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Journal of Biomedical Materials... Aug 2020The standard of care for intermediate stage hepatocellular carcinoma is transarterial chemoembolization (TACE). Drug-eluting bead TACE (DEB-TACE) has emerged as a...
The standard of care for intermediate stage hepatocellular carcinoma is transarterial chemoembolization (TACE). Drug-eluting bead TACE (DEB-TACE) has emerged as a leading form of TACE, as it uses highly calibrated microspheres to deliver consistent embolization and controlled drug release to the tumor microenvironment. We report here on doxorubicin (DOX)-loaded polyphosphate glass microspheres (PGM) as a novel resorbable, radiopaque, preloaded DEB-TACE platform. Coacervate composed of polyphosphate chains complexed with Ba , Ca , and Cu can be loaded with DOX prior to PGM synthesis, with PGM production achieved using a water-in-oil emulsion technique at room temperature yielding highly spherical particles in clinically relevant size fractions. In vitro, DOX release was found to be linear, pH dependent, and in accordance with Type II non-Fickian transport. PGM degradation was characterized by an initial burst release of degradation products over 7 days, followed by a plateau in mass loss at approximately 75% over a period of several weeks. in vitro studies indicate that PGM degradation products, namely Cu , are cytotoxic and may interact with eluted DOX to impair its pharmacological activity. With additional compositional considerations, this approach may prove promising for DEB-TACE applications.
Topics: Antibiotics, Antineoplastic; Cell Survival; Chemoembolization, Therapeutic; Doxorubicin; Drug Delivery Systems; Drug Liberation; Emulsions; Glass; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Lethal Dose 50; Microspheres; Particle Size; Polyphosphates; Tumor Microenvironment
PubMed: 32100967
DOI: 10.1002/jbm.b.34594 -
Vascular Health and Risk Management 2022Several mechanisms have been explored for the anthracycline myocardial toxicity. These are free-radical generation, myocyte apoptosis, lipid peroxidation, mitochondrial...
BACKGROUND
Several mechanisms have been explored for the anthracycline myocardial toxicity. These are free-radical generation, myocyte apoptosis, lipid peroxidation, mitochondrial deterioration, and direct repression of muscle-specific gene expression. Adriamycin (Doxorubicin) is a potent anti-cancer agent. Adriamycin in prolonged use is fatal and generates free radicals that lead to dose-dependent cardiac toxicity.
OBJECTIVE
The intent of the study was to explore the protective activity of candesartan and quercetin in cardiomyopathy induced by doxorubicin in rats.
METHODS
To induce cardiac toxicity, rats were intraperitoneally treated with doxorubicin (06 equivalent injections of 2.5 mg/kg, i. p. at 48 hour interval for 02 consecutive weeks to achieve a cumulative dose of 15 mg/kg). Individual and combined oral treatment of candesartan (5 mg/kg/day) and quercetin (10 mg/kg/day) was administered for four weeks.
RESULTS
Following cardiomyopathy, heart/body weight ratio (3.526 × 10), serum creatine kinase (352.4±16.99 IU/L), lactate dehydrogenase (661.7±20.45 IU/L) levels were elevated in addition to altered lipid profile (TC - 118.4±4.25 mg/dL, TG - 263.3±9.99 mg/dL, VLDL - 52.66±1.99 mg/dL, LDL - 52.99±5.80 mg/dL and HDL - 12.78±0.36 mg/dL). The pre-cotreatment of candesartan and quercetin significantly restored the values to normal. The increased level of lipid peroxides (33.12±1.63 µmol/mg protein), serum troponin-T (1.82 ± 0.11 pg/mL) and nitric oxide (13.33±0.73 nmol/mg protein) level along with attenuating antioxidant profile, ie catalase, glutathione and superoxide dismutase (1.43±0.12 nmol/mg protein, 8.48±0.42 nmol/mg protein and 2.09±0.031 U/mg protein) were reversed to normal. Morphometry and histopathologic changes represented a beneficial effect of single and combination pre-cotreatment of drugs which significantly decreases adriamycin cardiac toxicity.
CONCLUSION
The overall result depicts more beneficial and cardioprotective effect of quercetin and candesartan combination as compared to their individual effects in doxorubicin treated animals. Therefore, this combination might be a suitable option to treat the cardiotoxic effect of doxorubicin.
