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Takakura Y 《Pharmaceutical research》2011,28(4):691-693
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Lipid-based Nanoparticles for Nucleic Acid Delivery 总被引:4,自引:0,他引:4
Abstract Lipid-based colloidal particles have been extensively studied as systemic gene delivery carriers. The topic that we would
like to emphasize is the formulation/assembly of lipid-based nanoparticles (NP) with diameter under 100 nm for delivering
nucleic acid in vivo. NP are different from cationic lipid–nucleic acid complexes (lipoplexes) and are vesicles composed of lipids and encapsulated
nucleic acids with a diameter less than 100 nm. The diameter of the NP is an important attribute to enable NP to overcome
the various in vivo barriers for systemic gene delivery such as: the blood components, reticuloendothelial system (RES) uptake, tumor access,
extracellular matrix components, and intracellular barriers. The major formulation factors that impact the diameter and encapsulation
efficiency of DNA-containing NP include the lipid composition, nucleic acid to lipid ratio and formulation method. The particle
assembly step is a critical one to make NP suitable for in vivo gene delivery. NP are often prepared using a dialysis method either from an aqueous-detergent or aqueous-organic solvent
mixture. The resulting particles have diameters about 100 nm and nucleic acid encapsulation ratios are >80%. Additional components
can then be added to the particle after it is formed. This ordered assembly strategy enables one to optimize the particle
physico-chemical attributes to devise a biocompatible particle with increased gene transfer efficacy in vivo. The components included in the sequentially assembled NP include: poly(ethylene glycol) (PEG)-shielding to improve the particle
pharmacokinetic behavior, a targeting ligand to facilitate the particle–cell recognition and in some case a bioresponsive
lipid or pH-triggered polymer to enhance nucleic acid release and intracellular trafficking. A number of groups have observed
that a PEG-shielded NP is a robust and modestly effective system for systemic gene or small interfering RNA (siRNA) delivery. 相似文献
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Schillinger U Wexel G Hacker C Kullmer M Koch C Gerg M Vogt S Ueblacker P Tischer T Hensler D Wilisch J Aigner J Walch A Stemberger A Plank C 《Pharmaceutical research》2008,25(12):2946-2962
Purpose
Gene delivery from biomaterials has become an important tool in tissue engineering. The purpose of this study was to generate a gene vector-doted fibrin glue as a versatile injectable implant to be used in gene therapy supported tissue regeneration.Methods
Copolymer-protected polyethylenimine(PEI)-DNA vectors (COPROGs), naked DNA and PEI-DNA were formulated with the fibrinogen component of the fibrin glue TISSUCOL® and lyophilized. Clotting parameters upon rehydration and thrombin addition were measured, vector release from fibrin clots was determined. Structural characterizations were carried out by electron microscopy. Reporter and growth factor gene delivery to primary keratinocytes and chondrocytes in vitro was examined. Finally,chondrocyte colonized clots were tested for their potency in cartilage regeneration in a osteochondral defect model.Results
The optimized glue is based on the fibrinogen component of TISSUCOL®, a fibrin glue widely used in the clinics, co-lyophilized with copolymer-protected polyethylenimine(PEI)- DNA vectors (COPROGs). This material, when rehydrated, forms vector-containing clots in situ upon thrombin addition and is suitable to mediate growth factor gene delivery to primary keratinocytes and primary chondrocytes admixed before clotting. Unprotected PEI-DNA in the same setup was comparatively unsuitable for clot formation while naked DNA was ineffective in transfection. Naked DNA was released rapidly from fibrin clots (>70% within the first seven days) in contrast to COPROGs which remained tightly immobilized over extended periods of time (0.29% release per day). Electron microscopy of chondrocytecolonized COPROG-clots revealed avid endocytotic vector uptake. In situ BMP-2 gene transfection and subsequent expression in chondrocytes grown in COPROG clots resulted in the upregulation of alkaline phosphatase expression and increased extracellular matrix formation in vitro. COPROG-fibrinogen preparations with admixed autologous chondrocytes when clotted in situ in osteochondral defects in the patellar grooves of rabbit femura gave rise to luciferase reporter gene expression detectable for two weeks (n=3 animals per group). However, no significant improvement in cartilage formation in osteochondral defects filled with autologous chondrocytes in BMP-2-COPROG clots was achieved in comparison to controls (n=8 animals per group).Conclusions
COPROGs co-lyophilized with fibrinogen are a simple basis for an injectable fibrin gluebased gene-activated matrix. The preparation can be used is complete analogy to fibrin glue preparations that are used in the clinics. However, further improvements in transgene expression levels and persistence are required to yield cartilage regeneration in the osteochondral defect model chosen in this study. 相似文献5.
