Nano-Rifabutin entrapment within glucan microparticles enhances protection against intracellular Mycobacterium tuberculosis

Abstract

Recently, yeast-derived glucan particles (GP) have emerged as novel drug delivery agents that provide for receptor-mediated uptake by phagocytic cells expressing β-glucan receptors. In our previous study, we prepared GP loaded with high payload (40.5 + 1.9%) of rifabutin (RB) nano-particles [(RB-NPs)-GP]. We investigated the anti-mycobacterial efficacy and cellular activation responses within Mycobacterium tuberculosis (M. tuberculosis) infected J774 macrophage cells following exposure to the (RB-NPs)-GP formulation. The exposure was seen to augment a robust innate immune response including the induction of reactive oxygen and nitrogen species, autophagy and apoptosis within M. tuberculosis infected macrophage. Further, the efficacy testing of these particles in murine macrophage exhibited that the (RB-NPs)-GP formulation enhanced the efficacy of RB drug by ∼2.5 fold. The study suggests that the set of innate responses conducive to killing intracellular bacteria evoked by (RB-NPs)-GP play a pivotal role in impeding the intracellular M. tuberculosis survival, resulting in enhanced efficacy of the formulation. Our results establish that the (RB-NPs)-GP formulation not only activate M. tuberculosis infected, immune-suppressed macrophage, but also adds significantly to the efficacy of loaded drug, and thus forms a promising approach that should be explored further as an alternative or adjunct form of TB therapy.

Highlights

• Nano-Rifabutin loaded Glucan microparticles [(RB-NPs)-GP] administered to M. tuberculosis infected macrophage.

• (RB-NPs)-GP induces appropriate innate immune responses in host macrophage.

• Mycobactericidal Effect of Rifabutin was markedly enhanced by its nano-entrapment in GP.

• Intracellular drug delivery supplements the innate response in M. tuberculosis infected macrophage.

Keywords:

• β-Glucan
• rifabutin nanoparticles
• innate immune response
• tuberculosis
• mycobactericidal effect

Acknowledgements

The authors like to gratefully acknowledge Dr. Amit Misra and Dr. K.K. Srivastava, Council of Science and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow for providing access to highly sophisticated instruments and for access to Mycobacterial Culture Laboratory. Authors are thankful to DST for infrastructural support to the Department of Bio-sciences, Integral University under FIST program. We also acknowledge Integral University, Lucknow for providing the facilities to carry out this study. The manuscript communication number (MCN) of this article is IU/R&D/2018-MCN000369 as provided by the Research & Development Office, Integral University, Lucknow.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Financial support for this work was provided by the U.P. Council of Science and Technology (UPCST).