Topics: Humans; Rats; Animals; Cardiotoxicity; Quercetin; Doxorubicin; Myocardium; Antioxidants; Antibiotics, Antineoplastic; Cardiomyopathies; Oxidative Stress
PubMed: 36536768
DOI: 10.2147/VHRM.S381485 -
Journal of Materials Chemistry. B Jun 2021A lack of sufficient tumor penetration and low delivery efficiency are the main reasons for the limited clinical applications of nanocarriers in cancer treatment. Tumor...
A lack of sufficient tumor penetration and low delivery efficiency are the main reasons for the limited clinical applications of nanocarriers in cancer treatment. Tumor microenvironment responsive drug delivery systems have been attracting great interest in cancer therapy as the desired drug release can be achieved in the disease sites for optimal treatment efficiency. In this work, we developed a biodegradable nanohybrid drug delivery system with pH/redox/enzymatic sensitivity by the simple assembly of bovine serum albumin nano-units (about 5 nm) onto graphene oxide nanosheets in the presence of a naturally originating protein (gelatin). The nanoparticles can maintain a constant size under physiological conditions, while releasing 5 nm nano-units containing the drug upon triggering by the environment-mimicking protease highly expressed in the tumor microenvironment. Furthermore, after reaching the tumor tissue, the acidic, reductive, and enzymatic microenvironments turned on the switch for DOX release, and the combination of chemotherapy and photothermal therapy was achieved under the trigger of near-infrared light. The nanosystems have the potential to improve the penetration ability through the depth of the tumor tissue to enhance drug intracellular delivery and antitumor bioactivity.
Topics: Antibiotics, Antineoplastic; Cell Survival; Doxorubicin; Drug Delivery Systems; Humans; Hydrogen-Ion Concentration; MCF-7 Cells; Matrix Metalloproteinase 2; Nanostructures; Oxidation-Reduction; Tumor Microenvironment
PubMed: 34013937
DOI: 10.1039/d1tb00396h -
Glycoconjugate Journal Oct 2021We fabricated an amphiphilic folate-modified Bletilla striata polysaccharide (FA-BSP-SA) copolymer that exhibited good biocompatibility and superior antitumor effects....
We fabricated an amphiphilic folate-modified Bletilla striata polysaccharide (FA-BSP-SA) copolymer that exhibited good biocompatibility and superior antitumor effects. This study investigated the affinity between FA-BSP-SA and bovine serum albumin (BSA) via multispetroscopic approaches. Changes in the morphology and particle size showed that FA-BSP-SA formed a blurry "protein corona". Stern-Volmer equation demonstrated that FA-BSP-SA micelles decreased the fluorescence of BSA via static quenching. The measurement results of thermodynamic parameters (entropy change, enthalpy change, and Gibbs free energy) suggested that the binding between FA-BSP-SA and BSA was spontaneous in which Van der Waals forces and hydrogen bonding played major roles. The results from synchronous fluorescence, circular dichroism, and UV spectra also revealed that BSA conformation was slightly altered by decreasing α-helical contents. In addition, the antitumor effects in vitro of Dox@FA-BSP-SA micelles and the cellular uptake behavior of micelles in 4T1 cells were decreased after incubating with BSA.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibiotics, Antineoplastic; Anticoagulants; Cell Line, Tumor; Doxorubicin; Folic Acid; Ibuprofen; Mice; Micelles; Models, Molecular; Polysaccharides; Protein Binding; Protein Conformation; Protein Domains; Serum Albumin, Bovine; Warfarin
PubMed: 34586534
DOI: 10.1007/s10719-021-10022-y -
Journal of Ethnopharmacology Apr 2021Propolis extracts are widely used in traditional folk medicine and exhibit several properties such as antitumor, anti-inflammatory, and antimicrobial. However, these...
ETHNOPHARMACOLOGICAL RELEVANCE
Propolis extracts are widely used in traditional folk medicine and exhibit several properties such as antitumor, anti-inflammatory, and antimicrobial. However, these products have not been investigated in combination with medicines used in clinical practice.
AIM OF THE STUDY
This study aimed to evaluate the chemical composition of propolis extracts from Apis mellifera scutellata and different Meliponini species and characterize their cytotoxicity against tumor cells, antibacterial effects, and interference with the actions of doxorubicin and gentamicin.
MATERIALS AND METHODS
Chromatographic and spectrometric analyses were performed using ultra-high-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS). Propolis extracts were evaluated for cytotoxicity and synergism using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the antimicrobial activity was examined using the broth microdilution technique and synergism was investigated using checkerboard and time-kill assays.
