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Nanotechnology Feb 2019A new type of vapreotide-templated Ag/Au bimetallic nanoshells (Vap@Ag/AuNSs) were successfully designed and fabricated based on polypeptide-directed mineralization and...
A new type of vapreotide-templated Ag/Au bimetallic nanoshells (Vap@Ag/AuNSs) were successfully designed and fabricated based on polypeptide-directed mineralization and hierarchical self-assembly mechanisms under mild synthetic conditions. The nanoparticles with polypeptides serving as a core and coated Ag/Au bimetallic nanoshells exhibit diverse advantages, such as excellent biocompatibility, tumor targeting and low-cost. The Vap@Ag/AuNSs share excellent dispersibility, uniform size (120 nm) and a positive zeta potential (36.74 ± 4.49 mV), hence they easily accumulate in negatively charged tumor tissue. The results of thermal imaging, temperature variation assays and photothermal conversion efficiency (41.6%) indicated that Vap@Ag/AuNSs have excellent photothermal conversion capability. Based on their photothermal response, as well as biocompatibility determined by MTT assay, the prominent anti-tumor effects of Vap@Ag/AuNSs have been verified by fluorescein diacetate staining. Therefore, Vap@Ag/AuNSs are novel and promising candidates for photothermal tumor therapy.
Topics: Antineoplastic Agents; Biocompatible Materials; Gold; Minerals; Nanoshells; Silver; Somatostatin; Temperature
PubMed: 30520422
DOI: 10.1088/1361-6528/aaf0db -
Materials Science & Engineering. C,... Dec 2018Based on the self-assembly properties of vapreotide acetate (Vap), one kind of novel vapreotide acetate‑gold nanoflowers (Vap-AuNFs) was fabricated for the first time...
Based on the self-assembly properties of vapreotide acetate (Vap), one kind of novel vapreotide acetate‑gold nanoflowers (Vap-AuNFs) was fabricated for the first time by biomimetic mineralization method using Vap as a template. The Vap-AuNFs possessed anisotropic structure with a large absorption cross-section, which were face-centered cubic crystalline, exhibiting a remarkable monodisperse, narrow size (154 nm) distribution and good stability in aqueous solution. The apparent anisotropy of the gold nanostructure with high molar extinction coefficient can cause significantly higher plasmon absorption of Vap-AuNFs in the near infrared (NIR) region compared with Au nanoparticles (AuNPs), so the nanocomplex can induce remarkably enhanced photothermal conversion efficiency under NIR light irradiation. Breathtakingly, Vap-AuNFs exhibited superior biocompatibilities compared to AuNPs, as well as enhanced Hela cells lethality under NIR irradiation. This novel method was simple, low cost and green for the design and preparation of anisotropic gold nanoflowers with outstanding NIR laser-induced local hyperthermia, highlighting their potential applications in biomedical fields.
Topics: Gold; HeLa Cells; Humans; Hyperthermia, Induced; Metal Nanoparticles; Neoplasms; Phototherapy; Somatostatin
PubMed: 30274105
DOI: 10.1016/j.msec.2018.08.017 -
Neuropsychopharmacology : Official... Jul 2017Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an...
Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst or sst knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst or sst but not sst or sst receptor agonists produced rapid and sustained inhibition of HPA axis. sst agonists selectively produced anxiolytic-like behaviors whereas both sst and sst agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sstKO mice and depressive-like behaviors observed in both sstKO and sstKO strains. Both hippocampal sst and sst receptors selectively inhibit stress-induced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders.
Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Behavior, Animal; Corticosterone; Emotions; Hippocampus; Hypothalamo-Hypophyseal System; Male; Mice; Mice, Knockout; Octreotide; Pituitary-Adrenal System; Receptors, Somatostatin; Somatostatin; Stress, Psychological
PubMed: 27986975
DOI: 10.1038/npp.2016.281 -
Journal of Clinical Gastroenterology 2017Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort... (Observational Study)
Observational Study
GOALS/BACKGROUND
Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality.
STUDY
Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared.
RESULTS
Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%.
CONCLUSIONS
AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.
