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971.
通过分离人胚胎肾细胞(HEK293)中基质金属蛋白酶1(MMPl)基因序列,利用基因工程技术在大肠杆菌中表达并纯化了包涵体复性的MMP1;采用融合表达硫氧还蛋白(Thioredoxin,TrxA)的方法获得了可溶性的MMPl-TrxA复合蛋白,在TrxA蛋白和MMP1活性中心之间引入了一个肠激酶切割位点,通过酶切作用获得可溶性MMP1.明胶酶谱分析法对体外表达的MMP1和体内(尿液中)MMP1进行了分析比较.结果表明,TrxA蛋白能够显著提高MMP1的可溶性,且可溶性MMP1的明胶降解活性是复性的MMP1降解活性的1.54倍,与尿液中的MMP1的明胶酶降解活性相当.因此,明胶酶谱法是一种有效的、高灵敏的MMP1检测方法,所表达的可溶性MMP1为小分子探针筛选提供了更可靠的分子靶点. 相似文献
972.
Prof. Dr. Bernhard Kräutler 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(32):11280-11287
B12‐antimetabolites are compounds that counteract the physiological effects of vitamin B12 and related natural cobalamins. Presented here is a structure‐ and reactivity‐based concept of the specific ′antivitamins B12′: it refers to analogues of vitamin B12 that display high structural similarity to the vitamin and are ′locked chemically′ to prevent their metabolic conversion into the crucial organometallic B12‐cofactors. Application of antivitamins B12 to healthy laboratory animals is, thus, expected to induce symptoms of B12‐deficiency. Antivitamins B12 may, hence, be helpful in elucidating still largely puzzling pathophysiological phenomena associated with B12‐deficiency, and also in recognizing physiological roles of B12 that probably still remain to be discovered. 相似文献
973.
Controlled Chemical Derivatisation of Carbon Nanotubes with Imaging,Targeting, and Therapeutic Capabilities 下载免费PDF全文
Dr. Cécilia Ménard‐Moyon Dr. Hanene Ali‐Boucetta Dr. Chiara Fabbro Dr. Olivier Chaloin Prof. Kostas Kostarelos Dr. Alberto Bianco 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(42):14886-14892
In drug delivery, carbon nanotubes (CNTs) hold a great potential as carriers because of their ability to easily cross biological barriers and be internalised into cells. Their high aspect ratio allows multi‐functionalisation and their development as a multimodal platform for targeted therapy. In this article, we report the controlled covalent derivatisation of triple‐functionalised CNTs with the anticancer drug gemcitabine, folic acid as a targeting ligand and fluorescein as a probe. The anticancer activity of gemcitabine was maintained after covalent grafting onto the CNTs. The functionalised nanotubes were internalised into both folate‐positive and negative cells, suggesting the passive diffusion of CNTs. Overall, our approach is versatile and offers a precise chemical control of the sidewall functionalisation of CNTs and the possibility to manoeuvre the types of functionalities required on the nanotubes for a multimodal therapeutic strategy. 相似文献
974.
Synthesis and Analysis of the Structure,Diffusion and Cytotoxicity of Heterocyclic Platinum(IV) Complexes 下载免费PDF全文
Freddy J. Macias Krishant M. Deo Benjamin J. Pages Prof. Paul Wormell Dr. Jack K. Clegg Dr. Yingjie Zhang Dr. Feng Li Dr. Gang Zheng Dr. Jennette Sakoff Dr. Jayne Gilbert Prof. Janice R. Aldrich‐Wright 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(47):16990-17001
We have developed six dihydroxidoplatinum(IV) compounds with cytotoxic potential. Each derived from active platinum(II) species, these complexes consist of a heterocyclic ligand (HL) and ancillary ligand (AL) in the form [Pt(HL)(AL)(OH)2]2+, where HL is a methyl‐functionalised variant of 1,10‐phenanthroline and AL is the S,S or R,R isomer of 1,2‐diaminocyclohexane. NMR characterisation and X‐ray diffraction studies clearly confirmed the coordination geometry of the octahedral platinum(IV) complexes. The self‐stacking of these complexes was determined using pulsed gradient stimulated echo nuclear magnetic resonance. The self‐association behaviour of square planar platinum(II) complexes is largely dependent on concentration, whereas platinum(IV) complexes do not aggregate under the same conditions, possibly due to the presence of axial ligands. The cytotoxicity of the most active complex, exhibited in several cell lines, has been retained in the platinum(IV) form. 相似文献
975.
