethyl chitosan-based hypoxia-responsive nanoparticles loaded with DOX and TSIIA for the treatment of breast cancer. The results demonstrated that these hypoxia-responsive nanoparticles not only improved the delivery efficiency of the drugs but also enhanced the therapeutic efficacy of DOX. The average size of nanoparticles was about 200-220 nm, the optimal drug loading and encapsulation efficiency of TSIIA in DOX/TSIIA NPs were 9.06 % and 73.59 %, respectively. Hypoxia-responsive behavior were recorded in vitro, while the synergistic efficacy is significantly exhibited in vivo and the tumor inhibitory rate was 85.87 %. Notably, TUNEL assay and immunofluorescence staining verified that the combined nanoparticles exerted a synergistic anti-tumor effect by inhibiting tumor fibrosis, decreasing the expression of HIF-1α and inducing tumor cell apoptosis. Collectively, this carboxymethyl chitosan-based hypoxia-responsive nanoparticles could have promising application prospect for effective breast cancer therapy.
Subject(s)
Breast Neoplasms , Chitosan , Nanoparticles , Humans , Female , Doxorubicin/pharmacology , Breast Neoplasms/drug therapy , Cell Line, Tumor , Drug CarriersABSTRACT
Three crystal complexes were designed and synthesised through the solvothermal method, with Cu2+ , Zn2+ , and Cd2+ ions as the metal centres and 2,4,6-tri(2-pyridyl)-s-triazine (TPTZ) and terephthalate (BDC2- ) as the ligands. Their compositions were determined to be Cd(TPTZ)Cl2 (Cd-MOF), {[Zn(TPTZ)(BDC)] â 3H2 O}n (Zn-MOF), and Cu2 (PCA)2 (BDC)(H2 O)2 (Cu-MOF) (PCA- =2-pyridinium amide), respectively. Cd-MOF can adsorb 90 % of Congo red (CR) in 10â s at room temperature and atmospheric pressure, and CR removal was complete at 20â s over a wide pH range. The adsorption capacity for CR reached 1440â mg g-1 in 5â min. Selective adsorption was demonstrated in mixed dyes. The adsorption kinetic data agree well with the pseudo-second-order kinetic model. The Temkin model was successfully used to evaluate the adsorption isotherms of CR on Cd-MOF at room temperature, suggesting that adsorption occurs through a hybrid of monolayer and multilayer mechanisms.
ABSTRACT
Bioactive substances such as probiotics are becoming a research hotspot in the field of tissue regeneration due to their excellent regulatory functions. Here, we proposed to load Lactobacillus casei onto a bilayer silk fibroin/sodium alginate (SF/SA) scaffold to endow the scaffold with both antibacterial and regenerative properties. The performance of the scaffold was characterized systemically. The L. casei-loaded scaffolds (L-SF/SA) bring in lactic acid, which has antibacterial and wound healing properties. In vitro, the cell-free supernatant (CFS) of L. casei inhibited the transformation of fibroblasts to myofibroblasts and relieved the endoplasmic reticulum stress (ERS). In vivo, L-SF/SA accelerated the healing of infected wounds in SD rats. The L-SF/SA reduced the bacterial load, induced M2 polarization of macrophages, increased angiogenesis, regulated collagen ratio, and alleviated the ERS, thereby promoting scarless wound healing and increasing hair follicle regeneration. Therefore, probiotic-functionalized silk fibroin/alginate scaffolds showed potential in the infected wound healing.
Subject(s)
Fibroins , Probiotics , Rats , Animals , Fibroins/pharmacology , Alginates/pharmacology , Rats, Sprague-Dawley , Wound Healing , Tissue Scaffolds , Anti-Bacterial Agents , SilkABSTRACT
At present, monotherapy of tumor has not met the clinical needs, due to high doses, poor efficacy, and the emergence of drug resistance. Combination therapy can effectively solve these problems, which is a better option for tumor suppression. Based on this, we developed a novel glutathione-sensitive drug delivery nanoparticle system (OMT/CMCS-CYS-RB NPs) for oral cancer treatment. Briefly, carboxymethyl chitosan (CMCS) was used as a carrier to simultaneously load Rose Bengal (RB) and oxymatrine (OMT). The OMT/CMCS-CYS-RB NPs prepared by ion crosslinking were spheres with a stable structure. In addition, the nanoparticles can be excited in vitro to generate a large amount of singlet oxygen, which has a good photodynamic effect. In vitro anti-tumor activity study showed that the nanoparticles after the laser enhanced therapeutic efficacy on tumor cells compared with the free drug and exhibited well security. Furthermore, OMT/CMCS-CYS-RB NPs could inhibit the PI3K/AKT signaling pathway in oxidative stress, and realize tumor apoptosis through mitochondria-related pathways. In conclusion, this combination delivery system for delivering RB and OMT is a safe and effective strategy, which may provide a new avenue for the tumor treatment.
