Engineered Organic Particles of Controlled Size, Shape and Surface Chemistry for

尺寸、形状和表面化学受控的工程有机颗粒

基本信息

  • 批准号:
    7802860
  • 负责人:
  • 金额:
    $ 32.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-05-01 至 2013-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The overall goal for this project is to elucidate the mechanisms by which organic nanoparticles of controlled shape, controlled site-specific surface chemistry, tunable particle matrix composition and tunable modulus undergo endocytosis and to use these findings to engineer the intracellular release of siRNA within mammalian cells to achieve effective gene knockdown. This information, in combination with on-going efforts to understand the bio-distribution of shape controlled particles, will help to establish the rules for the rational design of nano-carriers for the effective in vivo delivery of siRNA. This will be accomplished using a unique particle synthesis method developed at the University of North Carolina called PRINT, Particle Replication in Non- wetting Templates. PRINT is an off-shoot of the emerging lithographic processes used to fabricate devices in the microelectronics industry. In aims 1 and 2, the effect of nanoparticle composition, size, shape, surface charge and ligand choice on the cellular uptake of non-targeted and targeted nanoparticles will be examined. The kinetics of cellular internalization of the nanoparticles and the effect of charge and the spatial arrangement and the density of the ligands on the particle surface will be investigated with regard to specific pathways for cellular internalization of particles. Aim 3 will explore the rational design of PRINT nanoparticles for non-targeted and targeted in vitro delivery of siRNA. As the PRINT particles enter a cell, the particulate carriers will release the siRNA based on a stimuli induced biological or chemical degradation mechanism. The effectiveness of intracellular delivery monitored by luciferase gene silencing will be evaluated as a function of particle matrix composition, particle size and shape and pathway of internalization. Aim 4 will explore rational design of PRINT nanoparticles for targeted in vivo delivery of siRNA. The PRINT nanoparticles with encapsulated anti-luciferase siRNA will be decorated with cell specific ligands (folate, transferrin) and intravenously injected into tumor bearing mice. The efficacy and efficiency of siRNA delivery to the tumor will be evaluated as a function of particle surface and matrix chemistries. Understanding the detailed interplay between particle surface chemistry and shape on effective transfection both in vitro as well as in vivo is of significant importance. PUBLIC HEALTH RELEVANCE: Small interfering RNA (siRNA) has the potential to revolutionize the treatment of a number of life threatening human diseases, particularly cancer, but one obstacle facing researchers and companies attempting to develop siRNA therapies, or any type of nucleic acid therapeutic, is efficient and specific delivery of the polyanionic molecules into the cells, tissues or organ systems of choice. Using a technique known as PRINTTM (Particle Replication in Non-wetting Templates), we are able to fabricate nanoparticles with precise control over the particle size, shape, composition, cargo and surface properties to create truly engineered drug therapies that can be used to overcome the obstacles facing researchers and to provide the tools for the rational design of nano-carriers for the effective delivery of therapeutics in vitro and in vivo.
描述(申请人提供):该项目的总体目标是阐明可控形状、可控位置特定表面化学、可调颗粒基质组成和可调模数的有机纳米颗粒进行内吞作用的机制,并利用这些发现来设计哺乳动物细胞内siRNA的释放,以实现有效的基因敲除。这些信息与正在进行的了解形状可控颗粒的生物分布的努力相结合,将有助于建立合理设计纳米载体的规则,从而有效地在体内传递siRNA。这将使用北卡罗来纳大学开发的一种独特的粒子合成方法来完成,该方法被称为Print,即非湿润模板中的粒子复制。印刷术是微电子工业中用于制造器件的新兴平版印刷工艺的副产品。在目标1和目标2中,将研究纳米颗粒的组成、大小、形状、表面电荷和配体选择对非靶向和靶向纳米颗粒的细胞摄取的影响。关于纳米粒子细胞内化的特定途径,将研究纳米粒子细胞内化的动力学以及电荷和配基在粒子表面的空间排列和密度的影响。目的3探索用于非靶向和靶向体外传递siRNA的印迹纳米粒的合理设计。当印刷颗粒进入细胞时,颗粒载体将基于刺激诱导的生物或化学降解机制释放siRNA。通过荧光素酶基因沉默监测的细胞内传递的有效性将作为颗粒基质组成、颗粒大小和形状以及内化途径的函数来评估。目的4探索用于体内靶向递送siRNA的印刷纳米颗粒的合理设计。包裹了抗荧光素酶siRNA的印刷纳米颗粒将被细胞特异性配体(叶酸、转铁蛋白)修饰,并静脉注射到荷瘤小鼠体内。SiRNA传递到肿瘤的效果和效率将作为颗粒表面和基质化学的函数进行评估。了解颗粒表面化学和形状对体外和体内有效转导的详细相互作用具有重要意义。 与公共卫生相关:小干扰RNA(SiRNA)有可能彻底改变许多威胁生命的人类疾病的治疗方法,特别是癌症,但试图开发siRNA疗法或任何类型的核酸疗法的研究人员和公司面临的一个障碍是,多阴离子分子高效和特定地输送到所选的细胞、组织或器官系统。使用一种名为PRINTTM(非润湿模板中的颗粒复制)的技术,我们能够制造出对颗粒大小、形状、成分、载物和表面属性进行精确控制的纳米颗粒,以创建可用于克服研究人员面临的障碍的真正工程药物疗法,并为合理设计纳米载体提供工具,以便在体外和体内有效地输送治疗药物。