RESULTS
The chemical characterization revealed the presence of 63 compounds, and the extracts showed selective cytotoxicity against tumor cell lines. Propolis extracts of mandaçaia and mirim exerted selective synergistic cytotoxicity in combination with doxorubicin. Except for the tubuna extract, all evaluated extracts exhibited antibacterial effects on gram-positive strains. Mandaçaia and mirim extracts exerted a synergistic effect with gentamicin; however, only mandaçaia extract exerted a selective effect.
CONCLUSION
Propolis could be a source of antineoplastics and antibiotics. These natural products may reduce the occurrence of doxorubicin and gentamicin related adverse effects, resistance, or both.
Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Bees; Cell Survival; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; HeLa Cells; Hep G2 Cells; Humans; MCF-7 Cells; Propolis; Tandem Mass Spectrometry
PubMed: 33307049
DOI: 10.1016/j.jep.2020.113662 -
The Journal of Antibiotics Feb 2022New three macrocyclic diolides, named bispolides C-E (1-3), were isolated from a fermentation broth of the actinomycete strain MG372-hF19, which produces an indole...
New three macrocyclic diolides, named bispolides C-E (1-3), were isolated from a fermentation broth of the actinomycete strain MG372-hF19, which produces an indole glycoside and leptomycins as we reported previously. The absolute structures of compounds 1-3 were elucidated by NMR and X-ray crystallography. Compounds 1-3 diverge from the known nine bispolides in their different alkylation patterns on the 20-membered macrocyclic diolide skeleton and the side chain in their planar structures. Furthermore, compounds 1-3 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci and cytotoxic activity against human cancer cell lines. Among them, compound 3 has the most potent biological activities against bacteria and tumor cells. Additionally, using a membrane-potential-sensitive fluorescence probe, we found that compounds 1-3 and elaiophylin have a similar effect on membrane potential in A549 human lung cancer cells.
Topics: A549 Cells; Actinobacteria; Alkylation; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Cell Line, Tumor; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Enterococcus; Humans; Macrolides; Magnetic Resonance Spectroscopy; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Structure; Streptomycetaceae; Vancomycin Resistance
PubMed: 34873311
DOI: 10.1038/s41429-021-00492-5 -
Bioorganic & Medicinal Chemistry Mar 2022The construction of multistimuli-responsive nanoaggregate has become one of the increasingly significant research topics in supramolecular chemistry. We herein reported...
The construction of multistimuli-responsive nanoaggregate has become one of the increasingly significant research topics in supramolecular chemistry. We herein reported the pH- and glutathione dual-responsive supramolecular assemblies fabricated by the disulfide-containing pillar[4]arene and tetraphenylethylene derivatives possessing different alkyl chains in length. Morphological characterization experiments showed the binary supramolecular assemblies formed well-defined nanoparticles, which could facilitate their endocytosis in cells. More remarkably, due to the compact nanostructures and the existence of acidifiable carboxyl group and bioreducible disulfide linkage in pillar[4]arene, the obtained nanoaggregates presented high drug-loading efficiency and sustained drug release behaviors, as well as the targeted fluorescence imaging ability in cancer cells. Thus, it can be envisioned that such microenvironment-adaptable supramolecular nanoassemblies featuring dual stimuli-responsiveness and fluorescence-imaging abilities may be developed as more appealing nanosystems for the therapy of refractory disease.
Topics: Antibiotics, Antineoplastic; Calixarenes; Cell Line; Cell Proliferation; Disulfides; Dose-Response Relationship, Drug; Doxorubicin; Drug Liberation; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Optical Imaging; Structure-Activity Relationship
PubMed: 35131545
DOI: 10.1016/j.bmc.2022.116649 -
Journal of the American Chemical Society Jan 2020We report the genome-guided discovery of sungeidines, a class of microbial secondary metabolites with unique structural features. Despite evolutionary relationships with...
We report the genome-guided discovery of sungeidines, a class of microbial secondary metabolites with unique structural features. Despite evolutionary relationships with dynemicin-type enediynes, the sungeidines are produced by a biosynthetic gene cluster (BGC) that exhibits distinct differences from known enediyne BGCs. Our studies suggest that the sungeidines are assembled from two octaketide chains that are processed differently than those of the dynemicin-type enediynes. The biosynthesis also involves a unique activating sulfotransferase that promotes a dehydration reaction. The loss of genes, including a putative epoxidase gene, is likely to be the main cause of the divergence of the sungeidine pathway from other canonical enediyne pathways. The findings disclose the surprising evolvability of enediyne pathways and set the stage for characterizing the intriguing enzymatic steps in sungeidine biosynthesis.
