Design of Mannose-Coated Rifampicin nanoparticles modulating the immune response and Rifampicin induced hepatotoxicity with improved oral drug delivery

We have demonstrated the enhanced in vivo oral efficacy and enhanced hepatoprotective effects of preactivated thiolated chitosan (Cht) nanoparticles (NPs) for tuberculosis. The mannose anchored preactivated thiolated chitosan nanoparticles (MPTCht-NPs) were prepared and charac-terized in terms of their particle size, in vitro entrapment efficiency (EE%) and zeta potential (mV). NPs were also evaluated in terms of mucoadhesion, % hemolysis, permeation enhancement, in vivo pharmacokinetics, toxicity and immunomodulation. NPs exhibited an average particle size of 307 nm with 19 folds enhanced permeation in comparison to conventional Rifampicin (Rif) formulation across everted rat intestine. The evaluation of in vivo pharmacokinetic parameters indicated 16 folds improvement in oral bioavailability in comparison to Rif alone following oral administration in rabbits. There was significant difference in the levels of serum transaminases, oxidative stress markers, and expression levels of anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) genes between Rif treated and NPs treated groups. The serum transaminases levels were normal with MPTCht-NPs treated groups as compared to Rif treated groups while the levels of glutathione were markedly increased in MPTCht-NPs treated group. Furthermore, the levels of Bax were enhanced with the MPTCht-NPs treatment. In summary, these findings revealed that the designed NPs may act as promising therapeutic strategy against tuberculosis in a dose-dependent manner while providing the immunomodulation and hepatoprotective effect. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of King Saud University.

Automated summary

The preactivated thiolated chitosan nanoparticles show enhanced in vivo oral efficacy and hepatoprotective effects for tuberculosis treatment, with significantly improved permeation and oral bioavailability compared to conventional formulations. Additionally, the nanoparticles provide immunomodulation and improve liver function through modulation of gene expression levels and markers of oxidative stress.