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

摘要 由严重急性呼吸系统综合征（SARS）引起的2019年冠状病毒病（COVID-19）爆发 冠状病毒2（SARS-CoV-2）已经导致具有显著发病率和死亡率的全球大流行。尽管 尽管有广泛的努力，但还远不能肯定有效的疫苗会很快问世。因此开发 对于这种毁灭性疾病的新疗法至关重要。然而，到目前为止，没有具体的治疗方法， 用于预防或治疗COVID-19。先前的研究表明，SARS-CoV-2感染 通过病毒刺突糖蛋白与细胞表面血管紧张素转换酶2相互作用 ACE 2是一种在肺泡上皮II型中发现的膜结合单羧肽酶， （AECII）细胞在肺中。ACE 2的一个重要功能是降解血管紧张素II，这限制了几种血管紧张素II的表达。 血管紧张素II与血管紧张素II 1型（AT1）受体结合导致的有害作用，包括 血管收缩、增强的炎症和血栓形成。SARS-CoV-2进入细胞的能力显著降低， 调节ACE 2。细胞膜外部部位ACE2的缺失导致肺动脉压升高， 炎症和凝血。纳米颗粒越来越多地被提议作为肺部药物递送载体。 纳米颗粒也可以作为治疗诊断策略的成像探针。我们的长期目标是发展一个 用于制造治疗肺部感染广泛治疗药物的有效和高效的方案 利用新兴的siRNA和分子成像技术治疗疾病。该项目的总体目标是 设计一种新的方法，将ACE2靶向纳米治疗药物引入肺AECII细胞， SARS-CoV-2与ACE2之间的相互作用这些纳米治疗药物还将携带靶向AT1的siRNA。 受体阻断炎症和血栓形成过程的进展，局部血管紧张素II 多动触发SARS-CoV-2感染。此外，纳米治疗剂将具有 超顺磁性纳米颗粒核，其可以提供一种使用超顺磁性纳米颗粒核非侵入性地评估药物递送的方法。 磁粒子成像（MPI）。MPI提供高灵敏度检测和深度独立定量， 纵向研究。这项工作的成果将包括一种新的图像引导的方法来提供纳米药物 到肺部。这是重要的，因为这些纳米药物将能够靶向表达ACE 2的细胞， 并阻止SARS-CoV-2进入细胞。这些纳米药物也会沉默表达的 AT1受体阻断炎症和血栓形成过程的进展，这些过程通常由 降低ACE 2。该项目还将展示MPI在肺部应用中的实用性，例如评估 气雾剂递送的效率和均匀性，以及在体内追踪雾化的纳米药物。

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.