Investigating and Characterizing Non-Viral, Biocompatible Delivery Vehicles for Nucleic Acid Nanoparticles

研究和表征核酸纳米粒子的非病毒、生物相容性递送载体

• 批准号: 10629227
• 负责人: Yelixza Avila
• 金额: $ 3.93万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2024-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10629227
• 关键词: 3-Dimensional; Address; Amines; Architecture; Back; Behavior; Binding; Biodistribution; Biological; Biological Assay; Biological Markers; Cancer cell line; Cancerous; Categories; Cell Line; Cell Survival; Cells; Clinical; Collaborations; Communication; Complex; DNA; Data; Databases; Dendrimers; Dimensions; Disease; Electrostatics; Fiber; Formulation; Future; Gene Silencing; Generations; Genetic; Growth; Harvest; Human; Human Cell Line; Immune; Immune response; Immune system; Immunologic Stimulation; Investigation; Leadership; Learning; MicroRNAs; Modality; Nanotechnology; North Carolina; Nucleic Acids; Pathway interactions; Patients; Pharmacologic Substance; Property; RNA; RNA Interference Therapy; Research; Research Personnel; Resources; Role; Shapes; Small Interfering RNA; Structure; Students; Techniques; Testing; Therapeutic; Therapeutic Agents; Transfection; Universities; Virus Diseases; Western Blotting; Work; analog; behavior in vitro; biomaterial compatibility; clinically relevant; comparative; delivery vehicle; design; exosome; experience; experimental study; in vitro Assay; interest; nanocarrier; nanoparticle; nanoparticle delivery; nuclease; nucleic acid-based therapeutics; personalized therapeutic; pre-clinical; prevent; programs; rational design; scaffold; skills; success; symposium; uptake

PROJECT SUMMARY Nucleic acid nanoparticles (NANPs) have the ability to simultaneously deliver a cocktail of multiple therapeutic nucleic acids (TNAs) that can treat diseases by targeting several biological pathways. However, in order to be functional, NANPs require a delivery vehicle to enter cells while being protected from naturally occurring nucleases. There have been studies showing that amine-terminated polyamidoamine (-NH2) PAMAM dendrimers have successfully delivered TNAs such as small interfering RNAs, and micro RNAs into cells while efficiently protecting them, but these studies deep dive into only one generation of dendrimers. This proposal aims to investigate and compare five different generations of (-NH2) PAMAM dendrimers to interpret how each will behave as a carrier for several representative NANPs. A second delivery platform that will be investigated are exosomes that are harvested from cancerous and non-cancerous human cell lines. Exosomes naturally pass biological information from cell to cell and we would be utilizing this natural communication machinery to deliver NANPs. Each exosome carries different biomarkers corresponding to the cell line of origin, and these biomarkers can be used to identify the exosome type and tune their biodistribution, immunorecognition and cellular uptake. Along with exosomal identification, the type of the NANP embedded into the exosome complex may additionally contribute to their biological behavior, which is what we would like to investigate in this current proposal. Once competed, this investigation will supply information regarding the role that synthetic and naturally occurring vehicles have on immune response and efficacy, as well as how NANPs' architectural parameters (e.g., 3D vs 2D vs 1D) influence their delivery and immune response. The broad and long-term objectives for this work would be to categorize a database focused on the in vitro behavior of NANPs complexed to their vehicles to include the immune response, protection, and efficacy of the NANP-carrier platform. In collecting this data, and compiling it, future nucleic acid based therapeutics could be rationally designed with specific parameters and tailored immune recognition and function based on what a patient requires. All proposed experiments will be completed by the applicant who will collaborate with the necessary personal to learn any supplemental techniques needed. In addition to completing the proposed work, the applicant will be serving as a leader in more than one graduate organization where the applicant will be gaining professional, communicative, and leadership skills needed to network when presenting this work at conferences. The University of North Carolina at Charlotte is a space that is experiencing exponential growth that is focused on student success and provides valuable resources for students and researchers to utilize.

项目概要 核酸纳米颗粒 (NANP) 能够同时提供多种物质的混合物 治疗性核酸（TNA）可以通过靶向多种生物途径来治疗疾病。然而，在 为了发挥作用，NANP 需要一种运载工具进入细胞，同时受到自然保护 发生核酸酶。 有研究表明，胺封端的聚酰胺胺（-NH2）PAMAM树枝状聚合物 已成功将小干扰 RNA 和微小 RNA 等 TNA 高效递送至细胞内 保护它们，但这些研究仅深入研究了一代树枝状聚合物。该提案旨在 研究并比较五种不同代的 (-NH2) PAMAM 树枝状聚合物，以解释每种聚合物的作用 作为几个代表性 NANP 的载体。 将要研究的第二个递送平台是从癌症和癌症中收获的外泌体。 非癌性人类细胞系。外泌体自然地将生物信息从一个细胞传递到另一个细胞，我们会 利用这种自然的通信机制来传递 NANP。每个外泌体携带不同的生物标志物 对应于来源的细胞系，这些生物标志物可用于识别外泌体类型并调整 它们的生物分布、免疫识别和细胞摄取。除了外泌体鉴定之外， 嵌入外泌体复合物中的 NANP 可能还有助于其生物学行为，即 我们想在当前提案中调查什么。 一旦完成，这项调查将提供有关合成和天然物质的作用的信息 出现的载体对免疫反应和功效的影响，以及 NANP 的结构参数 （例如，3D vs 2D vs 1D）影响它们的传递和免疫反应。广泛而长期的目标 这项工作将对一个数据库进行分类，该数据库专注于 NANP 与其复合物的体外行为。 载体包括 NANP 载体平台的免疫反应、保护和功效。在收集这个 数据并对其进行编译，未来基于核酸的疗法可以通过特定的合理设计 根据患者的需要参数和定制的免疫识别和功能。 所有提议的实验将由申请人完成，申请人将与必要的人员合作 个人学习所需的任何补充技术。除了完成拟议的工作外， 申请人将在多个研究生组织中担任领导者，在这些组织中申请人将获得 在会议上展示这项工作时需要建立人际网络的专业、沟通和领导技能。 北卡罗来纳大学夏洛特分校是一个正在经历指数级增长的空间，专注于 帮助学生取得成功，并为学生和研究人员提供宝贵的资源。