The Alabama Drug Discovery Alliance is a collaboration between the University of Alabama at Birmingham and Southern Research
Institute that aims to support the discovery and development of therapeutic molecules that address an unmet medical need.
The alliance builds on the expertise present at both institutions and has the dedicated commitment of their respective technology
transfer and intellectual property offices to guide any commercial opportunities that may arise from the supported efforts.
Although most projects involve high throughput screening, projects at any stage in the drug discovery and development pathway
are eligible for support. Irrespective of the target and stage of any project, well-functioning interdisciplinary teams are
crucial to a project’s progress. These teams consist of investigators with a wide variety of expertise from both institutions
to contribute to the program’s success. 相似文献
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目的 为中国小核酸药物研发企业的研发战略规划和专利战略制定提供参考。方法 通过智慧芽专利数据库检索小核酸药物配体缀合技术相关专利,通过人工标引的方式筛选获得该领域的核心专利及外围专利。首先对相关专利整体进行申请趋势分析,其次对小核酸药物配体缀合3类技术的核心专利进行详细分析。结果与结论 从整体来看,小核酸药物配体缀合递送技术绝大多数核心专利均掌握在Ionis、Alnylam、Arrowhead、Arbutus等国际顶尖核酸药物研发企业手中,而中国企业的研究能力和专利布局强度较弱。小核酸药物配体缀合递送技术主要包括半乳糖衍生物缀合递送技术、脂质衍生物缀合递送技术、细胞穿透肽缀合递送技术。其中最具发展潜力的是半乳糖衍生物缀合递送技术。脂质衍生物缀合递送技术近年来相对于半乳糖衍生物缀合递送技术所受到的关注度相对较低,多数专利布局时间过早,大都处于失效状态。细胞穿透肽缀合递送技术近年来越来越受到重视。 相似文献
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Ernesto Freire 《Chemical biology & drug design》2009,74(5):468-472
High throughput screening and other techniques commonly used to identify lead candidates for drug development usually yield compounds with binding affinities to their intended targets in the mid‐micromolar range. The affinity of these molecules needs to be improved by several orders of magnitude before they become viable drug candidates. Traditionally, this task has been accomplished by establishing structure activity relationships to guide chemical modifications and improve the binding affinity of the compounds. As the binding affinity is a function of two quantities, the binding enthalpy and the binding entropy, it is evident that a more efficient optimization would be accomplished if both quantities were considered and improved simultaneously. Here, an optimization algorithm based upon enthalpic and entropic information generated by Isothermal Titration Calorimetry is presented. 相似文献
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《Expert opinion on drug discovery》2013,8(9):873-883
ABSTRACTIntroduction: Classic antidepressants that modulate monoaminergic systems are not sufficiently effective and require long systematic application. Recent studies suggest that substances that modulate glutamatergic system may produce an antidepressant effect which is not only faster but also more sustained.Areas covered: In this paper, the authors summarize the results of studies on antidepressant action of ketamine in patients with severe refractory depression, which have demonstrated high efficacy in a very short time after a single dose. Due to the adverse effects of ketamine that substantially exclude it from the daily use by patients, efforts have been made to find other NMDA receptor antagonists, which could mimic the therapeutic effect of ketamine but without the side effects. Intensive studies to elucidate ketamine’s mechanism of antidepressant action have also been conducted. Herein, the results of research showing that metabotropic glutamate (mGlu) receptors could be the target of novel antidepressants are also presented.Expert opinion: The intensive preclinical and clinical research on NMDA and mGlu receptor ligands, which is currently going on, could contribute to the awaited breakthrough in the field of novel antidepressant drug discovery. This line of research may also lead to a new understanding of the biological basis of depression. 相似文献