Subject(s)
Chitosan , Nanoparticles , Neoplasms , Humans , Rose Bengal/pharmacology , Chitosan/chemistry , Phosphatidylinositol 3-Kinases , Drug Delivery Systems , Nanoparticles/chemistryABSTRACT
We combined phosphoinositol-3-kinin inhibitor IPI-549 and photodynamic Chlorin e6 (Ce6) on carboxymethyl chitosan to develop a novel drug delivery nanoparticle (NP) system (Ce6/CMCS-DSP-IPI549) and evaluate its glutathione (GSH) sensitivity and targeting ability for breast cancer treatment. The NPs were spherical with a uniform size of 218.8 nm, a stable structure over 7 days. The maximum encapsulation efficiency was 64.42%, and NPs drug loading was 8.05%. The NPs released drugs within tumor cells due to their high GSH concentration, while they maintained structural integrity in normal cells, which have low GSH concentration. The cumulative release rates of IPI-549 and Ce6 at 108 h were 70.67% and 40.35% (at GSH 10 mM) and 8.11% and 2.71% (at GSH 2µM), respectively. The NPs showed a strong inhibitory effect on 4T1 cells yet did not affect human umbilical vein endothelial cells (HUVECs). After irradiation by a 660 nm infrared laser for 72 h, the survival rate of 4T1 cells was 15.51%. Cellular uptake studies indicated that the NPs could accurately release drugs into tumor cells. In addition, the NPs had a good photodynamic effect and promoted the release of reactive oxygen species to damage tumor cells. Overall, the combination therapy of IPI-549 and Ce6 is safe and effective, and may provide a new avenue for the treatment of breast cancer.
Subject(s)
Breast Neoplasms , Chlorophyllides , Nanoparticles , Photochemotherapy , Porphyrins , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Chlorophyllides/therapeutic use , Endothelial Cells/pathology , Female , Glutathione , Humans , Isoquinolines , Nanoparticles/chemistry , Photosensitizing Agents , Porphyrins/chemistry , Pyrazoles , PyrimidinesABSTRACT
Interactions between different cell types in the tumor microenvironment (TME) affect tumor growth. Tumor-associated fibroblasts produce C-X-C motif chemokine ligand 13 (CXCL13) which recruits B cells to the TME. B-cells in the TME differentiate into regulatory B cells (Bregs) (IL-10+CD1d+CD5+CD138+CD19+). We highlight these Breg cells as a new important factor in the modulation of the immunosuppressive TME in different desmoplastic murine tumor models. In addition, CXCL13 also stimulates epithelial-mesenchymal transition (EMT) of the tumor cells. The tumorigenic roles of CXCL13 led us to explore an innovative anti-cancer strategy based on delivering plasmid DNA encoding a CXCL13 trap to reduce Bregs differentiation and normalize EMT, thereby suppressing tumor growth. CXCL13 trap suppressed tumor growth in pancreatic cancer, BRAF-mutant melanoma, and triple-negative breast cancer. In this study, following treatment, the affected tumor remained dormant resulting in prolonged progression-free survival of the host.