项目成果

期刊论文数量(0)
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专利数量(0)

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JOSEPH M. DESIMONE其他文献

JOSEPH M. DESIMONE的其他文献

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{{ truncateString('JOSEPH M. DESIMONE', 18)}}的其他基金

PRINT: Nanoparticles: "Calibration Quality" Nano-tools for Studying the Effect of
打印:纳米颗粒:用于研究效果的“校准质量”纳米工具
  • 批准号:
    8540371
  • 财政年份:
    2013
  • 资助金额:
    $ 32.44万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8540392
  • 财政年份:
    2013
  • 资助金额:
    $ 32.44万
  • 项目类别:
Education/Training and Outreach Activities
教育/培训和外展活动
  • 批准号:
    8540394
  • 财政年份:
    2013
  • 资助金额:
    $ 32.44万
  • 项目类别:
Developmental Projects and Trans-Alliance Activities
发展项目和跨联盟活动
  • 批准号:
    8540395
  • 财政年份:
    2013
  • 资助金额:
    $ 32.44万
  • 项目类别:
Carolina Center of Cancer Nanotechnology Excellence
卡罗莱纳州癌症纳米技术卓越中心
  • 批准号:
    7963527
  • 财政年份:
    2010
  • 资助金额:
    $ 32.44万
  • 项目类别:
Carolina Center of Cancer Nanotechnology Excellence
卡罗莱纳州癌症纳米技术卓越中心
  • 批准号:
    8309355
  • 财政年份:
    2010
  • 资助金额:
    $ 32.44万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7982960
  • 财政年份:
    2010
  • 资助金额:
    $ 32.44万
  • 项目类别:
Carolina Center of Cancer Nanotechnology Excellence
卡罗莱纳州癌症纳米技术卓越中心
  • 批准号:
    8136711
  • 财政年份:
    2010
  • 资助金额:
    $ 32.44万
  • 项目类别:
Developmental Projects and Trans-Alliance Activities
发展项目和跨联盟活动
  • 批准号:
    7982962
  • 财政年份:
    2010
  • 资助金额:
    $ 32.44万
  • 项目类别:
PRINT: Nanoparticles: "Calibration Quality" Nano-tools for Studying the Effect of
打印:纳米颗粒:用于研究效果的“校准质量”纳米工具
  • 批准号:
    7982949
  • 财政年份:
    2010
  • 资助金额:
    $ 32.44万
  • 项目类别:

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