Active pulmonary targeting against tuberculosis (TB) via triple-encapsulation of Q203, bedaquiline and superparamagnetic iron oxides (SPIOs) in nanoparticle aggregates

Abstract

Tuberculosis (TB) has gained attention over the past few decades by becoming one of the top ten leading causes of death worldwide. This infectious disease of the lungs is orally treated with a medicinal armamentarium. However, this route of administration passes through the body's first-pass metabolism which reduces the drugs' bioavailability and toxicates the liver and kidneys. Inhalation therapy represents an alternative to the oral route, but low deposition efficiencies of delivery devices such as nebulizers and dry powder inhalers render it challenging as a favorable therapy. It was hypothesized that by encapsulating two potent TB-agents, i.e. Q203 and bedaquiline, that inhibit the oxidative phosphorylation of the bacteria together with a magnetic targeting component, superparamagnetic iron oxides, into a poly (D, L-lactide-co-glycolide) (PDLG) carrier using a single emulsion technique, the treatment of TB can be a better therapeutic alternative. This simple fabrication method achieved a homogenous distribution of 500 nm particles with a magnetic saturation of 28 emu/g. Such particles were shown to be magnetically susceptible in an in-vitro assessment, viable against A549 epithelial cells, and were able to reduce two log bacteria counts of the Bacillus Calmette-Guerin (BCG) organism. Furthermore, through the use of an external magnet, our in-silico Computational Fluid Dynamics (CFD) simulations support the notion of yielding 100% deposition in the deep lungs. Our proposed inhalation therapy circumvents challenges related to oral and respiratory treatments and embodies a highly favorable new treatment regime.

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

“…Indeed, large quantities of inhaled drugs are commonly lost during inhalation and/or lead to superfluous deposition in undesired airways or lung lobes, thus undermining the greater potential of inhalation therapy [166,167]. Moreover, reducing lung toxicities and associated side effects is still challenging when considering for example inhaled chemotherapies [168][169][170]. Although important progress has been unfolding [72,86,171], delivering in vitro models with strong human in vivo correlation remains a major challenge in advancing therapeutic endpoints (Figure 2).…”

Nanosized Drug Delivery Systems to Fight Tuberculosis

“…The use of magnetic NPs is one of the new strategies for the treatment of TB. In 2019, Poh et al investigated the co-encapsulation of BDQ and Q203 along with supermagnetic iron oxide NPs into 500 nm PLGA NPs [ 145 ]. Q203 is a promising first-class candidate against Mtb which is currently under phase II clinical trials [ 163 ].…”

“…DC: drug carrier (empty NPs). Adapted from reference [ 145 ], used under Creative Commons BY 4.0 license.…”

Focused targeting of inhaled magnetic aerosols in reconstructed in vitro airway models

“…after reaching the target airway depth) is necessary in order to achieve localized targeting. To address this issue, we ran an experiment with no BH using a simple glass tube with a diameter corresponding to a representative average adult human trachea (16.5 mm), as motivated by recent in silico (Pourmehran et al, 2015) and in vitro studies (Poh et al, 2019). Even at the low flow rate implemented in our experiment (i.e.…”

“…lung lobe), using both dry powders and nebulized suspensions (Hasenpusch et al, 2012;Price et al, 2017;Redman et al, 2011;Xie et al, 2010a). From a toxicity standpoint, SPIONs have been in clinical use as imaging contrast agents for many years (Bellin, 2006;Saito et al, 2005) and can be combined with various therapeutics (Dames et al, 2007;Poh et al, 2019) (e.g. chemotherapy, antibiotics).…”