Topics: Decision Support Techniques; Disease Progression; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Predictive Value of Tests; Risk Assessment; Risk Factors; Time Factors; Treatment Failure; United States
PubMed: 27779613
DOI: 10.1097/MCG.0000000000000733 -
Oncotarget Apr 2016Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood-brain barrier...
Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood-brain barrier (BBB) restricts the movement of antitumor drugs from blood to brain, thus leading to the poor prognosis with high recurrence rate. In the present study, the targeting conjugates of cholesterol polyethylene glycol polyethylenimine (CHOL-PEG2000-PEI) and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) were newly synthesized for transporting drugs across the BBB and targeting glioma cells and GSCs. The multifunctional targeting vinorelbine plus tetrandrine liposomes were constructed by modifying the targeting conjugates. The studies were undertaken on BBB model, glioma cells, GSCs, and glioma-bearing mice. In vitro results showed that multifunctional targeting drugs-loaded liposomes with suitable physicochemical property could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit glioma cells and GSCs, penetrate and destruct the GSCs spheroids, and induce apoptosis via activating related apoptotic proteins. In vivo results demonstrated that multifunctional targeting drugs-loaded liposomes could significantly accumulate into brain tumor location, show the specificity to tumor sites, and result in a robust overall antitumor efficacy in glioma-bearing mice. These data suggested that the multifunctional targeting vinorelbine plus tetrandrine liposomes could offer a promising strategy for treating brain glioma.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzylisoquinolines; Brain Neoplasms; Cell Line, Tumor; Glioma; Liposomes; Mice; Mice, Inbred ICR; Molecular Targeted Therapy; Neoplastic Stem Cells; Random Allocation; Vinblastine; Vinorelbine
PubMed: 27029055
DOI: 10.18632/oncotarget.8360 -
Biomaterials Jun 2014A somatostatin analog, vapreotide (VAP), can be used as a ligand for targeting drug delivery based on its high affinity to somatostatin receptors (SSTRs), which is...
A somatostatin analog, vapreotide (VAP), can be used as a ligand for targeting drug delivery based on its high affinity to somatostatin receptors (SSTRs), which is overexpressed in many tumor cells. RNA interference plays an important role on downregulation of vascular endothelial growth factor (VEGF), which is important for tumor growth, progression and metastasis. To improve tumor therapy efficacy, the vapreotide-modified core-shell type nanoparticles co-encapsulating VEGF targeted siRNA (siVEGF) and paclitaxel (PTX), termed as VAP-PLPC/siRNA NPs, were developed in this study. When targeted via somatostatin receptors to tumor cells, the VAP-PLPC/siRNA NPs could simultaneously delivery siVEGF and PTX into cells and achieve a synergistic inhibition of tumor growth. Interestingly, in vitro cell uptake and gene silencing experiments demonstrated that the targeted VAP-PLPC/siRNA NPs exhibited significant higher intracellular siRNA accumulation and VEGF downregulation in human breast cancer MCF-7 cells, compared to those of the non-targeted PEG-PLPC/siRNA NPs. More importantly, in vivo results further demonstrated that the targeted VAP-PLPC/siRNA NPs had significant stronger drug distribution in tumor tissues and tumor growth inhibition efficacy via receptor-mediated targeting delivery, accompany with an obvious inhibition of neovascularization induced by siVEGF silencing. These results suggested that the co-delivery of siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles would be a promising approach for tumor targeted therapy.
Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Cycle; Down-Regulation; Drug Delivery Systems; Female; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Nanoparticles; Paclitaxel; RNA Interference; RNA, Small Interfering; Receptors, Somatostatin; Somatostatin; Vascular Endothelial Growth Factor A
PubMed: 24680191
DOI: 10.1016/j.biomaterials.2014.03.012 -
Organic & Biomolecular Chemistry Oct 2013Prochiral malonic diesters containing a quaternary carbon center have been successfully transformed into a diverse set of (t)Boc-Fmoc-α(2,2)-methyllysine-OH analogues...
