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

基本信息

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
项目类别：
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

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

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项目摘要

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快速改变景观卫生保健。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）到各个层面的生物学相互作用到组织和器官，细胞内运输和内体释放。不幸的是肿瘤学，高效脂质纳米颗粒（LNP）的全身递送到实体瘤的差异很差积累很大程度上是由于这些材料之间基本相互作用的知识存在差距和生物系统。在这里，我们建议研究结构性关系（SAR）纳米粒子载体通过使用化学和拓扑多样的脂肪聚合物库。调整RNA-LNP的生物界面。利用合并的条形码和串行深度机械机制测定法，我们将检验我们的中心假设，即定义的一系列第一原理关系控制 LNP在体内的生物物理相互作用。使用癌症模型，我们将与空间和时间相关联 MRNA在目标组织和细胞中具有LNP的生物物理化学特性的细胞积聚生物界面。该项目的目的是建立一个理化特性的框架，以指导基于RNA-LNP的癌症纳米医学的发展。我们将通过追求以下目的：目标1- LNP生物界面的结构和拓扑微调。目标2-阐明 LNP相对于全身，组织级和细胞内分布的生物学相互作用。目的 3-研究在多模式乳腺癌的背景下LNP的生物学相互作用和功效治疗。这项研究的直接结果将用于推进使用肿瘤学中的纳米技术。我们的项目将对LNP的角色产生关键而详细的了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帮助整个纳米医学的未来发展。