Human Serum Albumin Conjugated Nanoparticles for pH and Redox‐Responsive Delivery of a Prodrug of Cisplatin 下载免费PDF全文
Hongdong Shi Qinqin Cheng Siming Yuan Xin Ding Prof. Yangzhong Liu 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(46):16547-16554
Platinum anticancer drugs are particularly in need of controlled drug delivery because of their severe side effects. Platinum(IV) agents are designed as prodrugs to reduce the side effects of platinum(II) drugs; however, premature reduction could limit the effect as a prodrug. In this work, a highly biocompatible, pH and redox dual‐responsive delivery system is prepared by using hybrid nanoparticles of human serum albumin (HSA) and calcium phosphate (CaP) for the PtIV prodrug of cisplatin. This conjugate is very stable under extracellular conditions, so that it protects the platinum(IV) prodrug in HSA. Upon reaching the acidic and hypoxic environment, the platinum drug is released in its active form and is able to bind to the target DNA. The Pt–HSA/CaP hybrid inhibits the proliferation of various cancer cells more efficiently than cisplatin. Different cell cycle arrests suggest different cellular responses of the PtIV prodrug in the CaP nanocarrier. Interestingly, this delivery system demonstrates enhanced cytotoxicity to tumor cells, but not to normal cells. 相似文献
976.
Deena M. Butryn Michael S. Gross Lai-Har Chi Arnold Schecter James R. Olson Diana S. Aga 《Analytica chimica acta》2015
The presence of polybrominated diphenyl ethers (PBDEs) and their hydroxylated (OH-BDE) and methoxylated (MeO-BDE) analogs in humans is an area of high interest to scientists and the public due to their neurotoxic and endocrine disrupting effects. Consequently, there is a rise in the investigation of the occurrence of these three classes of compounds together in environmental matrices and in humans in order to understand their bioaccumulation patterns. Analysis of PBDEs, OH-BDEs, and MeO-BDEs using liquid chromatography-mass spectrometry (LC-MS) can be accomplished simultaneously, but detection limits for PBDEs and MeO-BDEs in LC-MS is insufficient for trace level quantification. Therefore, fractionation steps of the phenolic (OH-BDEs) and neutral (PBDEs and MeO-BDEs) compounds during sample preparation are typically performed so that different analytical techniques can be used to achieve the needed sensitivities. However, this approach involves multiple injections, ultimately increasing analysis time. In this study, an analytical method was developed for a “one-shot” analysis of 12 PBDEs, 12 OH-BDEs, and 13 MeO-BDEs using gas chromatography with tandem mass spectrometry (GC-MS/MS). This overall method includes simultaneous extraction of all analytes via pressurized liquid extraction followed by lipid removal steps to reduce matrix interferences. The OH-BDEs were derivatized using N-(t-butyldimethylsilyl)-N-methyltrifluoroacetamide (TBDMS-MTFA), producing OH-TBDMS derivatives that can be analyzed together with PBDEs and MeO-BDEs by GC-MS/MS in “one shot” within a 25-min run time. The overall recoveries were generally higher than 65%, and the limits of detection ranged from 2 to 14 pg in both breast milk and serum matrices. The applicability of the method was successfully validated on four paired human breast milk and serum samples. The mean concentrations of total PBDEs, OH-BDEs, and MeO-BDEs in breast milk were 59, 2.2, and 0.57 ng g−1 lipid, respectively. In serum, the mean total concentrations were 79, 38, and 0.96 ng g−1 lipid, respectively, exhibiting different distribution profiles from the levels detected in breast milk. This “one-shot” GC-MS/MS method will prove useful and cost-effective in large-scale studies needed to further understand the partitioning behavior, and ultimately the adverse health effects, of these important classes of brominated flame retardants in humans. 相似文献
977.
The study of complex protein mixtures and their interactions in cells and tissues has been difficult due to the tedious process involved in their characterization and analysis. The recent emergence of fast‐evolving and state‐of‐the‐art proteomics methodologies has provided a rapid and scalable platform for understanding the comprehensive proteome profiles from complex whole tissues or cells of various biological sources. Therefore, proteomics has been increasingly valuable to examine real‐time changes in protein expression of various tissues or body fluids from patients with various diseases, especially cancer, resulting in the identification of clinically useful biomarkers for diagnosis, prognosis and disease staging. In this review, we focus on potential biomarkers for (1) Helicobacter pylori‐associated gastric cancer, (2) hepatocellular carcinoma (HCC), and (3) renal cell carcinoma (RCC). In addition to the conventional gel‐based proteomics (1‐D or 2‐D gels), we have utilized a more advanced proteomic approach by incorporating stable isotope dimethyl labelling and shotgun proteomics strategy in combination with nanoliquid chromatography and tandem mass spectrometry (nanoLC‐MS/MS) to better characterize the biomarkers in several cancer tissues. By establishing a high‐throughput proteomics platform based on multiple reaction monitoring (MRM), we have successfully detected and analyzed potential protein markers at low concentrations in various normal and tumor tissues. This platform not only highlights the utility of proteomics for biomarker discovery but also can be uniquely applied to disease‐oriented translational medicine for diagnosis of diverse types of cancers and other diseases. 相似文献
978.
