Microencapsulated Isoniazid-Loaded Metal–Organic Frameworks for Pulmonary Administration of Antituberculosis Drugs

Abstract

Tuberculosis (TB) is an infectious disease that causes a great number of deaths in the world (1.5 million people per year). This disease is currently treated by administering high doses of various oral anti-TB drugs for prolonged periods (up to 2 years). While this regimen is normally effective when taken as prescribed, many people with TB experience difficulties in complying with their medication schedule. Furthermore, the oral administration of standard anti-TB drugs causes severe side effects and widespread resistances. Recently, we proposed an original platform for pulmonary TB treatment consisting of mannitol microspheres (Ma MS) containing iron (III) trimesate metal–organic framework (MOF) MIL-100 nanoparticles (NPs). In the present work, we loaded this system with the first-line anti-TB drug isoniazid (INH) and evaluated both the viability and safety of the drug vehicle components, as well as the cell internalization of the formulation in alveolar A549 cells. Results show that INH-loaded MOF (INH@MIL-100) NPs were efficiently microencapsulated in Ma MS, which displayed suitable aerodynamic characteristics for pulmonary administration and non-toxicity. MIL-100 and INH@MIL-100 NPs were efficiently internalized by A549 cells, mainly localized in the cytoplasm. In conclusion, the proposed micro-nanosystem is a good candidate for the pulmonary administration of anti-TB drugs.

Unraveling the pulmonary drug delivery carriers in inhalable nanostructures

“…A common research trend for both safety and drug delivery aspects was that more categories of nanomaterials were introduced to the list of inhalable nanosystems, e.g., MWCNT (Migliaccio et al 2021) and metal-organic frameworks (MOF) (Fernández-Paz et al 2021), whose toxicities and therapeutic efficacies were evaluated.…”

Advanced drug delivery and therapeutic strategies for tuberculosis treatment

“…INH-administered mannitol microspheres containing iron(III) trimesate metal organic framework (MOF) MIL-100 nanoparticles demonstrated adequate encapsulation efficiency and aerodynamics for pulmonary delivery. In vitro testing in human alveolar adenocarcinoma basal epithelial cells revealed effective internalization, indicating that it is suited for deep lung ATD administration [80]. Fucoidan microparticles loaded with ATDs demonstrated good affinity, aerodynamic features, and no cytotoxicity to lung epithelial cells or THP-1 macrophages [186].…”

“…Niosomes loaded with hydrophilic D-cycloserine and lipophilic ethionamide kill drug-resistant TB by releasing 96% of ethionamide and 97% of D-cycloserine [130]. Antimycobacterial drugs Niosome Due to the targetability of the drug a low dose of the drug can provide efficient treatment of TB [75] Optimum level of drug entrapment efficiency, reducing the dose, dosing frequency, and toxicity in J744A.1 mouse macrophages [76] Aluminum nitride-and aluminum phosphide-doped graphene quantum dots Less toxic and more hydrophobic [77] Chitosan nanotube Prolonged the release time of the drug, providing a uniform release rate [78] Multiwall carbon nanotubes Increased lethality against M. tuberculosis [79] Mannitol microsphere containing iron (III) trimesate metal-organic framework MIL-100 nanoparticles ↑ Encapsulation efficiency and aerodynamics; efficient internalization in cytoplasm, making it suitable for deep lung delivery [80] Hydrogel-forming microneedle arrays ↑ Permeation aiding transdermal delivery with lyophilized reservoir [81] Calcium ion-Sodium Alginate-Piperine-based microspheres ↑ Entrapment efficiency; prolonged release and oral bioavailability [82] Rifampicin Niosome By controlling the niosome size, major portion of the drug can be concentrated in the lung region [83] Effective compartmentalization of the drug can be achieved in the lymphatic system [84] Mannosylated dendrimer ↓ Drug release rate in pH 7.4; ↑ Drug release in pH 5.0 and alveolar macrophage uptake; biocompatibility; site-specific delivery [85] Microsphere Preferential accumulation of drug in lungs; delivery can be done through respiratory tract [86] Liposome Drug release in a controlled manner for a longer period of time [87] G4-PAMAM dendrimer Higher stability and pH depended release of the drug [88] Liquid-crystalline folate nanoparticle Sustained release; ↓ Cytotoxicity [89] G1-G3 PAMAM dendritic microsphere PAMAM G3 dendritic microsphere was identified as the suitable drug carrier for the pulmonary delivery [90] Liquid crystalline nanoparticles ↓ Minimum inhibitory concentration (MIC) against S.aureus due to enhanced solubility and strong membrane fusion of drug [91] Mono-oleate based liquid crystals Sustained release and 93% loading frequency [92] Alginate-cellulose nanocrystal hybrid nanoparticles ↑ Drug encapsulation and sustained release action [93] Inulin functionalized with vitamin E (INVITE) micelle ↑ Mucoadhesion properties to the mucin and comparable antimicrobial property against grampositive bacteria [94] Cross-linked poly-β-cyc...…”

Nanosized Drug Delivery Systems to Fight Tuberculosis

“…The introduction of inhalable formulations would represent unprecedented progress for the treatment of TB. Therefore, it is not surprising that all first-line antitubercular drugs have been studied for pulmonary administration: INH [ 94 , 95 , 96 ], RFP [ 97 , 98 , 99 ], PZA [ 100 , 101 ], and EMB [ 102 ]. Several routes can be used for drug pulmonary administration [ 103 ].…”