Dithiol-Functionalized Dendritic Polyglycerol: A Novel Reducing Agent for Mucolytic Therapy

Cystic fibrosis (CF) and other muco-obstructive lung diseases are characterized by elevated viscoelasticity of airway mucus caused by an increased density of disulfide crosslinks leading to impaired mucus functions. This study describes the synthesis of a dithiol-functionalized dendritic polyglycerol (dPG-DTBA) as novel polymeric reducing agent with mucolytic activity, which we investigate with sputum from patients with CF. We developed a polymer conjugate with multiple reducing functionalities by integrating dithiobutylamine (DTBA) into a reportedly biocompatible dendritic polyglycerol scaffold, which could be synthesized in gram scale. After a physicochemical compound characterization, we assessed the influence of dPG-conjugation of DTBA on cytotoxicity and thiol stability. Utilizing a mucus-mimetic hydrogel, we examined the impact of dPG-DTBA on viscoelastic properties via macrorheological measurements at two distinct treatment durations, demonstrating a superior reducing capacity of the polymer. Finally, we evaluate the mucolytic potential of dPG-DTBA in Western blot analyses of treated CF sputum samples in comparison to the clinically approved N-acetylcysteine (NAC). We show that dPG-DTBA reduces multimer intensity of the secreted mucins MUC5B and MUC5AC significantly more effectively than NAC with similar potency as unconjugated DTBA. Our findings provide a rationale for advancing the novel reducing polymer system dPG-DTBA as a candidate mucolytic agent to improve mucus viscoelastic properties and facilitate mucociliary clearance in patients with CF and potentially other muco-obstructive pulmonary disorders.