Inhaled penindolone-loaded nanoparticles outperform oseltamivir for suppression of influenza A virus infection

Influenza A viruses (IAVs) necessitate urgently development of novel treatment approaches due to their high variability and widespread drug resistance. Penindolone (PND), distinct from anti-IAVs drugs on the market, is a promising IAVs inhibitor specifically targeting both HA1 and HA2 subunits of virus hemagglutinin. However, its clinical utility is hindered by poor water solubility and inadequate oral bioavailability. This study was for the first time to propose a practical and potent delivery approach for PND against IAVs. Inhalable PND-loaded nanoparticles (PND-NPs) were obtained through hydrophobic interactions of PND and monomethoxy poly(ethylene glycol)-poly(D, l-lactide) copolymer, realizing efficient loading of PND. The in vitro experiments demonstrated that PND-NPs exhibited lower cytotoxicity and more potent antiviral activity against IAVs than free PND (IC50 2.5 μM vs. 42.9 μM for A/Virginia/ATCC1/2009 and 11 μM vs. 73 μM for A/Puerto Rico/8/3 (PR/8)), thus expanding the therapeutic window. In the PR/8 infected mice model, the local delivery of PND-NPs via aerosolized inhalation demonstrated that PND-NPs, superior to the effects of the clinical drug oseltamivir, effectively reduced viral load and pro-inflammatory cytokines in the lungs, and significantly prolonged the survival time of mice (twice as long as the oseltamivir treatment group). Overall, non-invasive inhalation therapy with PND-NPs holds significant promise for clinical application in the antiviral domain.