Drug self-framework delivery system-coated gold nanorods for multi-modal imaging and combination therapy for breast cancer.

Herein, we report a multifunctional nanodrug (Au NRs@DSFDSs NPs) by coating a drug self-framework delivery system (DSFDS) on Au NRs with absorption at 1300 nm via simple condensation polymerization, with the purpose of developing an efficient theranostic nanoagent with multi-modal imaging ability, and synergistic chemo-photothermal therapy (CT-PTT) for the monitoring and suppression of tumor growth. Thus, this strategy provides a new idea for the design of a multifunctional platform for the accurate and effective image-guided treatment of tumors.

Mechanism of Yangxinshi Intervention on Cardiac Fibrosis in Diabetic Cardiomyopathy Based on Network Pharmacology.

BACKGROUND: Cardiac fibrosis (CF) is major myocardial change in diabetic cardiomyopathy (DCM). Yangxinshi as a Chinese medicine formula is used to treat cardiovascular diseases. However, the exact effective mechanism of Yangxinshi on CF is still uncertain. Hence, based on the pharmacological network, predicting the active components, potential targets and pathways of Yangxinshi on diabetic fibrosis require to be further studied. MATERIALS AND METHODS: By using Cytoscape 3.6.0 Bisogenet plug-in, the active components of Yangxinshi were obtained and screened through TCMSP, and the PPI network of DCM-CF was constructed and then screened by CytoNCA plug-in. GO analysis and KEGG pathway enrichment analysis were carried out by Cluego plug-in. Combined with the results of network pharmacological analysis, cells in vitro were performed to verify the CF stimulated with high glucose or intervence with Yangxinshi, and the expressions of Cbl-b, p-smad2, and α-SMA were detected. RESULTS: Yangxinshi might play a key role in reversing cardiac fibrosis in individuals with DCM by regulating the signal pathway of CBL and promoted the expression of Cbl-b and inhibited the expression of p-smad2 and α-SMA, verifying some predictive work via network pharmacology. CONCLUSION: Based on network pharmacology, this study demonstrates that the beneficial effect of Yangxinshi on CF is related to the Cbl-b/smad2 pathway, providing an idea for the therapeutic effect of Yangxinshi on cardiac fibrosis in DCM.

Polyphosphazene-Based Drug Self-Framed Delivery System as a Universal Intelligent Platform for Combination Therapy against Multidrug-Resistant Tumors.

Combination therapy is a burgeoning research field due to the advantages of the synergistic contributions from incorporating drugs and promising potentials in the therapy of aggressive tumors with multidrug resistance (MDR). Given the great efforts, it is extremely difficult to coordinate pharmacokinetics between drugs and elucidate the mechanism of synergistic effects. Additionally, limited by the inherent solubility of anticancer drugs, a common strategy for simultaneously delivering various drugs is yet a challenging target. To overcome these, we develop a drug self-framed delivery system (DSFDS) via treating multiple drugs as monomers to constructing cyclomatrix polyphosphazene nanoparticles (CPPZ NPs). Notably, it is a superflexible common platform to realize the rational design of combination therapy, which is verified by delivering doxorubicin (DOX) with mitoxantrone (Mit), resveratrol (RES), curcumin (Cur), and porphyrin (TPP). As a proof of concept, DOX-RES-CysM-CPPZ NP was selected to evaluate the therapeutic feasibility of DSFDSs. Obvious improvement in killing MDR tumors indicated an efficient combination therapy. The corresponding synergistic mechanism of DOX and RES was also addressed in this work. Throughout cutting-edge research, the drug self-framed delivery system is drawing promising blueprint for combination therapy.

Carotid artery plaque intervention with Tongxinluo capsule (CAPITAL): A multicenter randomized double-blind parallel-group placebo-controlled study.

To determine whether the traditional Chinese medicine Tongxinluo (TXL) is efficacious at retarding the progression of carotid atherosclerotic lesions, a total of 1,212 patients with a focal intima-media thickness (IMT) of ≥1.2 mm of the carotid arteries received TXL or placebo capsules in addition to current routine therapy. The primary outcome was between-group differences in annualized change in mean IMT of 12 sites of bilateral carotid arteries over 24 months. The secondary outcomes were between-group differences in plaque area, vascular remodeling index (RI), serum levels of lipids and high-sensitivity C-reactive protein, and a composite of first major cardiovascular events. The results showed that the annualized change in mean IMT in the TXL and placebo groups was -0.00095 (95% CI, -0.00330 to 0.00141) mm and 0.01312 (95% CI, 0.01076 to 0.01548) mm, respectively, with a difference between the two groups of -0.01407 (95% CI, -0.01740 to -0.01073) mm (P < 0.001). Compared with placebo, TXL treatment significantly reduced the change from baseline in the plaque area and RI, as well as the first major cardiovascular events. In conclusion, TXL retarded the progression of mean IMT, plaque area and vascular remodeling of the carotid artery with a good safety profile.

