Nanoscale Functional Dendrimer-DNA Assemblies

纳米级功能性树枝状聚合物-DNA 组装体

• 批准号: 7193251
• 负责人: MARK W. GRINSTAFF
• 金额: $ 16.25万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-04 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193251
• 关键词: Address; Affect; Architecture; Basic Science; Benchmarking; Binding; Biological; Biological Assay; Biology; Biomimetics; Cancer Patient; Cells; Characteristics; Charge; Chromosomes; Class; Classification; Cleaved cell; Colon Carcinoma; DNA; DNA Binding; DNA Packaging; Databases; Dendrimers; Development; Differential Scanning Calorimetry; Disease; Electrostatics; Endocytosis; Esters; Evaluation; Fluorescence Resonance Energy Transfer; Formazans; Future; Galactosidase; Gene Delivery; Gene Proteins; Generations; Genes; Genetic Transcription; Goals; Histones; Hydrogen Bonding; Hydrophobic Interactions; In Vitro; Investigation; Lead; Lipids; Medicine; Methods; Methylation; Microscopic; Modification; Molecular; NIH Program Announcements; Nanostructures; Nanotechnology; Non-Viral Vector; Nuclear; Numbers; Pathway interactions; Patient Care; Phosphorylation; Polymers; Preparation; Process; Property; Protein p53; Proteins; Public Health; Range; Rate; Reaction; Reporter Genes; Research; Research Personnel; Safety; Shapes; Structure; System; TP53 gene; Techniques; Today; Transfection; Transmission Electron Microscopy; Treatment Protocols; Tumor Suppressor Genes; Vaccines; Viral Vector; base; cancer cell; cancer therapy; colon cancer cell line; controlled release; cytotoxicity; design; esterase; gene therapy; improved; innovation; insight; interest; macromolecule; nanoscale; nanoscience; novel; programs; research clinical testing; response; size; synthetic construct; therapeutic gene; vector

DESCRIPTION (provided by applicant): This proposal describes the preparation and evaluation of new gene delivery vehicles composed of dendritic amphiphiles and DNA. These new functional dendritic amphiphiles undergo an electrostatic transition from cationic to anionic via an esterase-catalyzed reaction intracellularly to release DMA from the nanoscale assembly. We hypothesize that this change in electrostatic interactions with DNA will lead to increased gene transfection levels. A detailed, systematic investigation is proposed that entails the following three specific aims for this three-year R21 proposal: Aim 1. Determine the key molecular characteristics of the dendritic amphiphile required for binding and release of DNA. Aim 2. Characterize the nanoscale assemblies formed with the dendritic amphiphiles, and dendritic amphiphiles and DNA. Aim 3. Evaluate functional interactions of dendritic amphiphile/DNA assemblies with cells in vitro and deliver the p53 gene to colon cancer cells. The results of successful completion of this study will be: 1) one or more functional dendritic amphiphiles for delivery of the p53 gene to colon cancer cells; 2) a database of structure-property relationships; and 3) insight into the design of optimized dendritic vectors. These studies will also provide detailed physicochemical and biological information on this new class of dendritic amphiphiles and their corresponding assemblies, which is key for the future development of functional dendrimer/DNA assemblies for gene delivery. Relevance to Public Health: Innovative strategies to treat or cure colon cancer are still needed. Today, the current treatment protocols have resulted in improved patient care but the response rate remains only about 35% for metastatic colon cancer patients. In this proposal new well-defined polymers are described for the delivery of a tumor suppressor gene for the treatment of colon cancer.

描述(申请人提供)：本提案描述了由树枝状两亲分子和DNA组成的新型基因传递载体的制备和评价。这些新的功能树枝状两亲分子通过酯酶催化的细胞内反应经历了从阳离子到阴离子的静电转变，从而从纳米级组装中释放出DMA。我们假设，这种与DNA的静电相互作用的变化将导致基因转染率的增加。为这项为期三年的R21提案提出了一项详细、系统的调查，包括以下三个具体目标：目标1.确定结合和释放DNA所需的树枝状两亲分子的关键分子特征。目的2.表征树枝状两亲分子和树枝状两亲分子与DNA形成的纳米尺度的组装。目的3.体外评价树突状两亲性DNA组件与细胞的功能相互作用，并将P53基因导入结肠癌细胞。成功完成这项研究的结果将是：1)一个或多个功能树突状两亲分子，用于将p53基因输送到结肠癌细胞；2)结构-性质关系数据库；以及3)优化树突状载体的设计。这些研究还将提供这类新的树状两亲分子及其相应组件的详细物理化学和生物学信息，这对于未来开发用于基因传递的树状大分子/DNA组件是关键。与公共卫生相关：仍然需要治疗或治愈结肠癌的创新策略。今天，目前的治疗方案已经改善了患者的护理，但转移性结肠癌患者的应答率仍然只有35%左右。在这项建议中，描述了一种新的明确定义的聚合物，用于输送肿瘤抑制基因用于治疗结肠癌。