Vascular Targeting of Nanocarriers for RNA

RNA 纳米载体的血管靶向

基本信息

批准号：
10093767
负责人：
Vladimir R Muzykantov
金额：
$ 72.62万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-05 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10093767
关键词：
Acute Lung Injury Affinity Anti-Inflammatory Agents Antibodies Area Benchmarking Binding Biological Biological Products Biological Response Modifier Therapy Blood Vessels Brain Cell Adhesion Molecules Cell membrane Cells Cerebrovascular system Cerebrum Clinical Coupled Development Disease Dose Drug Delivery Systems Drug Kinetics Elements Endocytosis Endothelial Cells Endothelium Engineering Epitopes Extrahepatic Flow Cytometry Formulation Functional disorder Future Goals Human Inflammation Intercellular adhesion molecule 1 Isotopes Ligands Lipids Liver Lung Medical Messenger RNA Methods Microscopy Modeling Modification Mus Nanotechnology Organ Pharmacotherapy Pilot Projects Proteins RNA RNA delivery Recombinants Reporter Signal Transduction Site Spleen Stroke Surface Testing Therapeutic Thrombomodulin Thrombosis Time Tissues Transgenes Translating Translations Vascular Cell Adhesion Molecule-1 base cell type clinical application in vivo imaging intravenous injection lead candidate mouse model nanobodies nanocarrier nanomedicine nanoparticle nanotechnology platform novel novel strategies prophylactic protective effect real-time images spatiotemporal targeted treatment transgene expression uptake

项目摘要

Clinical approval of Lipid Nano Particles (LNP) for RNA heralded the advent of nanotechnology- based pharmacotherapy. Yet, RNA delivery to extra-hepatic sites remains a major unmet challenge. Weissman pioneered modifications of mRNA providing effective translation in diverse cell types, while Muzykantov introduced “vascular targeting”, nanomedicine strategy for drug delivery to desired areas in the vasculature. Here we converge these advances to devise nanocarriers targeting RNA to desired sites of transgene synthesis and therapeutic action. We found that ligands of Inter-Cellular Adhesion Molecule-1 (ICAM) conjugated to nanocarriers, direct ICAM-LNP (ILNP) to accumulate in lungs, especially, in the inflamed lungs, with trivial cerebral uptake. In opposite, LNP targeting to Vascular Cell Adhesion Molecule-1 (VCAM) provides trivial pulmonary uptake of VCAM-LNP (VLNP), and selective uptake in the inflamed brain, surpassing the benchmarks by orders of magnitude. VLNP loaded with mRNA encoding endothelial multifunctional anti-thrombotic and anti-inflammatory protein thrombomodulin (TM) provides transgene synthesis and protective effect in the inflamed CNS unrivaled by other agents. We will characterize and if needed reiteratively re-engineer targeting features of this powerful nanotechnology platform, by pursuing the following Specific Aims. Aim 1: Multi-scale spatiotemporal mapping of vascular targeting of ILNP and VLNP. Using isotope tracing and real time imaging, in vivo microscopy and flow cytometry, we will define PK/BD, dynamics of LNP localization and reporter transgene activity in the sites of desirable therapeutic action. Aim 2: Targeting therapeutic thrombomodulin RNA to lung and brain. We will characterize salient parameters of TM transgene expression, beneficial and unintended effects of ILNP and VLNP in naive mice and in mouse models of pulmonary and cerebral inflammation. Aim 3: Translational development of LNP. We will upgrade LNP to clinically applicable format via site-specific conjugation of small recombinant ligands. This study will define key specification parameters of a novel nanotechnology platform for selective delivery of RNA to desirable cells and cellular compartments in brain, lungs and likely other organs. It will establish proof of principle for a new nanomedicine approach for effective, specific and safe biological pharmacotherapy of ALI and stroke, with future expansion to other diseases.

脂质纳米颗粒（LNP）用于RNA的临床批准预示了纳米技术的冒险基于药物疗法。然而，RNA向外部位的交付仍然是一个重大的未得到挑战。魏斯曼（Weissman Muzykantov引入了“血管靶向”，纳米医学策略，用于输送到所需地区在脉管系统中。在这里，我们将这些进步汇聚在一起，将靶向RNA的纳米载体设计为所需的转化合成和治疗作用的位置。我们发现细胞间的配体粘附分子1（ICAM）与纳米载体共轭，直接ICAM-LNP（ILNP）积聚 LNP尤其是在发炎的肺部，具有琐碎的大脑吸收。血管细胞粘附分子-1（VCAM）提供VCAM-LNP（VLNP）的巨大肺摄取，并在发炎的大脑中有选择性吸收，通过数量级超过基准。 VLNP 带有编码内皮多功能抗栓性和抗炎蛋白的mRNA 血小板调节蛋白（TM）在发炎的CNS中提供转化合成和受保护作用由其他代理人无与伦比。我们将表征并在需要时重新设计目标通过追求以下特定目的，这个强大的纳米技术平台的特征。目标1： ILNP和VLNP血管靶向的多尺度空间时间映射。使用同位素跟踪和实时成像，体内显微镜和流式细胞仪，我们将定义PK/BD，LNP的动力学在理想的治疗作用部位的定位和记者转化活性。目标2：靶向治疗性血小板结合蛋白RNA对肺和大脑。我们将表征显着参数 TM转基因表达，ILNP和VLNP在幼稚小鼠中的有益和意外影响在肺和脑注射的小鼠模型中。目标3：LNP的翻译发展。我们将通过小重组的位点特异性结合升级到临床适用格式配体。这项研究将定义一个新型纳米技术平台的关键规范参数选择性递送RNA向所需的细胞和大脑，肺部以及其他可能的其他细胞室器官。它将为新的纳米医学方法建立原则证明，以实现有效，具体和安全的ALI和中风的生物学药物疗法，将来将来扩展到其他疾病。