Ring‐Opening Polymerization of Prodrugs: A Versatile Approach to Prepare Well‐Defined Drug‐Loaded Nanoparticles 下载免费PDF全文
Dr. Jinyao Liu Dr. Wenge Liu Isaac Weitzhandler Dr. Jayanta Bhattacharyya Dr. Xinghai Li Dr. Jing Wang Yizhi Qi Dr. Somnath Bhattacharjee Dr. Ashutosh Chilkoti 《Angewandte Chemie (International ed. in English)》2015,54(3):1002-1006
The synthesis of polymer–drug conjugates from prodrug monomers consisting of a cyclic polymerizable group that is appended to a drug through a cleavable linker is achieved by organocatalyzed ring‐opening polymerization. The monomers polymerize into well‐defined polymer prodrugs that are designed to self‐assemble into nanoparticles and release the drug in response to a physiologically relevant stimulus. This method is compatible with structurally diverse drugs and allows different drugs to be copolymerized with quantitative conversion of the monomers. The drug loading can be controlled by adjusting the monomer(s)/initiator feed ratio and drug release can be encoded into the polymer by the choice of linker. Initiating these monomers from a poly(ethylene glycol) macroinitiator results in amphiphilic diblock copolymers that spontaneously self‐assemble into micelles with a long plasma circulation, which is useful for systemic therapy. 相似文献
979.
Multivalent Polymer Nanocomplex Targeting Endosomal Receptor of Immune Cells for Enhanced Antitumor and Systemic Memory Response 下载免费PDF全文
Sun‐Young Kim Min Beom Heo Dr. Geum‐Sook Hwang Youngae Jung Dr. Do Yeol Choi Prof. Dr. Yeong‐Min Park Prof. Dr. Yong Taik Lim 《Angewandte Chemie (International ed. in English)》2015,54(28):8139-8143
We have designed and synthesized linear polymer‐based nanoconjugates and nanocomplexes bearing multivalent immunostimulatory ligands and also demonstrated that the synthetic multivalent nanocomplexes led to an enhanced stimulation of immune cells in vitro and antitumor and systemic immune memory response in vivo. We have developed hyaluronic acid (HA)‐based multivalent nanoconjugates and nanocomplexes for enhanced immunostimulation through the combination of multivalent immune adjuvants with CpG ODNs (as a TLR9 ligand) and cationic poly(L ‐lysine) (PLL; for the enhancement of cellular uptake). The multivalent HA‐CpG nanoconjugate efficiently stimulated the antigen‐presenting cells and the multivalent PLL/HA‐CpG nanocomplex also led to an enhanced cellular uptake as well as continuous stimulation of endosomal TLR9. The mice vaccinated with dendritic cells treated with the multivalent nanocomplex exhibited tumor growth inhibition as well as a strong antitumor memory response. 相似文献
980.
Tracking Cancer Metastasis In Vivo by Using an Iridium‐Based Hypoxia‐Activated Optical Oxygen Nanosensor 下载免费PDF全文
Xianchuang Zheng Huang Tang Chen Xie Jialiang Zhang Prof. Wei Wu Prof. Xiqun Jiang 《Angewandte Chemie (International ed. in English)》2015,54(28):8094-8099
We have developed a nanosensor for tracking cancer metastasis by noninvasive real‐time whole‐body optical imaging. The nanosensor is prepared by the formation of co‐micelles from a poly(N‐vinylpyrrolidone)‐conjugated iridium(III) complex (Ir‐PVP) and poly(ε‐caprolactone)‐b‐poly(N‐vinylpyrrolidone) (PCL‐PVP). The near‐infrared phosphorescence emission of the nanosensor could be selectively activated in the hypoxic microenvironment induced by cancer cells. The detection ability of the nanosensor was examined in cells and different animal models. After intravenous injection, the nanosensor can be effectively delivered to the lung and lymph node, and cancer cell metastasis through bloodstream or lymphatics can be quickly detected with high signal‐to‐background ratio by whole‐body imaging and organ imaging. Moreover, the nanosensor exhibits good biocompatibility both in vitro and in vivo. The nanosensor is believed to be a powerful tool for the diagnosis of cancer metastasis. 相似文献