Development of Inhalable ATRA-Loaded PLGA Nanoparticles as Host-Directed Immunotherapy against Tuberculosis
Ahmad Z. Bahlool,
Sarinj Fattah,
Andrew O’Sullivan,
Brenton Cavanagh,
Ronan MacLoughlin,
Joseph Keane,
Mary P. O’Sullivan,
Sally-Ann Cryan
Affiliations
Ahmad Z. Bahlool
School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
Sarinj Fattah
School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
Andrew O’Sullivan
School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
Brenton Cavanagh
Cellular and Molecular Imaging Core, Royal College of Surgeons in Ireland RCSI, D02 YN77 Dublin, Ireland
Ronan MacLoughlin
School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
Joseph Keane
Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College Dublin, The University of Dublin, D08 9WRT Dublin, Ireland
Mary P. O’Sullivan
Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College Dublin, The University of Dublin, D08 9WRT Dublin, Ireland
Sally-Ann Cryan
School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
Developing new effective treatment strategies to overcome the rise in multi-drug resistant tuberculosis cases (MDR-TB) represents a global challenge. A host-directed therapy (HDT), acting on the host immune response rather than Mtb directly, could address these resistance issues. We developed an HDT for targeted TB treatment, using All Trans Retinoic Acid (ATRA)-loaded nanoparticles (NPs) that are suitable for nebulization. Efficacy studies conducted on THP-1 differentiated cells infected with the H37Ra avirulent Mycobacterium tuberculosis (Mtb) strain, have shown a dose-dependent reduction in H37Ra growth as determined by the BACT/ALERT® system. Confocal microscopy images showed efficient and extensive cellular delivery of ATRA-PLGA NPs into THP-1-derived macrophages. A commercially available vibrating mesh nebulizer was used to generate nanoparticle-loaded droplets with a mass median aerodynamic diameter of 2.13 μm as measured by cascade impaction, and a volumetric median diameter of 4.09 μm as measured by laser diffraction. In an adult breathing simulation experiment, 65.1% of the ATRA PLGA-NP dose was inhaled. This targeted inhaled HDT could offer a new adjunctive TB treatment option that could enhance current dosage regimens leading to better patient prognosis and a decreasing incidence of MDR-TB.
