Designing inhaled protein therapeutics for topical lung delivery: what are the next steps?

Abstract

Drug delivery in the airways by inhalation can be used for local and/or systemic action, depending on the ability of the aerosolized drug to cross the air-blood barrier. For proteins, this is partly conditioned by the drug's molecular weight, as well as aerosol characteristics. This editorial focuses on protein inhalation for topical delivery purposes. Even though systemic applications (such as insulin inhalation) are not considered herein, it is worth noting that systemic diffusion following topical delivery may happen in some cases, and provide therapeutic benefit (as is the case for granulocyte-macrophage colony-stimulating factor (GM-CSF)).

Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID‐19

“…In respiratory medicine, treatments are often delivered as aerosolized protein therapeutics as diffusion of proteins from the blood to the lungs can be limited. 86 Interestingly, nebulized anticoagulant therapy with antithrombin or heparin has been shown to reduce lung injury without an increase in systemic bleeding in animal models [87][88][89] and ALI patients. 90 However, as discussed, heparin will prevent further fibrin deposition but will be ineffective in the removal of pre-existing fibrin.…”

Computational Design of ACE2-Based Peptide Inhibitors of SARS-CoV-2

“…The proposed small peptides could be used as inhaled therapeutics for topical lung delivery, providing an efficient way to combat COVID-19. 18…”

Developing inhaled protein therapeutics for lung diseases

“…deamidation and hydrolysis), temperature and pH changes, and aggregation (through agitation of the aqueous carrier) [ 21 ]. Furthermore, across all nebuliser types, the process of nebulisation exposes the protein to physical stresses such as shearing forces and heat, as well as the large air-liquid interface (ALI) that could alter protein conformation and/or structure through denaturation, chemical modifications (oxidation, deamidation), and aggregation [ 4 , 15 ]. Device-specific limitations such as the shear forces generated by jet nebulisers, and the temperature increases that occur in ultrasonic nebulisers, can also lead to protein degradation.…”

“…Notably, as macromolecules, proteins have a relatively poor ability to penetrate the epithelial layer to reach the deep parenchyma lung. However, depending on the molecular weight and aerosol characteristics, a portion of the proteins would be able to reach the abluminal side of the epithelium or the air-blood interface in the thin alveolar wall, triggering local or even systemic immune signalling that may provide beneficial therapeutic effect in some cases [ 15 ].…”

“…Removal of the stressor may be spontaneously reversible (for some single domain proteins), but is usually irreversible for most of the larger multi-domain proteins [ 67 ]. Surface-induced aggregation is one of the common mechanisms of non-covalent aggregation, and one example of when it occurs is during the process of nebulisation [ 15 , 67 ]. As most proteins are amphiphilic and surface active, they have a tendency towards adsorption at the ALI.…”