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Triazine Derivatized Biomaterials for Nucleic Acid Delivery

用于核酸输送的三嗪衍生生物材料

基本信息

批准号：
1802432
负责人：
Dennis Bong
金额：
$ 50万
依托单位：
Ohio State University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1802432&HistoricalAwards=false
关键词：
Triazine Derivatized Biomaterials Nucleic Acid

项目摘要

PART 1: NON-TECHNICAL SUMMARYThe goal of this project is to develop and investigate new bioinspired materials that can package and protect gene therapeutics from degradation and enhance their efficacy. Gene therapy, the therapeutic delivery of nucleic acid into a patient's cells as a drug to treat disease, has the potential to be a general treatment for any disease with a genetic determinant. However, protection of genetic cargo from degradation and clearance, as well as delivery to the correct tissue location is a significant challenge. Two major approaches will be applied to produce these new biomaterials: 1) combination of natural components with an artificial scaffold; and 2) modification of natural biomaterial scaffolds with synthetic components. The artificial components are designed to bind gene therapeutics, while the natural components impart targeting function and biocompatibility. The artificial biomaterials will thus mask the presence of the therapeutic cargo, protecting it from degradation. Natural biological components such as sugars and lipids are expected to enhance water-solubility, biocompatibility and targeting of gene therapy to the correct biological target. These new biomaterials will be tested for their abilities to mimic natural packaging and protection strategies. This research could lead to the development of more efficient therapeutic products through a potentially general method and thus accelerate the emergence of new therapies based on bioinspired biomaterial carriers. Given the importance of molecular therapies for biomedical problems, these new biomaterials could have a significant impact on human health. PART 2: TECHNICAL SUMMARYThis proposal uses a simple synthetic motif to generate a new family of nucleic acid reactive biomaterials from readily available native ligands and polymers. This novel approach uses triazine derivatization to unify nucleic acid binding with cell-surface targeting in a multifunctional carrier design. It is the goal of this proposal to develop a general synthetic approach to transform synthetic and native biomaterials into nucleic acid carrier platforms, and elucidate the structural basis of functional intracellular delivery. This creative and original approach will yield the following expected outcomes: 1) A facile synthetic method to generate novel non-electrostatic nucleic acid binders from synthetic and biomolecular backbones; 2) a general method to transform native ligands into nucleic acid carriers; and 3) a method to target native T/U-rich nucleic acids. This research will impact targeted delivery of both RNA and DNA and enable intracellular targeting of native nucleic acid components with carriers in which binding can be decoupled from electrostatics. This decoupling allows for the fine tuning of nitrogen/phosphate (N/P) ratios geared towards uptake and release, rather than complexation. Importantly, these findings will enable the next vertical step in design of synthetic biomaterials for targeted nucleic acid chemistry delivery.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

第一部分：该项目的目标是开发和研究新的生物启发材料，可以包装和保护基因治疗剂免受降解，并提高其功效。基因疗法，即将核酸作为药物递送到患者的细胞中以治疗疾病，具有成为具有遗传决定因素的任何疾病的一般治疗的潜力。然而，保护遗传货物免于降解和清除，以及递送到正确的组织位置是一个重大挑战。将采用两种主要方法来生产这些新的生物材料：1）天然成分与人工支架的组合; 2）用合成成分修饰天然生物材料支架。人工成分被设计为结合基因治疗剂，而天然成分赋予靶向功能和生物相容性。因此，人造生物材料将掩盖治疗货物的存在，保护其免受降解。天然生物成分如糖和脂质有望增强水溶性、生物相容性和基因治疗靶向正确的生物靶点。这些新的生物材料将被测试其模仿自然包装和保护策略的能力。这项研究可以通过潜在的通用方法开发更有效的治疗产品，从而加速基于生物启发生物材料载体的新疗法的出现。鉴于分子疗法对生物医学问题的重要性，这些新的生物材料可能对人类健康产生重大影响。第二部分：技术概述该提议使用简单的合成基序从容易获得的天然配体和聚合物产生新的核酸反应性生物材料家族。这种新的方法使用三嗪衍生化统一核酸结合与细胞表面靶向的多功能载体设计。这是本提案的目标是开发一种通用的合成方法，将合成和天然生物材料转化为核酸载体平台，并阐明功能性细胞内递送的结构基础。这种创造性和原创性的方法将产生以下预期结果：1）从合成和生物分子主链产生新型非静电核酸结合剂的简易合成方法; 2）将天然配体转化为核酸载体的一般方法;和3）靶向天然富含T/U的核酸的方法。这项研究将影响RNA和DNA的靶向递送，并使天然核酸组分与载体的细胞内靶向成为可能，其中结合可以与静电分离。这种解耦允许微调氮/磷（N/P）比率，以适应吸收和释放，而不是络合。重要的是，这些发现将使下一个垂直步骤，在设计合成生物材料的靶向核酸化学delivery.This奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。