Subject(s)
B-Lymphocytes, Regulatory , Cancer-Associated Fibroblasts , Pancreatic Neoplasms , Triple Negative Breast Neoplasms , Animals , B-Lymphocytes, Regulatory/metabolism , Chemokine CXCL13/genetics , Chemokine CXCL13/metabolism , Humans , Mice , Pancreatic Neoplasms/metabolism , Triple Negative Breast Neoplasms/therapy , Tumor MicroenvironmentABSTRACT
Oral cancer is a common life-threatening malignancy having high mortality and morbidity rates. During the treatment process, individuals unavoidably experience severe side effects. It is essential to develop safer and more effective strategies. Currently, extracellular vesicles (EVs) and biomimetic nanoparticles are nanomedicines with long-term blood circulation and lower off-target toxicity that orchestrate immune responses and accumulate specifically in tumor sites. EVs create a synergetic effect by encapsulating drugs and collaborating with naturally loaded elements in the EVs. Biomimetic nanoparticles retain the characteristic features of the synthetic nanocarriers and inherit the intrinsic cell membrane functionalities. This review outlines the properties, applications, challenges, pros and cons of EVs and biomimetic nanoparticles, providing novel perspectives on oral cancer.
This review explains how extracellular vesicles (EVs) and biomimetic nanoparticles are emerging as nanomedicines applied in oral cancer. EVs are phospholipid bilayer vesicles, mainly including exosomes and microvesicles, responsible for intercellular communication and cargo transport. EVs can carry RNA, metabolites and other molecular payloads. Biomimetic nanomedicines are synthetic nanoparticles coated with the parent or host cell membrane to escape the immune system and elevate targeting ability. Various cell membranes have been used for camouflaging nanoparticles, such as red blood cells, white blood cells, platelets, mesenchymal stem cells and cancer cell membranes. During the treatment process, individuals unavoidably experience severe side effects. It is essential to develop safer and more effective strategies. Currently, EVs and biomimetic nanoparticles are nanomedicines with long-term blood circulation and lower off-target toxicity that orchestrate immune responses and accumulate specifically in tumor sites. EVs create a synergetic effect by encapsulating drugs and collaborating with naturally loaded elements in the EVs. Biomimetic nanoparticles retain the characteristic features of the synthetic nanocarriers and inherit the intrinsic cell membrane functionalities. This review outlines the properties, applications, challenges, pros and cons of EVs and biomimetic nanoparticles, providing novel perspectives on oral cancer.
Subject(s)
Extracellular Vesicles , Mouth Neoplasms , Nanoparticles , Humans , Drug Delivery Systems , Nanomedicine , Biomimetics , Extracellular Vesicles/metabolism , Mouth Neoplasms/drug therapyABSTRACT
We developed a new on-line method of ultra-performance liquid chromatography coupled with biochemical detection (UHPLC-BCD) to screen acetylcholinesterase (AChE) inhibitors in complex matrixes. Chromatography separation was performed using an Xtimate UHPLC C18 column (100 mm × 2.1 mm, 1.8 µm) and a gradient elution with methanol-0.1% formic acid at a flow rate of 0.08 mL/min. The BCD was based on a colorimetric method using Ellman's reagent, and the detection wavelength was at 405 nm. Galanthamine was used as a positive reference to validate the methodology. The detection and quantitation limits of the UHPLC-BCD method were 0.018 and 0.060 µg, respectively. A functional equation was generated in terms of the negative peak area (X) and galanthamine concentration (Y, µg/mL). The regression equation was Y = 0.0028X2 + 0.4574X + 50.7776, R2 = 0.9993. UHPLC-fourier-transform mass spectrometry detection results revealed that five alkaloids showed obvious AChE inhibitory activities including coptisin, epiberberine, jatrorrhizine, berberine and palmatine. The relative AChE inhibitory activities of jatrorrhizine, berberine and palmatine in the Coptidis Rhizoma sample were equal to that of 257.0, 2355 and 283.9 µg/mL of galanthamine, respectively. This work demonstrated that the UHPLC-BCD method was convenient and feasible, and could be widely used for the screening and activity evaluation of the bioactive components in the complex extracts.
Subject(s)
Berberine Alkaloids , Berberine , Drugs, Chinese Herbal , Acetylcholinesterase , Berberine/analysis , Berberine Alkaloids/analysis , Cholinesterase Inhibitors , Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/chemistry , Galantamine , High-Throughput Screening AssaysABSTRACT
A self-supported dual-cation (Mo,Cu) co-doped Ni2P@ nickel foam catalyst (Mo,Cu-Ni2P@NF) has been prepared, and the co-doped samples can distort the lattice and expose a larger specific surface area, which provides more reaction locations, and exhibit an efficient water splitting performance.
