Programmable Mesocomposites for Controlled and Cell-targeted DNA Delivery

用于受控和细胞靶向 DNA 传递的可编程介观复合材料

基本信息

批准号：
7848679
负责人：
Hong Shen
金额：
$ 3.44万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848679
关键词：
Address Area Attention Basic Science Carbonates Cell Culture Techniques Cell Line Cells Clinical Clinical Medicine DNA DNA Vaccines DNA delivery Dendritic Cells Development Disease Drug effect disorder Effectiveness Exploratory/Developmental Grant Future Gene Expression Gene Targeting Genes Glycolic-Lactic Acid Polyester Goals Health Hereditary Disease Human In Vitro Inherited Injectable Ions Lead Libraries Ligands Lymphoma Malignant Neoplasms Methodology Minerals Modeling Mus Nature Oncogenes Pathogenesis Population Process Research Role Safety Scheme Signal Pathway Solutions Specific qualifier value Surface System Testing Therapeutic Tissues Translating Vaccines Viral base biodegradable polymer biological systems biomineralization cell behavior cell type chemical property clinical application cost cytotoxicity design flexibility gene therapy in vivo nanocomposite particle programs tissue regeneration tumor viral DNA

项目摘要

DESCRIPTION (provided by applicant): Developing systems capable of controlled and cell-targeted DNA delivery is essential to both basic science and clinical medicine. In the area of basic science, modulating a gene within a cell has the power to reveal or confirm the roles of specific components of signaling pathways and can lead to a mechanistic understanding of cell behavior, disease pathogenesis, and drug action. Alternatively, therapeutic strategies using DNA delivery are under development for inherited genetic disorders, cancer, and tissue regeneration. The successful application of DNA delivery for basic science and clinical medicine requires the ability to control the expression of target genes in the desired cell populations. Inspired by naturally occurring biomineralization processes, we have successfully developed DNA-doped carbonate nanocomposites on a cell culture-treated surface. By varying mineral compositions, the expression of genes in several cell lines can be modulated. Our preliminary studies have demonstrated the value of this approach. The programmable nature of mineral composites offers a great opportunity to tune delivery systems towards specific biological systems. In this R21 program, we aim to further explore this approach for future clinical and basic applications. This program will be accomplished through three specific aims: first, to establish a library of mineral solutions for delivering DNA to a variety of cell types by a high-throughput approach; second, to develop and optimize the process of biomineralization to program biodegradable polymer particles for controlled and cell-targeted DNA delivery in vivo; third, to test the effectiveness of programmable mesocomposites in a mouse tumor model by targeting DNA to dendritic cells (DCs) in vivo. The results derived from this application can be directly translated to a variety of clinical settings, including cancer gene therapy and DNA vaccines. Our inter-related three aims would demonstrate the value of programmable materials in complicated biological systems. This research program is to develop controlled and cell-targeted non-viral DNA delivery systems. The results can be directly translated to a variety of clinical applications including cancer gene therapy, DNA vaccines and tissue regenerations for the improvement of human health.

描述（由申请人提供）：开发能够控制和细胞靶向DNA的系统对于基础科学和临床医学都是必不可少的。在基础科学领域，调节细胞内的基因具有揭示或确认信号通路特定组成部分的作用，并可能导致对细胞行为，疾病发病机理和药物作用的机械理解。另外，使用DNA递送的治疗策略正在开发遗传性遗传疾病，癌症和组织再生。 DNA递送在基础科学和临床医学中的成功应用需要控制所需细胞群体中靶基因的表达的能力。受到自然存在的生物矿化过程的启发，我们在细胞培养处理的表面上成功地开发了掺杂的DNA碳酸盐纳米复合材料。通过改变矿物质的成分，可以调节几种细胞系中基因的表达。我们的初步研究证明了这种方法的价值。矿物质复合材料的可编程性质为调整递送系统的特定生物系统提供了绝佳的机会。在此R21计划中，我们旨在进一步探索这种方法，以供将来的临床和基本应用。该程序将通过三个具体目标来完成：首先，建立一个矿物解决方案库，以通过高通量方法将DNA传递到各种细胞类型的库中；其次，开发和优化生物矿化的过程以编程可生物降解的聚合物颗粒，以在体内受控和细胞靶向的DNA递送；第三，通过将DNA靶向体内的树突状细胞（DC），测试了在小鼠肿瘤模型中可编程中复合材料的有效性。该应用程序得出的结果可以直接转化为各种临床环境，包括癌症基因治疗和DNA疫苗。我们相互关联的三个目标将证明可编程材料在复杂的生物系统中的价值。该研究计划是开发受控和细胞靶向的非病毒DNA输送系统。结果可以直接转化为多种临床应用，包括癌症基因疗法，DNA疫苗和组织再生，以改善人类健康。