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.
Highlights
TB continues to be one of the principal 10 causes of death worldwide [1,2], and is the second leading cause of death (1.5 million people in the world per year [3]) due to an infectious disease, behind SARS-CoV-2 (>1.9 million deaths in 2020 [4])
Organization (WHO) consists of a difficult daily oral multidrug regimen that is prolonged in time, in which the treatment during the first two months is with INH, rifampicin, ethambutol, and pyrazinamide, and the following four months with INH and rifampicin [7]
The drug content was estimated by combining high-performance liquid chromatography (HPLC) and thermogravimetric analysis (TGA; Figure 1b)
Summary
TB continues to be one of the principal 10 causes of death worldwide [1,2], and is the second leading cause of death (1.5 million people in the world per year [3]) due to an infectious disease, behind SARS-CoV-2 (>1.9 million deaths in 2020 [4]). Organization (WHO) consists of a difficult daily oral multidrug regimen that is prolonged in time (often lasts up to 2 years), in which the treatment during the first two months is with INH, rifampicin, ethambutol, and pyrazinamide (first-line anti-TB drugs), and the following four months with INH and rifampicin [7]. The treatment efficacy was estimated to be of 85% [8], there are several factors that can negatively affect the success rate, such as: (i) the inappropriate use of anti-TB drugs (e.g., employed medicines of deficient quality or bad storage); (ii) low stability and poor oral absorption of anti-TB drugs; (iii) important first-pass metabolism of anti-TB drugs, making difficult to reach the granulomas and penetrate into the bacteria; and (iv) a too-long treatment duration (often lasts up to 2 years) that is generally associated with important undesirable side effects (e.g., depression, psychosis, kidney impairment, or resistances [8]). A controlled and targeted release of anti-TB drugs should be able to overcome these drawbacks and achieve a more effective treatment of TB
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