ABSTRACT
BACKGROUND: Oxaliplatin (OXE) combined with other chemotherapy drugs against colorectal cancer had been reported in the literature before, however, the efficacy of oxaliplatin combined with natural compounds was elusive. In addition, the clinical bioactivity and therapeutic dose of antitumor drugs are severely limited due to poor targeting and side effects. NDDSs offers an excellent strategy to overcome the disadvantages of small molecule anticancer drugs. METHODS: Here, we have prepared N,O-carboxymethyl chitosan Oxaliplatin nanoparticles (CMCS-OXE NPs) and N,O-carboxymethyl chitosan Resveratrol nanoparticles (CMCS-Res NPs) were prepared by ion crosslinking and emulsification crosslinking, respectively. RESULTS: The results revealed that the CMCS-OXE NPs exhibited a high encapsulation efficiency (60%) with a size of approximately 190.0 nm, and the CMCS-Res NPs exhibited a high encapsulation efficiency (65%) with a size of approximately 164.2 nm. The treatment with both types of nanoparticles combined exhibited more significant anti-colon cancer activity than the free drugs or either type of nanoparticle alone. In the in vivo experiments, the inhibition efficiency of the combined nanoparticle treatment was much stronger than the free drugs or either type of nanoparticle alone. CONCLUSIONS: Overall, combination of oxaliplatin and resveratrol into a nanoparticle-drug delivery systems (NDDSs) appears to be a promising strategy for colorectal cancer (CRC) therapy.
Subject(s)
Chitosan , Colonic Neoplasms , Nanoparticles , Chitosan/therapeutic use , Colonic Neoplasms/drug therapy , Drug Carriers/therapeutic use , Humans , Oxaliplatin , ResveratrolABSTRACT
This work aims to synthesize two novel 1-MT (1-Methyl-DL-tryptophan) grafted CMCS (carboxymethyl chitosan) polymer prodrugs CMCS-amido-1-MT and CMCS-ester-1-MT, and to further manufacture their nanoparticles for potential biomedical applications. The polymeric prodrugs are prepared by three-step chemical synthesis. The chemical structure of drugs is confirmed by FTIR and 1H-NMR. The drug loadings of the CMCS-amido-1-MT NPs and CMCS-ester-1-MT NPs are 11.43% and 10.18%, respectively. The surface morphology of the nanoparticles is spherical or nearly spherical, while the surface is smooth and the size distribution is uniform. The average particle size is both about 200 nm, while the polydispersity index is both about 0.15. The nanoparticles have a negative charge on the surface. The particle size and its distribution change little, when the two nanoparticles are tested in the simulated blood pH environment for 7 days. However, only the CMCS-ester-1-MT nanoparticles are pH-sensitive. The cell toxicity of the CMCS-ester-1-MT nanoparticles and the original drug are both in a dose- and time-dependent manner, while the nanoparticles enter cells by endocytosis. In ECA109 cells, the CMCS-ester-1-MT nanoparticles and the original drug both induce the apoptosis. CMCS-ester-1-MT NPs can activate the ATF4/CHOP pathway in endoplasmic reticulum stress, and achieve cancer suppression through mitochondrial-related apoptosis.
