Targeted liposomal nafamostat mesylate for the treatment of COVID-19

The coronavirus disease 2019 (COVID-19), induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly throughout the world, leading to massive morbidity and mortality. At present, there is no effective curative post-exposure treatment for COVID-19, with vaccination providing only a preventative measure. The high potency of nafamostat mesylate (NM) against SARS-CoV-2, demonstrated in vitro¹, highlights its potential as a drug candidate for COVID-19 drug therapy. Nonetheless, NM poor stability and short half-life in the circulation pose a significant limitation to its clinical usage. Encapsulating NM in targeted nanoparticles could confer improved circulation stability and effective accumulation in the lungs.

We aimed to develop a lung-targeted delivery system for NM. The delivery system is based on PEGylated liposomes conjugated to a targeting moiety- a peptide derived from apolipoprotein B100, identified as possessing high affinity to heparan sulfate. Heparan sulfate has a crucial role in mediating the SARS-CoV-2 entry into the lung epithelium, and is involved in the strong inflammatory response associated with SARS-CoV-2 infection.

We formulated and characterized targeted liposomal formulations encapsulating NM using the standard thin-film hydration method. The obtained liposomes possessed desired physicochemical properties, including size in the nanometer range, neutral surface charge, low polydispersity index, and relatively high drug loading. The liposomal formulations exhibited good stability in retaining their physicochemical properties with no leakage of the drug, and protecting it from degradation. In vitro cell assays demonstrated efficient engulfment by different cells RAW264.7 >> SMC> Caco-2. It was also found that the formulations are non-toxic at a wide range of concentrations and are suitable for further testing of their efficacy against the virus. Preliminary results in the Fraunhofer Society (FhG) demonstrated the formulations effective inhibition of SARS-CoV-2 infection in lung cells. Ongoing research is evaluating the biodistribution and activity of the formulations in vivo.

References:

1. Ellinger, Bernhard, et al. "Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection." (2020).‏