Topics: Antibiotics, Antineoplastic; Biosynthetic Pathways; Enediynes; Multigene Family
PubMed: 31922407
DOI: 10.1021/jacs.9b10086 -
ACS Chemical Biology Feb 2023Distinct among the enediyne antitumor antibiotics, the dynemicin subgroup is comprised of two discrete halves, an enediyne and an anthraquinone, but each is ultimately...
Distinct among the enediyne antitumor antibiotics, the dynemicin subgroup is comprised of two discrete halves, an enediyne and an anthraquinone, but each is ultimately derived from the same linear β-hydroxyhexaene precursor. The linkage of these two halves by an aryl C-N bond is examined here using a variety of experimental approaches. We demonstrate that this heterodimerization is specific for anthracenyl iodide as the corresponding bromo- and amino-substituted anthracenes do not support dynemicin biosynthesis. Furthermore, biochemical experiments and chemical model reactions support an S1 mechanism for the aryl C-N coupling in which electron transfer occurs to the iodoanthracene, followed by loss of an anthracenyl iodide and partition of the resulting aryl radical between C-N coupling and reduction by hydrogen abstraction. An enzyme pull-down experiment aiming to capture the protein(s) involved in the coupling reaction is described in which two proteins, Orf14 and Orf16, encoded by the dynemicin biosynthetic gene cluster, are specifically isolated. Deletion of from the genome abolished dynemicin production accompanied by a 3-fold increased accumulation of the iodoanthracene coupling partner, indicating the plausible involvement of this protein in the heterodimerization process. On the other hand, the deletion of only reduced dynemicin production to 55%, implying a noncatalytic, auxiliary role of the protein. Structural comparisons using AlphaFold imply key similarities between Orf14 and X-ray crystal structures of several proteins from enediyne BGCs believed to bind hydrophobic polyene or enediyne motifs suggest Orf14 templates aryl C-N bond formation during the central heterodimerization in dynemicin biosynthesis.
Topics: Anthracenes; Antibiotics, Antineoplastic; DNA; Enediynes; Iodides
PubMed: 36696117
DOI: 10.1021/acschembio.2c00709 -
Human & Experimental Toxicology Dec 2021Idarubicin (IDA) is an anthracycline antibiotic, frequently used for the treatment of various human cancers. rodent model studies have identified a variety of possible...
Idarubicin (IDA) is an anthracycline antibiotic, frequently used for the treatment of various human cancers. rodent model studies have identified a variety of possible adverse outcomes from IDA including heart effects like increased heart weights, myocardial histopathological injury, electrocardiogram abnormalities, and cardiac dysfunction. Despite significant investigations, the molecular mechanisms responsible for the cardiotoxicity of IDA have not been fully clarified. The aim of the current study was to investigate the effects of IDA on the HL-1 cardiac muscle cell. Different concentrations of IDA (10, 10, 10, and 10 M) were used at different time (6, 12, 24, and 48 h) periods, and the Cell Counting Kit-8 (CCK-8); 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) probe method; and enzyme-linked immunosorbent assay (ELISA) were used to detect the oxidative stress level. In addition, we used network analysis to predict IDA-induced cardiotoxicity. The TUNEL assay, qRT-PCR, ELISA assay, and Western blotting detection of related apoptotic factors including caspase family, Bax, and Bcl-2. Overall, we found that IDA was generally more toxic at high concentrations or extended durations of exposure. At the same time, IDA can increase the content of reactive oxygen species (ROS), malondialdehyde (MDA), and decrease the level of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) in cells, and increase the content of lactate dehydrogenase (LDH) and nitric oxide synthase (NOS) in the medium. Network analysis showed that the apoptosis signaling pathway was activated; specifically, the caspase family was involved in the signal pathway. The results of the TUNEL assay, qRT-PCR, ELISA, and Western blot found that IDA can activate apoptotic factors. The mechanism may be related to the activation of apoptosis signaling pathway. These results indicate that the cardiotoxic effects of IDA are most likely associated with oxidative stress and ROS formation, which finally ends in apoptotic factors' activation and induction of cell apoptosis.
Topics: Animals; Antibiotics, Antineoplastic; Antioxidants; Apoptosis; Cell Line; Humans; Idarubicin; Mice; Myocytes, Cardiac; Oxidative Stress; Reactive Oxygen Species
PubMed: 34787021
DOI: 10.1177/09603271211033774