Golden single-walled carbon nanotubes prepared using double layer polysaccharides bridge for photothermal therapy.

Golden single-walled carbon nanotubes (SWNTs) were prepared by growing gold nanoparticles onto the bilayer polysaccharide functionalized SWNTs. The layer-by-layer self-assembly of sodium alginate and chitosan on SWNTs provided an ideal surface with high density of active metal-binding groups such as amino and carboxylic acid groups, and then an approach of seed growth was adopted to facilitate the formation of gold nanoparticles coated SWNTs. The resulting golden SWNT hybrids have good water dispersibility and biocompatibility and tend to enter cancer cells. Interestingly, they have an enhanced NIR absorption and effectively transfer NIR laser into heat. The material can quickly cause localized hyperthermia, resulting in rapid cell death, and therefore appears to act as a highly effective photothermal converter for cancer ablation.

Facile synthesis of superparamagnetic Fe3O4@polyphosphazene@Au shells for magnetic resonance imaging and photothermal therapy.

Multifunctional nanoparticles were prepared by directly welding superparamagnetic Fe3O4 nanoparticles and Au shells together with highly cross-linked polyphosphazene as "glue" in a facile but effective way. The as-prepared particles can simultaneously take advantages of both magnetization of Fe3O4 core for magnetic resonance imaging diagnosis and strong near-infrared absorption of Au nanoshell for photothermal therapy.

Gold nanoparticles grown on ionic liquid-functionalized single-walled carbon nanotubes: new materials for photothermal therapy.

Gold nanoparticles were grown on single-walled carbon nanotubes (SWNTs) coated with a thiol-functionalized ionic liquid resulting in the formation of core-shell structures referred to as SWNT-IL-Au nanohybrid materials. The nanohybrid materials were characterized by high-resolution transmission electron microscopy (HR-TEM), Raman-, and UV/Vis absorption spectroscopy. The nanohybrid materials were found to enter lysosomes in HeLa cells and show negligible cytotoxicity. Interestingly, they have an enhanced NIR absorption that is effectively transferred into heat to cause localized hyperthermia, resulting in rapid cell death; overall, the material appears to have excellent properties for photothermal therapeutic applications.

Berbamine induces apoptosis in human hepatoma cell line SMMC7721 by loss in mitochondrial transmembrane potential and caspase activation.

OBJECTIVE: To investigate the effect of berbamine on human hepatoma cell line SMMC7721. METHODS: The effects of 24 h and 48 h incubation with different concentrations (0 to approximately 64 microg/ml) of the berbamine on SMMC7721 cells were evaluated using 3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay. Hoechst 33258 staining was conducted to distinguish the apoptotic cell, and the appearance of sub-G1 stage was determined by PI (propidium iodide) staining, the percentage of apoptotic cell was determined by flow cytometry following annexin V/PI staining. Flow cytometry was performed to analyze the cell cycle distribution and the mitochondrial membrane potential (psi(m)); the expression of activated caspase3 and caspase9 was analyzed by Western-blot. RESULTS: The proliferation of SMMC7721 was decreased after treatment with berbamine in a dose- and time-dependent manner. Berbamine could induce apoptosis in SMMC7721 cells and could cause cell cycle arrest in G0/G1 phase, to induce loss of mitochondrial membrane potential (psi(m)) and activate caspase3 and caspase9. Berbamine-induced apoptosis could be blocked by the broad caspase inhibitor z-VAD-fmk. CONCLUSION: Berbamine exerts antiproliferative effects on human hepatocellular carcinoma SMMC7721 cells. The anticancer activity of berbamine could be attributed partly to its inhibition of cell proliferation and induction of apoptosis in cancer cells through loss in mitochondrial transmembrane potential and caspase activation.

[The mechanism of apoptosis of chronic myeloid leukemia cells induced by the novel p210 bcr/abl inhibitor berbamine].

