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（限制在 30 行以内） COVID-19 于 2019 年 12 月出现，然后在 214 个国家/地区迅速传播。截至2020年5月15日，全球累计报告确诊病例超过450万例，死亡病例超过30万例对我们社会的重大健康和经济威胁。目前，一系列药物已获批用于其他适应症除了多种研究药物外，还对治疗 COVID-19 进行了研究。抗病毒药包括瑞德西韦、法匹拉韦、氯喹和羟氯喹已在这些临床中快速进行测试研究并证明了对 COVID-19 的初步功效。然而，这些研究也表明，接受瑞德西韦治疗的患者中有比例出现显着不良反应，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，使用氯喹和 COVID-19 患者使用羟氯喹引起了严重的安全问题，包括心律失常、心肌病和视网膜病。这些不良反应与其药物在体内的广泛分布有关。给药后全身，造成非目标重要器官的损害。因此，组织特异性递送抗病毒疗法将减轻副作用，同时保持其治疗 COVID-19 的功效。我们的假设是，肾脏可清除的超小型纳米载体可以选择性地负载抗病毒药物并递送他们治疗 COVID-19 并减少副作用。在我们的父 R01 (NIBIB #R01EB022230) 中，我们有开发了用于胰腺靶向、成像和图像引导手术的超小型纳米载体神经内分泌肿瘤。重要的是，超过 80% 的未结合剂量最终被排入尿液注射后 24 小时内、体循环后。这缩小了纳米载体的设计范围，包括靶向锚、成像部分和分布域，我们一直在努力创建一个互惠的每种化学成分为其他化学成分提供平衡特性的排列。有趣的是，在包合络合评估过程中，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 等人 Adv Mater，2020）。这一结果表明超小型纳米载体也可以由于未结合分子的快速肾脏清除，将抗病毒药物递送至靶点并减少副作用。因此，本次行政补充申请的最终目标是发展超小型与抗病毒药物复合治疗 COVID-19 的纳米疗法。通过装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至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) 开发用于抗病毒药物输送的肾脏可清除纳米载体；2) 评估药效学以及纳米载体在冠状病毒感染小鼠模型中的治疗效果。武装着近乎结合在纳米载体上的红外荧光团，我们还将监测其生物分布和清除实时成像系统下的抗病毒药物及其靶向性和治疗效果。

项目成果

期刊论文数量（40）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Real-Time Imaging of Brain Tumor for Image-Guided Surgery.

DOI：
10.1002/adhm.201800066
发表时间：
2018-08
期刊：
Advanced healthcare materials
影响因子：
10
作者：
Hu S;Kang H;Baek Y;El Fakhri G;Kuang A;Choi HS
通讯作者：
Choi HS

Cyanine Dyes Containing Quinoline Moieties: History, Synthesis, Optical Properties, and Applications.

DOI：
10.1002/chem.202003697
发表时间：
2021-03-01
期刊：
CHEMISTRY-A EUROPEAN JOURNAL
影响因子：
4.3
作者：
Ilina, Kristina;Henary, Maged
通讯作者：
Henary, Maged

Multivalent Mannose-Decorated NIR Nanoprobes for Targeting Pan Lymph Nodes.

DOI：
10.1016/j.cej.2018.01.008
发表时间：
2018-05-15
期刊：
Chemical engineering journal (Lausanne, Switzerland : 1996)
影响因子：
0
作者：
Wada H;Hyun H;Bao K;Lee JH;El Fakhri G;Choi Y;Choi HS
通讯作者：
Choi HS

Topical pH Sensing NIR Fluorophores for Intraoperative Imaging and Surgery of Disseminated Ovarian Cancer.

DOI：
10.1002/advs.202201416
发表时间：
2022-07
期刊：
ADVANCED SCIENCE
影响因子：
15.1
作者：
Yokomizo, Shinya;Henary, Maged;Buabeng, Emmanuel R.;Fukuda, Takeshi;Monaco, Hailey;Baek, Yoonji;Manganiello, Sophia;Wang, Haoran;Kubota, Jo;Ulumben, Amy Daniel;Lv, Xiangmin;Wang, Cheng;Inoue, Kazumasa;Fukushi, Masahiro;Kang, Homan;Bao, Kai;Kashiwagi, Satoshi;Choi, Hak Soo
通讯作者：
Choi, Hak Soo

Unconventional Secondary Structure Mimics: Ladder-Rungs.