Recent advances in PLGA micro/nanoparticle delivery systems as novel therapeutic approach for drug-resistant tuberculosis

Abstract

Tuberculosis is a severe infectious disease caused by Mycobacterium tuberculosis and is a significant public health concern globally. The World Health Organization (WHO) recommends a combination regimen of several drugs, such as rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (ETB), to treat tuberculosis. However, these drugs have low plasma concentrations after oral administration and require multiple high doses, which may lead to the occurrence and development of drug-resistant tuberculosis. Micro/Nanotechnology drug delivery systems have considerable potential in treating drug-resistant tuberculosis, allowing the sustained release of the drug and delivery of the drug to a specific target. These system properties could improve drug bioavailability, reduce the dose and frequency of administration, and solve the problem of non-adherence to the prescribed therapy. This study systematically reviewed the recent advances in PLGA micro/nanoparticle delivery systems as a novel therapeutic approach for drug-resistant tuberculosis.

Keywords: Mycobacterium tuberculosis; PLGA microparticles; PLGA nanoparticles; combination therapy; drug-resistant tuberculosis; inhalable therapy.

FIGURE 1

Estimated tuberculosis incidence rates, 2020 (excerpted from Global Tuberculosis Report, 2021; World Health Organization, Geneva).

FIGURE 2

Percentages of patients with multidrug-resistant tuberculosis globally. Reproduced with permission from Lange et al. (2019). Copyright © 2019 Elsevier Ltd.

FIGURE 3

PLGA-lipid hybrid nanocarriers. Reproduced with permission from Ghitman et al. (2020). Copyright © 2020 the Authors.

FIGURE 4

Schematic presentation of (A) alginate entrapped PLGA nanoparticles and (B) alginate coated PLGA nanoparticles. Reproduced with permission from Abdelghany et al. (2019). Copyright © 2019 Elsevier B. V.

FIGURE 5

PLGA-PEG nanoparticles loaded with CFZ and functionalized with a transferrin receptor-binding peptide for brain drug delivery. Reproduced with permission from de Castro et al. (2021) Copyright © 2021 Elsevier B. V.

FIGURE 6

Confocal images of phagocytosis obtained at 3 h (A), 5 h (B), and 24 h (C). MPF-1, fluorescein-loaded PLGA 502 MPs; MPF-2, fluorescein-loaded PLGA 502H MPs; MPF-L1, labrafil-modified fluorescein-loaded PLGA 502 MPs; MPF-L2, labrafil-modified fluorescein-loaded PLGA 502H MPs. Reproduced with permission from Marcianes et al. (2020). Copyright © 2022 Springer Nature Switzerland AG.

FIGURE 7

PLGA MPs trigger autophagic flux in Mtb-infected macrophages. (A) After a total of 24 h, infected macrophages were fixed and stained with anti-LAMP1_and anti-Mtb antibodies, and then observed by laser scanning confocal microscopy. The proportion of (B) LC3 positive Mtb phagosomes and (C) LC3 positive phagosomes which were also positive for LAMP1 were counted. Data represent the mean ± SEM of three independent experiments in which more than 100 phagosomes were counted for each condition. *p < 0.05. The white arrows indicate localization of Mtb phagosomes with GFP-LC3, blue arrows indicate co-localization of Mtb, GFP-LC3, and LAMP1. The results shown are the means of three independent experiments. Reproduced with permission from Lawlor et al. (2016). Copyright © 2016 the authors.

FIGURE 8

In vitro and in vivo efficacy of the inhalable PLGA microparticles loaded with trans-Retinoic acid (ATRA). Reproduced with permission from O’Connor et al. (2019). Copyright © 2018 Elsevier B. V.

FIGURE 9

(I) Morphological and histopathological changes in the lungs of mice post Mtb infection and treatment. Representative images showing gross anatomic morphology of whole lungs of Balb/c mice infected with virulent Mtb (H37Rv) and treated with various formulations (A–I,K–M) (scale bar: 10 mm). Yellow arrowheads indicate grey-white coloured tubercular nodules (lesion). Histological sections of (H,E) stained lungs of normal, infected and treated mice (a–h,j–m,l). Scale bar: 100 μm. Gross pathology photomicrograph showed granulomas (blue arrowheads) in the lungs (n = 6 animals/group). Graph show quantitative results of macroscopically detectable tubercular nodules per lung. (II) CFU counting in lungs from mice infected with Mtb. Tissue homogenates of each individual mouse were cultured in agar plates and CFU were counted and averaged. Reproduced with permission from Sharma et al. (2020). Copyright © 2020 Elsevier B. V.

FIGURE 10

BM2-LVFX-NPs for sonodynamic antimicrobial chemotherapy for BCG infection. Reproduced with permission from Li et al. (2021). Copyright © 2021 the authors.

FIGURE 11

Targeting ability of BM2-modified nanoparticles in vivo. (A) Fluorescence images of a BCG-infected rat at 3, 9, 24, 48, and 72 h post injection of DiR-labelled nanoparticles. (B) Quantitative fluorescence intensity (n = 3) of abscess tissue at different time points. (C) Biodistribution of DiR-labeled nanoparticles in major organs extracted from rats at 72 h post injection. (D) Quantitative analysis of fluorescence intensity (n = 3) in major organs. (E) CLSM images of Frozen section of abscess tissues at 24 h post-injection of DiR-loaded nanoparticles. The scale bar is 50 μm. Reproduced with permission from Li et al. (2021). Copyright © 2021 the authors.

FIGURE 12

In vivo SACT efficacy of BM2-LVFX-NPs combined with ultrasound. (A) The time-dependent abscess volume curves of infected rats in each group. (B) Colony counting analysis (Log10 CFU) of bacterial cultures from the abscess tissue in the rats after a 14-day treatment. **p < 0.01, ***p < 0.001. (C) Serum IFN-γ level of BCG-infected rats on Day 14 after treatment. (D) Histopathologic observation of the infected tissues of every group after being treated in various ways. The scale bar is 50 μm. Reproduced with permission from Li et al. (2021). Copyright © 2021 the authors.