Prochiral malonic diesters containing a quaternary carbon center have been successfully transformed into a diverse set of (t)Boc-Fmoc-α(2,2)-methyllysine-OH analogues through chiral malonic half-ester intermediates obtained via enzymatic (Pig Liver Esterase, PLE) hydrolysis. The variety of chiral half-ester intermediates, which vary from 1 to 6 methylene units in the side chain, are achieved in moderate to high optical purity and in good yields. The PLE hydrolysis of malonic diesters with various side chain lengths appears to obey the Jones's PLE model according to the stereochemical configurations of the resulting chiral half-esters. The established synthetic strategy allows the construction of both enantiomers of α(2,2)-methyllysine analogues, and a (S)-β(2,2)-methyllysine analogue from a common synthon by straightforward manipulation of protecting groups. Two different straightforward and cost effective synthetic strategies are described for the synthesis of α(2,2)-methyllysine analogues. The described strategies should find significant usefulness in preparing novel peptide libraries with unnatural lysine analogues. A Vapreotide analogue incorporating (S)-α(2,2)-methyllysine was prepared. However, the Vapreotide analogue with (S)-α-methyl-α-lysine is found to lose its specific binding to somatostatin receptor subtype 2 (SSTR2).
Topics: Animals; Hydrolysis; Liver; Lysine; Malonates; Molecular Structure; Protein Binding; Somatostatin; Stereoisomerism; Swine
PubMed: 23942875
DOI: 10.1039/c3ob41282b -
Neuroimmunomodulation 2013Vapreotide, a synthetic analog of somatostatin, has analgesic activity most likely mediated through the blockade of neurokinin-1 receptor (NK1R), the substance P...
OBJECTIVES
Vapreotide, a synthetic analog of somatostatin, has analgesic activity most likely mediated through the blockade of neurokinin-1 receptor (NK1R), the substance P (SP)-preferring receptor. The ability of vapreotide to interfere with other biological effects of SP has yet to be investigated.
METHODS
We studied the ability of vapreotide to antagonize NK1R in three different cell types: immortalized U373MG human astrocytoma cells, human monocyte-derived macrophages (MDM) and a human embryonic kidney cell line, HEK293. Both U373MG and MDM express endogenous NK1R while HEK293 cells, which normally do not express NK1R, are stably transformed to express human NK1R (HEK293-NK1R).
RESULTS
Vapreotide attenuates SP-triggered intracellular calcium increases and nuclear factor-κB activation in a dose-dependent manner. Vapreotide also inhibits SP-induced interleukin-8 and monocyte chemotactic protein-1 production in HEK293-NK1R and U373MG cell lines. Vapreotide inhibits HIV-1 infection of human MDM in vitro, an effect that is reversible by SP pretreatment.
CONCLUSIONS
Our findings indicate that vapreotide has NK1R antagonist activity and may have a potential application as a therapeutic intervention in HIV-1 infection.
Topics: Analgesics; Aprepitant; Calcium; Cell Line; Chemokine CCL2; Cytokines; Dose-Response Relationship, Drug; Drug Interactions; Gene Expression Regulation; Humans; Macrophages; Morpholines; NF-kappa B; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Receptors, Somatostatin; Signal Transduction; Somatostatin; Substance P; Transfection; gag Gene Products, Human Immunodeficiency Virus
PubMed: 23921645
DOI: 10.1159/000350468 -
The Journal of Biological Chemistry Sep 2013Somatostatin (SST) 14 and SST 28 activate somatostatin 2A receptors (SSTR2A) on enteric neurons to control gut functions. SST analogs are treatments of neuroendocrine...
