Inhalable poly (lactic-co-glycolic acid) (PLGA) microparticles encapsulating all-trans-Retinoic acid (ATRA) as a host-directed, adjunctive treatment for Mycobacterium tuberculosis (Mtb) infection.
Gemma O’Connor
Nitya Krishnan
Aidan Fagan Murphy
Joseph Cassidy
Seonadh O’Leary
Brian D Robertson
Joseph Keane
Mary P. O’Sullivan
Sally-Ann Cryan
10779/rcsi.12018966.v1
https://repository.rcsi.com/articles/journal_contribution/Inhalable_poly_lactic-co-glycolic_acid_PLGA_microparticles_encapsulating_all-trans-Retinoic_acid_ATRA_as_a_host-directed_adjunctive_treatment_for_Mycobacterium_tuberculosis_Mtb_infection_/12018966
Ending the tuberculosis (TB) epidemic by 2030 was recently listed in the
United Nations (UN) Sustainable Development Goals alongside HIV/AIDS
and malaria as it continues to be a major cause of death worldwide. With
a significant proportion of TB cases caused by resistant strains of
Mycobacterium tuberculosis (Mtb), there is an urgent need to develop new
and innovative approaches to treatment. Since 1989, researchers have
been assessing the anti-bacterial effects of the active metabolite of
vitamin A, all trans-Retinoic acid (ATRA) solution, in Mtb models. More
recently the antibacterial effect of ATRA has been shown to regulate the
immune response to infection via critical gene expression, monocyte
activation and the induction of autophagy leading to its application as a
host-directed therapy (HDT). Inhalation is an attractive route for
targeted treatment of TB, and therefore we have developed ATRA-loaded
microparticles (ATRA-MP) within the inhalable size range (2.07 ± 0.5 µm)
offering targeted delivery of the encapsulated cargo (70.5 ± 2.3%) to
the site of action within the alveolar macrophage, which was confirmed
by confocal microscopy. Efficient cellular delivery of ATRA was followed
by a reduction in Mtb growth (H37Ra) in THP-1 derived macrophages
evaluated by both the BACT/ALERT® system and enumeration of colony
forming units (CFU). The antibacterial effect of ATRA-MP treatment was
further assessed in BALB/c mice infected with the virulent strain of Mtb
(H37Rv). ATRA-MP treatments significantly decreased the bacterial
burden in the lungs alongside a reduction in pulmonary pathology
following just three doses administered intratracheally. The
immunomodulatory effects of targeted ATRA treatment in the lungs
indicate a distinct yet effective mechanism of action amongst the
formulations. This is the first study to-date of a controlled release
ATRA treatment for TB suitable for inhalation that offers improved
targeting of a HDT, retains antibacterial efficacy and improves
pulmonary pathology compared to ATRA solution.
2020-03-24 16:19:38
All-trans retinoic acid
intratracheal (IT)
microparticles
mouse model
THP-1 Cells
tuberculosis
Pharmaceutical Sciences