Nanotechnological formulation for pulmonary administration of drugs for the control of SARS-CoV-2

Abstract

The outbreak of the new Coronavirus disease, COVID-19, currently represents a threat to global public health. As part of a network project that seeks to use artificial intelligence and other strategies to quickly identify approved drugs to be repositioned for the treatment of COVID-19, our group is responsible for the development of the medicine for the administration of the most promising drugs identified. The objective of this project is to develop nanostructured lipid carriers (CLNs) as a platform for the pulmonary administration of drugs with potential anti-SARS-CoV-2 action, the virus that causes COVID-19. Based on the hypothesis that zwitterionic nanoparticles have surface properties similar to that of the virus, CLNs with different coatings will be developed in order to promote their mucopenetration and cell internalization, enabling the release of drugs in different portions of the respiratory tract. It is also believed that the CLNs can interact with the virus, inactivating it by disorganizing its protein layer or by detergent action derived from the composition of the nanoparticles. The administration of drugs directly to the respiratory tract is an attractive option for the treatment of COVID-19 because higher concentrations of drugs can reach the lungs, which represents the most devastated tissue after SARS-CoV-2 infection. In general, CLNs present good pulmonary deposition, low toxicity and high tolerability. However, the natural selectivity of mucus against the penetration of external agents imposes a critical obstacle to pulmonary administration of CLN. Thus, the CLNs stabilized with amphiphilic substances of distinctive hydrophilic-lipophilic balances will be coated with more hydrophilic substances, allowing the modulation of the zeta potential of the nanoparticles. The properties of nebulization, interaction with mucin and mucus penetration of these nanoparticles will then be evaluated. The CLNs with adequate nebulization and mucopenetration properties will be investigated for cellular internalization in pulmonary epithelium cells and for their potential of SARS-CoV-2 interaction/inactivation. The most promising CLNs will encapsulate or be functionalized with drugs of different mechanisms of action or therapeutic action against SARS-CoV-2. These substances will be selected from the network project to which this proposal is associated, which objective is the search for antivirals, as well as based on the current literature. In addition, iron oxide nanoparticles, which have antiviral properties, will also be incorporated into the CLNs aiming to target the CLN to the lungs using an external magnetic field. In vitro studies of cytotoxicity, cell internalization, co-localization and antiviral activity will be carried out; nanoparticle biodistribution studies after administration by nebulization and inhalation in a healthy animal model, under the influence or not of the magnetic field will be performed; and the treatment efficacy studies in an animal model infected with SARS-CoV-2 comparing pulmonary administration with intraperitoneal administration of CLNs will be conducted. (AU)