Image-Guided Drug Delivery for Pancreatic Neuroendocrine Tumor

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, posingsignificant health and economic threats to our society. Currently, an array of drugs approved for other indicationshave been studied, in addition to multiple investigational agents, for the treatment of COVID-19. Antiviralsincluding remdesivir, favipiravir, chloroquine, and hydroxychloroquine have been rapidly tested in these clinicalstudies and demonstrated preliminary efficacy against COVID-19. However, these studies also revealed that aproportion of patients receiving remdesivir had significant adverse effects, including multiple-organ dysfunctionsyndrome, septic shock, and acute liver and kidney injury. Similarly, the use of chloroquine andhydroxychloroquine 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 thewhole body after administration, causing damages in off-target vital organs. Therefore, tissue-specific deliveryof 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 deliverthem to treat COVID-19 with reduced side effects. In our parent R01 (NIBIB #R01EB022230), we havedeveloped ultrasmall nanocarriers for targeting, imaging, and image-guided surgery of pancreaticneuroendocrine tumors. Importantly, over 80% of the unbound dose was ultimately eliminated into the urinewithin 24 h post-injection after systemic circulation. This narrows the design of nanocarriers to include a targetinganchor, an imaging moiety, and a distribution domain, and we have worked diligently to create a reciprocalarrangement 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 drugsincluding imatinib (Kang et al. Adv Mater, 2020). This result suggests that ultrasmall nanocarriers can alsodeliver 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 ultrasmallnanotherapeutics that are complexed with antivirals to treat COVID-19. By payloading selected antiviral drugsinto the ultrasmall nanocarriers, we will be able to achieve image-guided drug delivery to the respiratory systemwith reduced side effects due to the rapid renal clearance of unbound drugs. To achieve this goal, we propose1) to develop renal clearable nanocarriers for antiviral drug delivery and 2) to evaluate the pharmacodynamicsand 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 ofantivirals as well as their targetability and therapeutic efficacy under the real-time imaging system.