RESUMO
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.
Assuntos
Antituberculosos/farmacologia , Diarilquinolinas/química , Compostos Férricos/química , Imidazóis/química , Pulmão/efeitos dos fármacos , Nanopartículas de Magnetita/química , Piperidinas/química , Piridinas/química , Tuberculose/tratamento farmacológico , Células A549 , Administração por Inalação , Antituberculosos/metabolismo , Disponibilidade Biológica , Linhagem Celular Tumoral , Diarilquinolinas/metabolismo , Diarilquinolinas/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Inaladores de Pó Seco/métodos , Humanos , Pulmão/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/metabolismoRESUMO
BACKGROUND: It has been hypothesized that by coupling magnetic particles to inhaled therapeutics, the ability to target specific lung regions (eg, only acinar deposition), or even more so specific points in the lung (eg, tumor targeting), can be substantially improved. Although this method has been proven feasible in seminal in vivo studies, there is still a wide gap in our basic understanding of the transport phenomena of magnetic particles in the pulmonary acinar regions of the lungs, including particle dynamics and deposition characteristics. METHODS: Here, we present computational fluid dynamics-discrete element method simulations of magnetically loaded microdroplet carriers in an anatomically inspired, space-filling, multi-generation acinar airway tree. Breathing motion is modeled by kinematic sinusoidal displacements of the acinar walls, during which droplets are inhaled and exhaled. Particle dynamics are governed by viscous drag, gravity, and Brownian motion as well as the external magnetic force. In particular, we examined the roles of droplet diameter and volume fraction of magnetic material within the droplets under two different breathing maneuvers. RESULTS AND DISCUSSION: Our results indicate that by using magnetic-loaded droplets, 100% of the particles that enter are deposited in the acinar region. This is consistent across all particle sizes investigated (ie, 0.5-3.0 µm). This is best achieved through a deep inhalation maneuver combined with a breath-hold. Particles are found to penetrate deep into the acinus and disperse well, while the required amount of magnetic material is maintained low (<2.5%). Although particles in the size range of ~90-500 nm typically show the lowest deposition fractions, our results suggest that this feature could be leveraged to augment targeted delivery.