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Principal Investigator: Hak Soo Choi
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2020
Award: $651,080
Funding agency: National Institute of Biomedical Imaging and Bioengineering
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.
Terms: <2019 novel coronavirus><2019-nCoV><Acute Renal Failure with Renal Papillary Necrosis><Administrative Supplement><Adverse effects><Affect><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Antiviral Agents><Antiviral Drugs><Antivirals><Arrhythmia><Assay><Bioassay><Biodistribution><Biologic Assays><Biological><Biological Assay><Blood Circulation><Blood Plasma><Blood Serum><Bloodstream><Body Tissues><COVID-19><COVID19><Caliber><Cancer Drug><Cardiac Arrhythmia><Cardiac Toxicity><Cardiomyopathies><Cardiotoxic><Cardiotoxicity><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Chemical Engineering><Chemicals><Chlorochin><Chloroquine><Circulation><Clinical Research><Clinical Study><Complex><Coronaviridae Infections><Coronavirus Infections><Country><DNA-Dependent RNA Polymerases><DNA-Directed RNA Polymerase><Death><Development><Diameter><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Targeting><Drugs><Emerging Communicable Diseases><Emerging Infectious Diseases><Equilibrium><Evaluation><Excretory function><Extinction><Extinction (Psychology)><Fluorescence><Foundations><GS-5734><Goals><Grant><Heart Arrhythmias><Histology><Hydroxychlorochin><Hydroxychloroquine><Hypotension><Image><Image-Guided Surgery><Imatinib><Injections><Injury to Kidney><Injury to Liver><Interdisciplinary Research><Interdisciplinary Study><Intracellular Communication and Signaling><Investigation><Island Cell Tumor><Islet Cell Neoplasm><Islet Cell Tumor><Khingamin><Kidney><Kidney Urinary System><Low Blood Pressure><Lung><Lung Respiratory System><MOF syndrome><Measures><Medication><Metabolic Glycosylation><Monitor><Multidisciplinary Collaboration><Multidisciplinary Research><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><NIBIB><NIR imaging><NIR optical imaging><Nano platform><Nano-technological platform><Nano-technology platform><Nanoplatform><Nanotechnological platform><National Institute of Biomedical Imaging and Bioengineering><Near-infrared Fluorescence Imaging><Near-infrared optical imaging><Neoplastic Disease Chemotherapeutic Agents><Organ><Oxychlorochin><Oxychloroquine><PanNets><Pancreatic Endocrine Neoplasm><Pancreatic Endocrine Tumor><Pancreatic Neuroendocrine Tumor><Parents><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Plaque Assay><Plasma><Plasma Serum><Property><Pulmonary Body System><Pulmonary Organ System><Pulmonary Pathology><RNA Polymerases><Receptor Protein><Renal clearance function><Reporting><Research><Respiratory System><Respiratory Tracts><Respiratory tract structure><Reticuloendothelial System, Serum, Plasma><Retinal Diseases><Retinal Disorder><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Safety><Septic Shock><Serum><Serum Proteins><Severe acute respiratory syndrome coronavirus 2><Signal Transduction><Signal Transduction Systems><Signaling><Social Support System><Societies><Support System><System><Testing><Therapeutic><Time><Tissues><Toxic effect><Toxicities><Treatment Efficacy><Tumor-Specific Treatment Agents><Urine><Urine Urinary System><Vascular Hypotensive Disorder><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virion><Virus><Virus Diseases><Virus Particle><Work><Wuhan coronavirus><acute kidney injury><acute liver injury><anti-cancer drug><anti-viral agents><anti-viral drugs><anti-viral efficacy><anti-virals><anticancer agent><anticancer drug><antiviral efficacy><balance><balance function><base><behavioral extinction><biological signal transduction><cardiac rhythm><corona virus disease 2019><coronavirus disease 2019><design><designing><developmental><drug distribution><drug/agent><excretion><fluorophore><glycosylation><health economics><heart rhythm><hepatic damage><hepatic injury><image guidance><image guided><image guided intervention><image-guided drug delivery><imaging><imaging system><improved><in vivo><intervention efficacy><intra-operative imaging><intraoperative imaging><kidney injury><liver damage><liver injury><lung pathology><mouse model><multiple organ system failure><murine model><myocardium disease><myocardium disorder><nano carrier><nano particle><nano therapeutic><nano-sized particle><nanocarrier><nanoparticle><nanosized particle><nanotechnology platform><nanotherapeutic><near infrared imaging><pancreatic NET><prevent><preventing><pulmonary><quantum><real-time images><realtime image><receptor><remdesivir><renal><renal clearance><renal injury><response><retina disease><retina disorder><retinopathy><side effect><site targeted delivery><small molecule><success><surgical imaging><targeted delivery><targeted drug therapy><targeted drug treatments><targeted imaging><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutically effective><therapy efficacy><tumor><uptake><viral RNA><viral infection><virus RNA><virus infection><virus-induced disease>