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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.

项目摘要/摘要(不超过30行) 新冠肺炎于2019年12月出现，随后迅速蔓延到214个国家。截至2020年5月15日，全球共报告450万多例确诊病例和30多万人死亡，构成对我们的社会构成重大的健康和经济威胁。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，还研究了用于治疗新冠肺炎的药物。抗病毒药物包括雷米西韦、法韦拉韦、氯喹和羟氯喹在内的药物已在这些临床上进行了快速测试研究并证明了对新冠肺炎的初步效果。然而，这些研究也表明，接受瑞希韦治疗的患者比例有显著的不良反应，包括多器官功能障碍。综合征、感染性休克和急性肝肾损伤。同样，氯喹和氯喹的使用新冠肺炎患者中的羟氯喹引发了严重的安全问题，包括心律失常。心肌病和视网膜病。这些不良反应与药物在人体内的广泛分布有关全身给药后，对靶外重要器官造成损害。因此，组织特异性递送抗病毒治疗药物的使用将减少不良反应，同时保持其治疗新冠肺炎的有效性。我们的假设是，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并递送他们要求新冠肺炎的副作用减少。在我们的父R01(NIBIB#R01EB022230)中，我们有开发超小型纳米载体，用于胰腺的靶向、成像和图像引导手术神经内分泌肿瘤。重要的是，超过80%的非结合剂量最终被排入尿液体循环后24小时内。这缩小了纳米载体的设计范围，使其包括靶向锚，一个成像部分，一个分发域，我们勤奋地工作，创造了一个互惠的每种化学成分为其他化学成分提供平衡性质的一种安排。有趣的是，在对包合物的评价中，我们发现这些纳米载体还可以输送其他类型的药物包括伊马替尼(Kang等人ADV Mater，2020)。这一结果表明，超小的纳米载体也可以将抗病毒药物输送到靶点，由于肾脏迅速清除未结合的分子而减少了副作用。因此，这个行政补充应用程序的最终目标是开发超小型与抗病毒药物复合治疗新冠肺炎的纳米疗法。通过有效加载选定的抗病毒药物进入超小型纳米载体，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脏清除，副作用减少。为了实现这一目标，我们建议 1)研制用于抗病毒药物传递的肾透明纳米载体；2)药效学评价以及纳米载体在冠状病毒感染小鼠模型中的治疗效果。配备了近乎- 红外荧光团连接在纳米载体上，我们还将监测生物分布和清除抗病毒药物及其在实时成像系统下的靶向性和治疗效果。