OBJECTIVE: To investigate the mechanism of apoptosis of chronic myeloid leukemia (CML) cells induced by the novel p210 bcr/abl inhibitor berbamine. METHODS: Human Ph+ CML leukemia K562 cells, which express endogenous p210 bcr/abl protein, were cultured in RPMI 1640 and treated with berbamine as indicated time and dose. Flow cytometry (FCM) and Annexin-V-Fluos/PI staining kit were used to evaluate the apoptosis of leukemic cells; FCM and cytoperm/cytofix plus Caspase-3-McAb-PE were employed to measure the leukemic cells with activated Caspase-3. Phosphorylation of p210 bcr/abl protein in the leukemic cells were assessed by a combination of immunoprecipitation (IP) with c-abl antibody and Western blotting with p-Tyr (pY99) antibody. The protein levels of p210 bcr/abl, Hsp90 and Hsp70 in the leukemic cells were determined by Western blotting with antibodies to c-abl, Hsp90, and Hsp70 respectively. RESULTS: After treatment with berbamine at 8 microg/ml for 48 h, the percentages of leukemic cells expressing activated caspase-3 and apoptotic cells were 45.69% and 48.43% respectively. IP and WB results showed that berbamine at low concentration markedly inhibited phosphorylation of p210 bcr/abl protein in the leukemia cells, and the amount of phosphorylated p210 bcr/abl in the leukemia cells exposed to berbamine at 8 microg/ml for 6 h were only 8.41% of that of untreated leukemia cells without the protein levels of p210 bcr/abl down-regulated. Significantly, berbamine also down-regulated chaperone Hsp90 protein, and the amount of Hsp90 protein in the leukemia cells treated with berbamine at 8 microg/ml for 48 h accounted for 18.37% of that of the untreated leukemia cells. Berbamine at 8 microg/ml had no obvious effect on chaperone Hsp70 protein expression associated with the resistance of leukemia cells to apoptosis. CONCLUSION: (1) Berbamine induces caspase-3-mediated apoptosis of Ph+ leukemia cells through inhibiting phosphorylation of p210 bcr/abl protein and down-regulating its chaperone Hsp90 protein. (2) Unlike Hsp90 inhibitor GA that upregulates Hsp70, berbamine has no obvious effect on chaperone Hsp70 protein expression in leukemia cells, suggesting that berbamine may be a novel class of Hsp90 inhibitor, and further study is required.

Down-regulation of P-glycoprotein expression in MDR breast cancer cell MCF-7/ADR by honokiol.

P-glycoprotein accounts for the most intrinsic and acquired cancer multidrug resistance. To inhibit the expression of P-glycoprotein is one of the effective ways to reverse cancer drug resistance. Honokiol, a naturally occurring compound, has been demonstrated to combat cancer through mechanisms including inhibition of angiogenesis and induction of apoptosis. Here, we show that honokiol down-regulated the expression of P-glycoprotein at mRNA and protein levels in MCF-7/ADR, a human breast MDR cancer cell line. The down-regulation of P-glycoprotein was accompanied with a partial recovery of the intracellular drug accumulation, and of the sensitivities toward adriamycin. This study reveals a novel function of honokiol as an anti-cancer agent.

Berbamine: a novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity.

Gleevec, which is an inhibitor of the bcr/abl tyrosine kinase, has been a remarkable success for the treatment of chronic myelogenous leukemia (CML). However, a significant proportion of patients chronically treated with Gleevec develop resistance. Here we describe the activity of a natural small molecular compound, berbamine from plant Berberis amurensis that can selectively induce cell death of both Gleevec-sensitive and -resistant Ph+ CML cells. The IC50 values of berbamine were 8.80 microg/ml in Gleevec-sensitive Ph+ CML cells, 11.34 microg/ml in Gleevec-resistant Ph+ CML cells, and 54.40 microg/ml in Ph- KG-1 cells, respectively. Similarly, berbamine was also found to display a selective anti-proliferative activity of primary leukemia cells from CML patients, and its IC50 values were 4.20-10.50 microg/ml in primary CML cells, and 185.20 microg/ml in normal bone marrow cells, respectively. More importantly, our studies demonstrate that berbamine down-regulates p210bcr/abl oncoprotein level, and induces apoptosis of bcr/abl+ cells through caspase-3-dependent pathway. These data suggest that berbamine might be a novel bcr/abl inhibitor with potent anti-leukemia activity.

[Study on effect of berbamine on multidrug resistance leukemia K562/Adr cells].

OBJECTIVE: To study the effect and mechanism of berbamine on the apoptosis of multidrug resistant leukemia K562/Adr cells and in reversing the drug resistance. METHODS: IC50 value of K562/Adr cell was determined with MTT method, cell apoptosis rate was analyzed by flow cytometry with Annexin V FITC-PI assay, with the peak and cell cycle detected by PI staining. At the same time, flow cytometry was also used in determining Caspase-3, P-GP protein expression and drug accumulating capacity in cells, and RT-PCR method was used to analyze the gene expression of mdr-1. RESULTS: Berbamine could inhibit human leukemia K562/Adr cell growth in dose-dependent manner, it could also induce cell apoptosis, increase the protein expression of Caspase-3 and the drug excretion capacity of cells, reduce the mRNA and protein expression levels of mdr-1 gene. CONCLUSION: Berbamine could activate Caspase-3 to induce human leukemia K562/Adr cell apoptosis, and by reducing mdr-1 gene expression to reverse its multidrug resistance.