In vivo tracking of inhaled ACE2 targeting theranostic nanodrugs delivery to the lungs using magnetic particle imaging

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ABSTRACT The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic with significant morbidity and mortality. Despite widespread efforts, it's far from certain that an effective vaccine will be available soon. Therefore, developing new therapeutics for this devastating disease is critically important. However, to date, no specific treatments are recommended to prevent or treat COVID-19. Previous studies have demonstrated that SARS-CoV-2 infects host cells through its viral spike glycoprotein interacting with cell-surface angiotensin-converting enzyme 2 (ACE2), which is a membrane-bound monocarboxypeptidase found in pulmonary alveolar epithelial type II (AECII) cells in the lung. An important function of ACE2 is to degrade angiotensin II, which limits several detrimental effects that result from angiotensin II binding to Angiotensin II type 1 (AT1) receptors, including vasoconstriction, enhanced inflammation, and thrombosis. The entry of SARS-CoV-2 into cells markedly down- regulates ACE2. Loss of ACE2 at the external site of the cell membrane results in increased pulmonary inflammation and coagulation. Nanoparticles are increasingly being proposed as lung drug delivery vehicles. Nanoparticles can also serve as imaging probes for theranostic strategies. Our long-term goal is to develop an effective and efficient protocol for manufacturing a wide range of therapeutic drugs to treat pulmonary infectious diseases using emerging siRNA and molecular imaging technologies. The overall objective of this project is to design a novel approach for introducing ACE2 targeting nanotherapeutics into pulmonary AECII cells to prevent interactions between SARS-CoV-2 and ACE2. These nanotherapeutics will also carry siRNA targeting the AT1 receptor to block the progression of inflammatory and thrombotic processes that local angiotensin II hyperactivity triggers following SARS-CoV-2 infection. In addition, the nanotherapeutics will have a superparamagnetic nanoparticle core, which can provide a way to non-invasively assess drug delivery using magnetic particle imaging (MPI). MPI provides high sensitivity detection and depth-independent quantitation for longitudinal studies. The output of this work will include a novel image-guided method for delivering nanodrugs to the lungs. This is significant because these nanodrugs will be capable of targeting ACE2-expressing cells, and preventing SARS-CoV-2 from entering the cells. These nanodrugs will also silence the expression of the AT1 receptor to block the progression of inflammatory and thrombotic processes that are normally induced by decreases in ACE2. This project will also demonstrate the utility of MPI for lung applications, such as evaluating the efficiency and uniformity of aerosol delivery, and tracking the aerosolized nanodrugs in vivo.