Combination Therapy Using Bilosome–Chitosan Nanocarriers for Effective Drug Delivery of Daclatasvir and Xanthone in COVID-19 and Acute Respiratory Distress Syndrome: A Preclinical Assessment

Abstract

Purpose: COVID-19 pandemic has driven the urgent need for effective antiviral treatments and strategies to combat its life-threatening complications. This study aims to develop a combination therapy approach using daclatasvir, as an antiviral agent, and xanthone, as a potent anti-inflammatory and antithrombotic compound, delivered via Bilosome-Chitosan Nanoparticles (BCNP).

Methods: The impact of varying the bilosome-to-chitosan ratio on the particle size (PS), zeta potential (ZP), and encapsulation efficiency (EE%) was evaluated. An optimized formula was prepared and tested for its antiviral activity and its potential for pulmonary protection in acute respiratory distress syndrome (ARDS) on mice model.

Results: The optimized formulation (O1) showed a PS of 222.67 nm, a polydispersity index of 0.368, a ZP of -19.10 mV, and EE% of 83.78% for xanthone and 78.98% for daclatasvir. Controlled release profiles were attained, with daclatasvir released over 24 h and xanthone sustained for up to 72 h. The optimized formula showed promising deposition lung profile when tested using MPPD modelling. O1 demonstrated strong antiviral activity against SARS-CoV-2, with a selectivity index (SI = 5.02) and an IC50 of 3.87 µM. Additionally, the formulation exhibited pulmonary protective effects by modulating the LncGAS5/ACE2 pathway, with significant improvements in the lungs of the mice model, offering a potential therapeutic strategy against ARDS, a severe and often fatal COVID-19 complication.

Conclusion: A successful BCNP formulation combining daclatasvir and xanthone was prepared, providing a promising combination therapy approach for COVID-19 treatment and ARDS prevention.