Subject(s)
Chitosan , Nanoparticles , Particle SizeABSTRACT
We aimed to combine glycyrrhetinic acid with doxorubicin to prepare, characterize and evaluate a drug delivery nano-system with REDOX sensitivity for the treatment of breast cancer. M-DOX-GA NPs prepared by nano sedimentation were spherical, with a particle size of 181 nm. And the maximum encapsulation efficiency and drug loading in M-DOX-GA NPs were 89.28% and 18.22%, respectively. Cytotoxicity and cellular uptake experiments of nanoparticles to KC cells, Cal-27 cells and 4T1 cells were studied by the CCK-8 method. The result indicated that M-DOX-GA NPs could accurately release the drug into the tumor cells, thus achieving the targeted release of the drug. Comparing the survival rate of the above three cells, it was found that M-DOX-GA NPs had a good tumor selectivity and had a more significant therapeutic effect on breast cancer. A 4T1-bearing mouse model was established, and the tumor inhibition rate was 77.37% after injection of nanoparticle solution for 14 d. Normal tissue H&E stained sections and TUNEL assay were verified M-DOX-GA NPs have excellent tumor suppressive effect, and can efficiently reduce the toxic side effects on normal organisms, and effectively avoided 4T1 cells metastasis. Immunofluorescence detection and Western-blot analysis figured a decline in both CUGBP1 and α-SMA, which verifying the TME remodeling induced by glycyrrhetinic acid. Collectively, the combination of doxorubicin and glycyrrhetinic acid is an effective and safe strategy for remodeling fibrotic TME by improving the therapeutic outcome for breast cancer.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibiotics, Antineoplastic/therapeutic use , Breast Neoplasms/drug therapy , Doxorubicin/therapeutic use , Glycyrrhetinic Acid/therapeutic use , Tumor Microenvironment/drug effects , Animals , Anti-Inflammatory Agents/administration & dosage , Antibiotics, Antineoplastic/administration & dosage , Cell Line, Tumor , Disease Models, Animal , Doxorubicin/administration & dosage , Drug Carriers/chemistry , Drug Synergism , Female , Glycyrrhetinic Acid/administration & dosage , Mice , Nanoparticles/chemistryABSTRACT
Layered rare-earth hydroxides (LREHs), as a series of special lamellar compounds having a similar structure to layered double hydroxides (LDHs), are becoming a new type of catalyst materials. In this study, we have prepared a series of uniform LREH (RE = Y, La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, and Tm) nanosheets through a reverse-microemulsion method. After deposition-precipitation of HAuCl4 and calcination, supported Au catalysts (denoted as Au/LREO) were subsequently obtained. The catalytic properties of all the derived Au/LREO catalysts were evaluated by aerobic conversion of glycerol to lactic acid under mild conditions (90 °C, 1 atm). Among these catalysts, Au/LPrO displays the best performances, including the highest glycerol conversion, lactic acid, and C3 product selectivity. Both the catalytic activities and the characterizations of the structure of Au/LREO indicate that the kind of rare-earth ions plays a key role in determining the Au particle size and its valence state and reducibility, which are the important factors correlated with the catalytic activities in glycerol conversion. In fact, the three features of gold particles, the extra-small size (â¼3 nm), high content of Au0 species, and high reducibility, are the essential prerequisites for achieving the superior catalytic performance of Au/LPrO.
ABSTRACT
In this paper, a photoinduced electron transfer (PET)& twisted intramolecular charge transfer (TICT)-based fluorescent probe (1) for detecting biothiols (GSH/Cys/Hcy) and hydrogen sulfide with fluorescence turn on was developed. The probe could recognize hydrogen sulfide over primary ions and selectively detect GSH/Cys/Hcy over other amino acids with fluorescence turn-on (an ESIPT process). H2S can be distinguished from GSH/Cys/Hcy with wavelength shift by UV-Vis spectra. In addition, detection limits for H2S/GSH/Cys/Hcy of probe 1 were 1.42 µM (0-100 µM), 0.13 µM (0-40 µM), 0.27 (0-30 µM), 0.22 µM (0-40 µM), respectively. The proposed thiolysis of the 2,4-dinitrochlorophenyl ether reaction in identification process was verified by the characteristic peak in 1H NMR and HRMS spectra. Finally, the biological imaging experiments and low cytotoxicity investigations in HeLa cells demonstrated that probe 1 could provide a promising method for the determination of H2S and biothiols in aqueous solution and living cells.
Subject(s)
Fluorescent Dyes , Hydrogen Sulfide , Cysteine , Glutathione , HeLa Cells , Homocysteine , Humans , Optical Imaging , Spectrometry, FluorescenceABSTRACT
Aim: To develop nanomedicines for immuno-therapy of oral dysplasia and oral squamous cell carcinoma. Materials & methods: All-trans retinoic acid (ATRA)-poly(lactide-co-glycolide acid) (PLGA)-poly(ethylene glycol) (PEG)-programmed death-ligand 1 (PD-L1) nanomedicines were fabricated by loading ATRA into PLGA-PEG nanocarriers and modification using an anti-PD-L1 antibody. Results: ATRA-PLGA-PEG-PD-L1 nanoparticles showed fast cellular uptake, significantly inhibited proliferation and induced apoptosis in DOK and CAL27 cells. Moreover, in C3H tumor-bearing mice, ATRA-PLGA-PEG-PD-L1 nanoparticles more specifically targeted tumor cells, enhanced anticancer activity and reduced side effects when compared with free ATRA. Furthermore, CD8+ T cells were activated around PD-L1 positive cells in the tumor microenvironment after treatment. Conclusion: ATRA-PLGA-PEG-PD-L1 nanoparticles had low toxicity, high biocompatibility and specifically targeted oral dysplasia and squamous carcinoma cells both in vitro and in vivo.
