Mechanistic insights on structure, topology and radiation effects on RNA nanomedicines

RNA纳米药物的结构、拓扑和辐射效应的机理见解

• 批准号: 10587705
• 负责人: Gaurav Sahay
• 金额: $ 57.03万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-10 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587705
• 关键词: 3-Dimensional; Address; Bar Codes; Basic Science; Biodistribution; Biological; Biological Assay; Biological Process; Biophysics; Breast Cancer therapy; Cancer Model; Cells; Characteristics; Chemical Structure; Chemicals; Clinical; Combined Modality Therapy; DNA; Data; Development; Diffusion; Disease; Dose; Endosomes; Engineering; Formulation; Future; Gene Delivery; Goals; Healthcare; Heel; Histopathology; Immunohistochemistry; Immunologics; In Vitro; Knowledge; Label; Libraries; Luciferases; Malignant Neoplasms; Measurement; Messenger RNA; Methodology; Migration Assay; Modification; Molecular; Molecular Target; Nanotechnology; Oncologist; Oncology; Organ; Outcomes Research; Periodicity; Population; Process; Property; Proteins; Protocols documentation; RNA; RNA Interference; RNA delivery; Radiation therapy; Radiosensitization; Rare Diseases; Role; Route; Scheme; Series; Solid Neoplasm; Structure; Structure-Activity Relationship; System; Technology; Testing; Therapeutic; Tissues; Transfection; Treatment Efficacy; Treatment Protocols; Tumor Volume; Vaccines; Viscosity; biological systems; bioluminescence imaging; calreticulin; cancer cell; cell killing; chemotherapy; clinical translation; clinically relevant; complex biological systems; design; dosage; effectiveness evaluation; expectation; experience; gene therapy; hydrophilicity; immunoregulation; improved; in vivo; individualized medicine; insight; lipid nanoparticle; mouse model; multidisciplinary; multimodality; mutant; nanoengineering; nanomaterials; nanomedicine; nanoparticle; novel; novel strategies; preclinical study; radiation effect; therapeutic RNA; tool; trafficking; tumor; tumor microenvironment; uptake; vaccine development; vaccine distribution

PROJECT ABSTRACT RNA therapeutics and their corresponding nanomedicines are poised to rapidly change the landscape of healthcare. To address needs in various diseases, RNA-based technologies must function in vivo with biological interactions at various levels from whole body (systemic biodistribution and immunological) to tissues and organs, to intracellular trafficking and endosomal release. Unfortunately in oncology, efficient systemic delivery of lipid nanoparticles (LNPs) to solid tumors has been plagued by poor tissue accumulation largely due to a gap in the knowledge of fundamental interactions between these materials and biological systems. Here we propose to investigate the structure-activity-relationship (SAR) of nanoparticle carriers through use of a chemically and topologically diverse library of lipopolymers fine- tuning the biointerface of RNA-LNP. Utilizing a combined barcoding and serial in-depth mechanistic assays, we will test our central hypothesis that a defined series of first-principles relationships govern the biophysical interactions of LNPs in vivo. Using cancer models, we will correlate the spatial and temporal accumulation of mRNA at target tissues and cells with biophysicochemical properties of the LNP biointerface. The goal of this project is to establish a framework of physiochemical properties to guide the development of RNA-LNP based cancer nanomedicines. We will achieve this goal by the pursuing the following aims: Aim 1 - Structural and topological fine-tuning of LNPs biointerface. Aim 2 - Elucidate the biological interactions of LNPs with respect to whole-body, tissue-level, and intracellular distributions. Aim 3 - Investigate the biological interaction and efficacy of LNPs in the context of multimodal breast cancer therapy. The immediate outcomes of this research will be applied toward advancing the use of nanotechnology in oncology. Our project will yield a critical and detailed understanding of the role the LNP biointerface and its effects on the fate of LNPs in complex biological systems as well as their efficacy. This invaluable knowledge would greatly aid in future developments in nanomedicine as a whole.

项目摘要 RNA疗法及其相应的纳米医学有望迅速改变人类的生活方式。 健康护理为了满足各种疾病的需求，基于RNA的技术必须在体内发挥作用， 从全身（全身生物分布和免疫学）到 组织和器官，细胞内运输和内体释放。不幸的是，在肿瘤学中， 脂质纳米颗粒（LNP）向实体瘤的全身递送一直受到不良组织 积累主要是由于在这些材料之间的基本相互作用的知识差距 和生物系统。在这里，我们建议调查的构效关系（SAR） 纳米颗粒载体通过使用化学和拓扑多样的脂聚合物精细- 调整RNA-LNP的生物界面。利用组合的条形码和序列深入机制 分析，我们将测试我们的中心假设，一个定义的一系列第一原则的关系支配 LNP在体内的生物物理相互作用。使用癌症模型，我们将把空间和时间 mRNA在靶组织和具有LNP生物药理化学特性的细胞中的蓄积 生物界面本项目的目标是建立一个理化性质的框架，以指导 开发基于RNA-LNP的癌症纳米药物。我们将通过以下方式实现这一目标： 目标1 -LNP生物界面的结构和拓扑微调。目标2 -阐明 LNP在全身、组织水平和细胞内分布方面的生物相互作用。目的 3 -研究LNP在多模式乳腺癌背景下的生物学相互作用和功效 疗法这项研究的直接结果将用于促进使用 肿瘤学中的纳米技术我们的项目将产生一个关键的和详细的了解的作用， 生物界面及其对LNP在复杂生物系统中的命运及其功效的影响。这 宝贵的知识将大大有助于未来的发展，纳米医学作为一个整体。