Somatostatin (SST) 14 and SST 28 activate somatostatin 2A receptors (SSTR2A) on enteric neurons to control gut functions. SST analogs are treatments of neuroendocrine and bleeding disorders, cancer, and diarrhea, with gastrointestinal side effects of constipation, abdominal pain, and nausea. How endogenous agonists and drugs differentially regulate neuronal SSTR2A is unexplored. We evaluated SSTR2A trafficking in murine myenteric neurons and neuroendocrine AtT-20 cells by microscopy and determined whether agonist degradation by endosomal endothelin-converting enzyme 1 (ECE-1) controls SSTR2A trafficking and association with β-arrestins, key regulators of receptors. SST-14, SST-28, and peptide analogs (octreotide, lanreotide, and vapreotide) stimulated clathrin- and dynamin-mediated internalization of SSTR2A, which colocalized with ECE-1 in endosomes and the Golgi. After incubation with SST-14, SSTR2A recycled to the plasma membrane, which required active ECE-1 and an intact Golgi. SSTR2A activated by SST-28, octreotide, lanreotide, or vapreotide was retained within the Golgi and did not recycle. Although ECE-1 rapidly degraded SST-14, SST-28 was resistant to degradation, and ECE-1 did not degrade SST analogs. SST-14 and SST-28 induced transient interactions between SSTR2A and β-arrestins that were stabilized by an ECE-1 inhibitor. Octreotide induced sustained SSTR2A/β-arrestin interactions that were not regulated by ECE-1. Thus, when activated by SST-14, SSTR2A internalizes and recycles via the Golgi, which requires ECE-1 degradation of SST-14 and receptor dissociation from β-arrestins. After activation by ECE-1-resistant SST-28 and analogs, SSTR2A remains in endosomes because of sustained β-arrestin interactions. Therapeutic SST analogs are ECE-1-resistant and retain SSTR2A in endosomes, which may explain their long-lasting actions.
Topics: Animals; Arrestins; Aspartic Acid Endopeptidases; Cell Line, Tumor; Endosomes; Endothelin-Converting Enzymes; Enteric Nervous System; Female; Gastrointestinal Agents; Golgi Apparatus; Male; Metalloendopeptidases; Mice; Neurons; Octreotide; Protein Transport; Proteolysis; Rats; Rats, Sprague-Dawley; Receptors, Somatostatin; Somatostatin; Somatostatin-28; beta-Arrestins
PubMed: 23913690
DOI: 10.1074/jbc.M113.496414 -
Tumour Biology : the Journal of the... Aug 2013The aim of this study was to introduce human somatostatin receptors subtype-2 (hsstr2) gene into A549 lung carcinoma cells in order to investigate the role of these...
The aim of this study was to introduce human somatostatin receptors subtype-2 (hsstr2) gene into A549 lung carcinoma cells in order to investigate the role of these receptors, and to observe the lethal effect of (131)I-RC-160 (RC-160, vapreotide, an analog of somatostatin) on transfected cells through tumor scintigraphy. Clones overexpressing SSTR2 were selected for radioligand-receptor binding assay and assessment of (125)I-RC-160 internalization. The methylthiazolyl tetrazolium test was used to observe the lethal effect of (131)I-RC-160, Na(131)I, and RC-160 on hSSTR2-transfected A549 cells (A549-hSSTR2). Planar imaging was performed with a gamma camera equipped with pinhole collimator in nude mice bearing both A549-hSSTR2 tumors overexpressing SSTR2 and A549-pcDNA3 (pcDNA3-transfected A549 cells) tumors as control. Images were obtained at 0.5, 6, and 24 h after injection of 3.7 × 10(6) Bq (99m)Tc-RC-160 via the tail vein. The inhibitory effects of (131)I-RC-160, RC-160, and Na(131)I on the tumors were recorded by measuring the tumor volumes. At the end of the study, the tumors were excised and HE staining was performed. The binding radioactivity (sum of membrane-bound and internalized radioligand) of A549-hSSTR2 cells was 18.24 ± 1.9 % of total counts added after 1 h of incubation, and was higher than that of A549-pcDNA3 cells 5.7 ± 1.4 % (P < 0.05). The inhibition ratio of A549-hSSTR2 cells was 78.8 ± 5.9 %. Clear images of tumor lesions in nude mice were achieved at 0.5 h post injection. In the A549-hSSTR2 xenograft tumor group, the growth of the tumors treated with (131)I-RC-160 was significantly inhibited as compared to tumors in the group treated with RC-160 (P < 0.01). This study demonstrated that it was possible to introduce hsstr2 to non-expressing tumor cell lines and treat tumors with radiolabeled somatostatin analogs.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Gene Transfer Techniques; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Transfection; Xenograft Model Antitumor Assays
PubMed: 23605323
DOI: 10.1007/s13277-013-0796-x