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Natércia F. Brás Pedro A. Fernandes Maria J. Ramos 《Chemical biology & drug design》2014,83(4):427-439
Renin (REN) is a key drug target to stop the hypertension cascade, but thus far only one direct inhibitor has been made commercially available. In this study, we assess an innovative REN inhibition strategy, by targeting the interface of the renin:angiotensinogen (REN:ANG) complex. We characterized the energetic role of interfacial residues of REN:ANG and identified the ones responsible for protein:protein binding, which can serve as drug targets for disruption of the REN:ANG association. For this purpose, we applied a computational alanine scanning mutagenesis protocol, which measures the contribution of each side chain for the protein:protein binding free energy with an accuracy of ≈ 1 kcal/mol. As a result, in REN and ANG, six and eight residues were found to be critical for binding, respectively. The leading force behind REN:ANG complexation was found to be the hydrophobic effect. The binding free energy per residue was found to be proportional to the buried area. Residues responsible for binding were occluded from water at the complex, which promotes an efficient pairing between the two proteins. Two druggable pockets involving critical residues for binding were found on the surface of REN, where small drug‐like molecules can bind and disrupt the ANG:REN association that may provide an efficient way to achieve REN inhibition and control hypertension. 相似文献
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相对传统新药研发模式,药物重定位策略发现药物新用途具有显著的成本效益优势,能加快药物上市步伐,满足恶性肿瘤、罕见病、个性化医疗等特定领域药物临床用药需求,因而被各界关注。本文主要介绍了药物重定位的一般流程与候选药物筛选路径,如从非理性设计方法向基于相似性、基于结构虚拟筛选、推理与机器学习等理性设计方法发现重定位药物的系统性转变。 相似文献
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The liver is a key organ for numerous metabolic pathways and involves many inherited diseases that, although being different in their pathology, are often caused by lack or overproduction of a critical gene product in the diseased cells. In principle, a straightforward method to fix such problem is to introduce into these cells with a gene-coding sequence to provide the missing gene product or with the nucleic acid sequence to inhibit production of the excessive gene product. Practically, however, success of nucleic acid-based pharmaceutics is dependent on the availability of a method capable of delivering nucleic acid sequence in the form of DNA or RNA to liver cells. In this review, we will summarize the progress toward the development of physical methods for nucleic acid delivery to the liver. Emphasis is placed on the mechanism of action, pros, and cons of each method developed so far. We hope the information provided will encourage new endeavor to improve the current methodologies or develop new strategies that will lead to safe and effective delivery of nucleic acids to the liver. 相似文献
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目的:建立小鼠组织中KS0604的定量分析方法.方法:采用组织消化结合基于离子交换和反相分配原理的两步固相萃取法,并采用无胶筛分毛细管电泳技术测定小鼠组织中的KS0604.结果:小鼠肾组织中KS0604在2.0~2 000 μg·g-1范围内呈良好线性,最低定量限LOQ为2.0 μg·g-1;其他组织中KS0604在1.3~128 μg·g-1范围内呈良好线性,最低定量限LOQ为1.3 μg·g-1;r>0.999.加样回收率试验RSD<10.82%,精密度试验RSD<2.3%,稳定性试验结果表明KS0604在小鼠组织中的稳定性良好.结论:该方法可用于定量检测小鼠组织中的KS0604. 相似文献