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Image-Guided Drug Delivery for Pancreatic Neuroendocrine Tumor

图像引导胰腺神经内分泌肿瘤给药

基本信息

批准号：
10167387
负责人：
Hak Soo Choi
金额：
$ 65.11万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-16 至 2022-09-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10167387
关键词：
2019-nCoV Acute Renal Failure with Renal Papillary Necrosis Administrative Supplement Adverse effects Affect Antineoplastic Agents Antiviral Agents Arrhythmia Biodistribution Biological Biological Assay Blood Circulation COVID-19 Caliber Cardiomyopathies Cardiotoxicity Cells Cessation of life Chemical Engineering Chemicals Chloroquine Clinical Research Complex Coronavirus Infections Country DNA-Directed RNA Polymerase Development Dose Drug Delivery Systems Drug Kinetics Drug Targeting Emerging Communicable Diseases Equilibrium Evaluation Excretory function Extinction (Psychology)Fluorescence Foundations Goals Grant Histology Hydroxychloroquine Hypotension Image Image-Guided Surgery Imatinib Injections Injury to Kidney Interdisciplinary Study Investigation Islet Cell Tumor Kidney Lung Measures Monitor Multiple Organ Failure National Institute of Biomedical Imaging and Bioengineering Near-infrared optical imaging Organ Parents Patients Pharmaceutical Preparations Pharmacodynamics Plaque Assay Plasma Property Pulmonary Pathology Renal clearance function Reporting Research Respiratory System Retinal Diseases Safety Septic Shock Serum Serum Proteins Signal Transduction Societies Support System System Testing Therapeutic Time Tissues Toxic effect Treatment Efficacy Urine Viral Viral Load result Virion Virus Virus Diseases Work acute liver injury anti-viral efficacy base design drug distribution fluorophore glycosylation health economics heart rhythm image guided image guided intervention image-guided drug delivery imaging system improved in vivo liver injury mouse model nanocarrier nanoparticle nanotechnology platform nanotherapeutic prevent quantum real-time images receptor remdesivir response side effect small molecule success targeted delivery targeted imaging targeted treatment tumor uptake viral RNA

项目摘要

Project Summary/Abstract (limit within 30 lines) The COVID-19 emerged in December 2019 and then spread rapidly over 214 countries. As of May 15, 2020, a total of more than 4.5M confirmed cases and over 300,000 deaths have been reported worldwide, posing significant health and economic threats to our society. Currently, an array of drugs approved for other indications have been studied, in addition to multiple investigational agents, for the treatment of COVID-19. Antivirals including remdesivir, favipiravir, chloroquine, and hydroxychloroquine have been rapidly tested in these clinical studies and demonstrated preliminary efficacy against COVID-19. However, these studies also revealed that a proportion of patients receiving remdesivir had significant adverse effects, including multiple-organ dysfunction syndrome, septic shock, and acute liver and kidney injury. Similarly, the use of chloroquine and hydroxychloroquine in COVID-19 patients has raised serious safety concerns including arrhythmias, cardiomyopathy, and retinopathy. These adverse effects are related to their wide distribution of drugs in the whole body after administration, causing damages in off-target vital organs. Therefore, tissue-specific delivery of antiviral therapeutics would ameliorate adverse effects while maintaining their efficacy to treat COVID-19. Our hypothesis that renal clearable ultrasmall nanocarriers can payload antiviral drugs selectively and deliver them to treat COVID-19 with reduced side effects. In our parent R01 (NIBIB #R01EB022230), we have developed ultrasmall nanocarriers for targeting, imaging, and image-guided surgery of pancreatic neuroendocrine tumors. Importantly, over 80% of the unbound dose was ultimately eliminated into the urine within 24 h post-injection after systemic circulation. This narrows the design of nanocarriers to include a targeting anchor, an imaging moiety, and a distribution domain, and we have worked diligently to create a reciprocal arrangement whereby each chemical composition provides balancing properties to the others. Interestingly, during the evaluation of inclusion complexation, we found that the nanocarriers can deliver other types of drugs including imatinib (Kang et al. Adv Mater, 2020). This result suggests that ultrasmall nanocarriers can also deliver antiviral drugs to the target with reduced side effects due to rapid renal clearance of unbound molecules. Therefore, the ultimate goal in this administrative supplement application is to develop ultrasmall nanotherapeutics that are complexed with antivirals to treat COVID-19. By payloading selected antiviral drugs into the ultrasmall nanocarriers, we will be able to achieve image-guided drug delivery to the respiratory system with reduced side effects due to the rapid renal clearance of unbound drugs. To achieve this goal, we propose 1) to develop renal clearable nanocarriers for antiviral drug delivery and 2) to evaluate the pharmacodynamics and therapeutic efficacy of the nanocarriers in mouse models of coronavirus infection. Armed with the near- infrared fluorophores conjugated on the nanocarrier, we will also monitor the biodistribution and clearance of antivirals as well as their targetability and therapeutic efficacy under the real-time imaging system.

项目概要/摘要（30行以内） COVID-19于二零一九年十二月出现，随后迅速蔓延至214个国家。截至2020年5月15日，全球共报告了超过450万例确诊病例和超过30万例死亡病例，对我们社会的健康和经济威胁。目前，一系列被批准用于其他适应症的药物除了多种研究药物外，还对用于治疗COVID-19进行了研究。抗病毒药包括remdesivir，favipiravir，chloroquine和hydroxychloroquine，已经在这些临床试验中快速测试，研究并证明了对COVID-19的初步疗效。然而，这些研究也表明，接受Remdesivir治疗的患者中有一部分有显著的不良反应，包括多器官功能障碍综合征、败血性休克和急性肝和肾损伤。同样，使用氯喹和羟氯喹在COVID-19患者中引起了严重的安全问题，包括心律失常，心肌病和视网膜病这些不良反应与药物在世界各地的广泛分布有关给药后全身，导致非靶向重要器官损伤。因此，组织特异性递送抗病毒治疗剂的使用将减轻不良反应，同时保持其治疗COVID-19的功效。我们假设肾脏可清除的超小纳米载体可以选择性地负载抗病毒药物，他们治疗COVID-19，减少副作用。在我们的父R 01（NIBIB #R01EB 022230）中，我们有开发了用于胰腺癌靶向、成像和图像引导手术的超小纳米载体，神经内分泌肿瘤重要的是，超过80%的未结合剂量最终消除到尿液中注射后24小时内，体循环后。这缩小了纳米载体的设计以包括靶向锚，成像部分和分布域，我们一直在努力创造一个互惠的这种布置使得每种化学组合物为其它化学组合物提供平衡性质。有趣的是，在评价包合物的过程中，我们发现纳米载体可以递送其他类型的药物包括伊马替尼（Kang et al. Adv Mater，2020）。这一结果表明，超小纳米载体也可以将抗病毒药物递送到靶点，由于未结合分子的快速肾清除而减少副作用。因此，在这个行政补充申请的最终目标是开发超小型与抗病毒药物复合以治疗COVID-19的纳米治疗药物。通过选择抗病毒药物我们将能够实现图像引导的药物输送到呼吸系统由于未结合药物的快速肾清除而降低了副作用。为了实现这一目标，我们建议 1)开发用于抗病毒药物递送的肾可清除纳米载体和2）评估药效学和纳米载体在冠状病毒感染的小鼠模型中的治疗功效。带着近- 结合在纳米载体上的红外荧光团，我们还将监测抗病毒药物以及它们在实时成像系统下的靶向性和治疗功效。