Subject(s)
Carcinoma, Squamous Cell , Mouth Neoplasms , Nanoparticles , Tretinoin , Animals , B7-H1 Antigen , CD8-Positive T-Lymphocytes , Carcinoma, Squamous Cell/drug therapy , Cell Line, Tumor , Mice , Mice, Inbred C3H , Mouth Neoplasms/drug therapy , Polyethylene Glycols , Squamous Cell Carcinoma of Head and Neck , Tumor MicroenvironmentABSTRACT
We induced changes in the tumor microenvironment (TME) through the synergistic actions of two drugs used in breast cancer therapy. The anti-fibrotic drug silibinin (SLB) targets tumor-associated fibroblasts and exerts immune-mediated anti-cancer effects. IPI-549, an efficient and highly selective phosphoinositide-3-kinase-gamma (PI3Kγ) inhibitor, was applied to alter the balance of immunosuppressive cells by inhibiting PI3Kγ molecules; it also promotes anti-tumor immunity. We developed nanoparticle formulations to encapsulate both drugs into the targeting carrier aminoethyl anisamide-polyethylene glycol-polycaprolactone (AEAA-PEG-PCL) respectively. The drugs were intravenously delivered in mice and resulted in an increase in anti-tumor efficacy and apoptotic tumor tissue compared with either IPI-549 or SLB alone in 4T1 breast cancer cell-derived tumors. Furthermore, a significant reduction in regulatory T (Treg) cells and myeloid suppressor cells (MDSCs) was observed. A normalized TME structure was also observed, including angiogenesis suppression, antifibrotic effects and the inhibition of collagen formation in the tumor tissue, significantly enhancing the anti-tumor effects. In summary, this combination strategy may offer an alternative treatment for breast cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Drug Carriers/chemistry , Isoquinolines/administration & dosage , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Silybin/administration & dosage , Administration, Intravenous , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Benzamides/chemistry , Breast Neoplasms/pathology , Cancer-Associated Fibroblasts , Cell Line, Tumor/transplantation , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Drug Synergism , Female , Humans , Isoquinolines/pharmacokinetics , Mice , Nanoparticles/chemistry , Polyesters/chemistry , Polyethylene Glycols/chemistry , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Silybin/pharmacokinetics , Tumor Microenvironment/drug effectsABSTRACT
This study aimed to develop, evaluate, and optimize the mPEG-PLA/vitamin E-TPGS mixed micelle drug delivery system to encapsulate celecoxib (CXB) and honokiol (HNK) for intravenous treatment of breast cancer. To this end, we formulated CXB-loaded mPEG-PLA/vitamin E-TPGS (PV-CXB) and HNK-loaded mPEG-PLA/vitamin E-TPGS (PV-HNK) mixed micelles and analyzed their characteristics. The 4T1 cell line was used for cytotoxicity determination and cellular uptake experiments, and for establishing a 4T1-bearing mouse model for histopathology, immunofluorescence, terminal deoxynucleotidyl transferase-mediated nick end labeling, and Western blot analysis. The synergistic effects of PV-CXB and PV-HNK combination therapy were investigated in vitro and in vivo using the coefficient of drug interaction values. The mean size of PV-CXB and PV-HNK prepared with optimal formulation was approximately 50 nm, with a spherical shape. PV-CXB and PV-HNK combination therapy exhibited cytotoxicity in 4T1 cells in vitro. However, the toxicity of PV-CXB and PV-HNK combination therapy was not apparent in normal tissues (heart, liver, spleen, lung, and kidney) in vivo and reduced the expression of collagen fibers in tumor tissues. Moreover, the combination therapy reduced the expression of tumor growth biomarkers (Foxp3, CD4, Gr-1, CD11b, CD31, Ki67, FoxM1, and VEGF). In addition, the tumor cell apoptosis rate reached 45.71 ± 0.62%. The combined treatment with PV-CXB and PV-HNK showed synergistic effect both in vitro and in vivo. Thus, the PV-CXB and PV-HNK drug delivery system could be used as a potential combination therapy for breast cancer .
