Image-Guided Drug Delivery for Pancreatic Neuroendocrine Tumor

图像引导胰腺神经内分泌肿瘤给药

• 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
• 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

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30行） COVID-19于2019年12月出现，然后迅速传播214个国家。截至2020年5月15日， 全世界据报道，总共有超过450万例确认的病例和30万以上死亡人数 对我们社会的重大健康和经济威胁。目前，一系列批准其他适应症的药物 除多种研究剂外，还研究了用于治疗COVID-19的研究。抗病毒药 包括Remdesivir，Favipiravir，氯喹和羟氯喹，已在这些临床中迅速进行了测试 研究并证明了对Covid-19的初步疗效。但是，这些研究还表明 接受Remdesivir的患者比例具有明显的不良反应，包括多器官功能障碍 综合征，败血性休克，急性肝和肾脏损伤。同样，使用氯喹和 COVID-19患者中的羟氯喹引起了严重的安全问题，包括心律不齐， 心肌病和视网膜病变。这些不良影响与它们在药物中的广泛分布有关 给药后的全身，造成脱靶重要器官的损害。因此，组织特异性递送 抗病毒治疗剂将减轻不良反应，同时保持其治疗COVID-19的功效。 我们的假设是，肾脏可净可清除纳米载体可以有效地有效地有效抗病毒药物并提供 他们以减少副作用来治疗COVID-19。在我们的父r01（nibib＃r01eb022230）中，我们有 开发了用于靶向，成像和图像引导的胰腺手术的超级纳米载体 神经内分泌肿瘤。重要的是，超过80％的未结合剂量最终被消除到尿液中 全身循环后24小时内注射后。这范围缩小了纳米载体的设计，以包括一个目标 锚点，成像部分和一个分配域，我们一直在努力创建倒数 每个化学成分为其他化学构成提供平衡特性。有趣的是， 在评估包容络合期间，我们发现纳米载体可以提供其他类型的药物 包括伊马替尼（Kang等人，Adv Mater，2020年）。这个结果表明，超级纳米载体也可以 由于未结合分子的快速清除，副作用降低了副作用。 因此，此行政补充应用程序的最终目标是开发超级 纳米疗法与抗病毒药复合以治疗covid-19。通过有效载荷选定的抗病毒药物 进入超级纳米载体，我们将能够实现图像引导的药物输送到呼吸系统 由于未结合药物的肾脏迅速清除，副作用降低。为了实现这一目标，我们提出 1）开发用于抗病毒药物的肾脏可透明纳米载体和2）评估药效学 纳米载体在冠状病毒感染的小鼠模型中的治疗功效。武装着近的 红外荧光团在纳米载体上结合，我们还将监视生物分布和清除率 在实时成像系统下，抗病毒药及其目标性和治疗功效。

项目成果

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)
• 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

Ovarian cancer-targeted near-infrared fluorophores for fluorescence-guided surgery.

• DOI: 10.21037/atm-22-6455
• 发表时间: 2023-03-31
• 期刊: ANNALS OF TRANSLATIONAL MEDICINE
• 作者: Kashiwagi, Satoshi;Choi, Hak Soo
• 通讯作者: Choi, Hak Soo