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药物有望迅速改变这一领域的格局 卫生保健。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）到各个层面的生物相互作用 组织和器官，细胞内运输和内体释放。不幸的是，在肿瘤学中，有效 向实体瘤全身输送脂质纳米颗粒（LNP）一直受到组织不良的困扰 积累很大程度上是由于对这些材料之间的基本相互作用的了解存在差距 和生物系统。在这里，我们建议研究结构-活动-关系（SAR） 纳米颗粒载体通过使用化学和拓扑多样化的脂聚合物精细库 调整RNA-LNP的生物界面。利用组合的条形码和串行深入机制 分析中，我们将测试我们的中心假设，即一系列定义的第一原理关系控制着 LNP 在体内的生物物理相互作用。使用癌症模型，我们将空间和时间关联起来 具有 LNP 生物理化特性​​的 mRNA 在靶组织和细胞中的积累 生物界面。该项目的目标是建立一个理化特性框架来指导 开发基于RNA-LNP的癌症纳米药物。我们将通过追求实现这一目标 以下目标： 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 在多模式乳腺癌中的生物相互作用和功效 治疗。这项研究的直接成果将用于推进 肿瘤学中的纳米技术。我们的项目将对 LNP 的作用产生批判性和详细的理解 生物界面及其对复杂生物系统中 LNP 命运的影响及其功效。这 宝贵的知识将极大地有助于整个纳米医学的未来发展。