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Biphenyl Compounds/therapeutic use , Breast Neoplasms/drug therapy , Celecoxib/therapeutic use , Lignans/therapeutic use , Polyesters/chemistry , Polyethylene Glycols/chemistry , Vitamin E/chemistry , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Biphenyl Compounds/administration & dosage , Celecoxib/administration & dosage , Lignans/administration & dosage , Mice , Mice, Inbred BALB CABSTRACT
BACKGROUND: Quantitation analysis and chromatographic fingerprint of multi-components are frequently used to evaluate quality of herbal medicines but fail to reveal activity of the components. It is necessary to develop a rational approach of chromatography coupled with activity detection for quality assessment of herbal medicines. METHODS: An on-line HPLC-ultraviolet detection-2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) free radical scavenging (HPLC-UV-ABTS) method was developed to obtain the chromatographic fingerprints and ABTS+⢠inhibition profiles (active fingerprints) of Rehmanniae Radix (Dihuang) and Rehmannia Radix Praeparata (Shu Dihuang). Eighteen compounds showing ABTS+⢠inhibition activity were identified by HPLC-fourier-transform mass spectrometry (HPLC-FTMS). Verbascoside was used as a positive control to evaluate the total activities of the samples and the contribution rate of each compound. The similarities of the chromatographic and active fingerprints were estimated by the vectorial angle cosine method. RESULTS: The results showed that the HPLC-UV-ABTS method could efficiently detect antioxidant activity of the herbal medicine samples. The antioxidants were different between the two herbs and several new antioxidants were identified in Shu Dihuang. A function equation was generated in terms of the negative peak area (x) and the concentrations of verbascoside (y, µg/mL), y = 2E-07 × 4 - 8E-05 × 3 + 0.0079 × 2 + 0.5755x + 1.4754, R2 = 1. Iridoid glycosides were identified as main antioxidants and showed their higher contributions to the total activity of the samples. The total contributions of the three main active components in the Dihuang and Shu Dihuang samples to the total activity, such as echinacoside, verbascoside and an unknown compound, were 39.2-58.1% and 55.9-69.4%, respectively. The potencies of the main active components in the Shu Dihuang samples were two to ten times those in the Dihuang samples. Similarity values for S12 in the chromatographic fingerprints and S03, S12 and P03 in the active fingerprints were less than 0.9. The three batches of samples might show their different quality with the other samples. CONCLUSIONS: The results suggested that the combination of "quantity-effect" research strategy and the HPLC-UV-ABTS analysis method could comprehensively evaluate the active components and quality of Dihuang and Shu Dhuang.
Subject(s)
Antioxidants/chemistry , Drugs, Chinese Herbal/chemistry , Plant Extracts/chemistry , Rehmannia/chemistry , Benzothiazoles , Chromatography, High Pressure Liquid , Free Radical Scavengers , Mass Spectrometry , Plant Roots/chemistry , Sulfonic AcidsABSTRACT
Reactions of 1,3-ketoesters, -diesters, -diketones, and -ketoamides with [Me4N][SeCF3] in the presence of an appropriate oxidant provided a series of 2-trifluoromethylselenolated 1,3-dicarbonyls in moderate to good yields. The trifluoromethylselenolation featured simplicity, mildness, high efficiency, transition-metal-free conditions, and compatibility of various oxidants, and represented the first oxidative trifluoromethylselenolation of 1,3-dicarbonyl compounds with [Me4N][SeCF3]. This protocol was also applicable to the oxidative trifluoromethylthiolation of 1,3-dicarbonyls with [Me4N][SCF3]/NCS, and oxidative trifluoromethylchalcogenation with nucleophilic XCF3 (X = O, S, and Se) reagents were compared. The results demonstrated that these nucleophilic XCF3 salts showed different reaction profiles towards 1,3-dicarbonyls under oxidation conditions.