ATRA-Loaded Nanoparticles as Inhalable Host-Directed Immunotherapy for Tuberculosis
Ahmad Z. Bahlool1,2,3, Sarinj Fattah1,2,4, Andrew O’Sullivan1,5, Brenton Cavanagh6, Ronan MacLoughlin1,5,7, Joseph Keane3, Mary P O’Sullivan3, Sally-Ann Cryan1,2,4,8
1 School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, D02 YN77, Dublin, Ireland
2 Tissue Engineering Research Group, Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin, Ireland
3 Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland
4 SFI Centre for Research in Medical Devices (CÚRAM), NUIG & RCSI, Dublin, Ireland
5 Research and Development, Science and Emerging Technologies, Aerogen Ltd, Galway Business Park, Dangan, Galway, Ireland
6 Cellular and Molecular Imaging Core, Royal College of Surgeons in Ireland RCSI, Dublin 2, Ireland
7 School of Pharmacy and Pharmaceutical Sciences, Trinity College, D02 PN40 Dublin, Ireland
8 SFI Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI and Trinity College Dublin, Dublin, Ireland.
Summary
Tuberculosis (TB) is the top bacterial infectious disease killer worldwide. The emergence of strains of multiple drug-resistant tuberculosis (MDR-TB) has pushed our available stock of anti-TB agents to the limit of effectiveness. An adjunctive, host-directed therapy (HDT) designed to act on the host, instead of the bacteria, could help address this issue. We successfully developed a host-directed formulation for TB, using All Trans Retinoic Acid (ATRA)-loaded PLGA nanoparticles. Confocal laser scanning microscopy (CLSM) showed efficient cellular delivery of ATRA-loaded NPs into macrophages. Efficacy studies conducted in THP-1 derived macrophages infected with the avirulent Mtb strain (H37Ra) have demonstrated a dose dependent reduction in mycobacterial growth as determined by the BACT/ALERT® liquid culture system. The formulation was integrated with a vibrating mesh nebulizer. Aerosol droplet size was characterized using laser diffraction and cascade impaction. The aerosol had a volumetric median diameter (VMD) of 4.09 μm and mass median aerodynamic diameter (MMAD) of 2.13 μm. 65.1% of the dose was inhaled in an adult breathing simulation which was generated using a breathing stimulator. A scalable nanomanufacturing approach was optimized using microfluidics mixing.
Key Message
This type of targeted inhaled HDT offers an innovative approach for TB treatment with the potential to enhance current therapeutic regimens thereby providing better prognosis for patients, and reducing the incidence rate of multi drug resistance tuberculosis (MDR-TB).