Dual targeting drug delivery strategy for precise medicine:Simultaneous nasal and lung delivery of metallodrug against SARS-CoV 2

Abstract

<p>In response to the COVID-19 pandemic threats caused by an emerging respiratory viral infection, a safe and efficient broad-spectrum antiviral therapy at the early onset of infection can significantly lead to a better therapeutic outcome (1). Novel aerosol drug delivery strategies are developed to target the entire respiratory tract as highly contagious viruses infect both the upper and lower respiratory tract. Ranitidine bismuth citrate (RBC) and related bismuth drugs, with broad-spectrum coronavirus activity (2), were reformulated as dual particle size powder formulations that target both the nasal cavity and deep lung by a single route of intranasal administration. Spray freeze drying (SFD) using appropriate atomizing nozzles produces distinctly large (>10 μm) and small (<5 μm) particles for nasal and lung deposition, respectively. By blending two formulations, a single powder formulation with bimodal size distribution and dual aerosol deposition characteristic was produced. The aerosol deposition profile could potentially be manipulated by varying the powder mixing ratio. Compared to unformulated RBC that was administered orally, intratracheal or intranasal administration of 400 times lower dose of RBC SFD powder to mice resulted in significantly higher drug accumulation in the lung. More importantly, this novel formulation reduced viral loads in the nasal turbinate and lung in the SARS-CoV-2 infected Syrian Hamster model. Overall, a dual targeting powder formulation of metallodrug RBC was developed with customizable nasal and lung deposition profile. This strategy may potentially be applied to precise metallodrug delivery and fight against future virus-related respiratory diseases.</p>