Enhancement of Antimycobacterial Activity of Rifampicin Using Mannose-Anchored Lipid Nanoparticles against Intramacrophage Mycobacteria.

Tuberculosis treatment requires a multidrug combination for the long-term, associated with adverse effects which lead to nonpatient compliance and the emergence of drug-resistant strains. Thus, mannose-anchored rifampicin-loaded solid lipid nanoparticles (M-RIF-SLNs) were developed to enhance the effect of rifampicin by selectively delivering to the macrophage, which led to the high intracellular killing of mycobacteria. The synthesized M-RIF-SLNs show a particle size of ∼100 nm and a drug loading of ∼8%. Cytotoxicity assay confirms that M-RIF-SLNs are not toxic up to 16 µg/mL (equivalent to incorporated rifampicin in SLN) toward THP-1-differentiated macrophages. An antimicrobial assay exhibits a reduction of minimum inhibitory concentration by 4-fold and 8-fold against wild-type and laboratory drug-resistant strains of M. smegmatis, respectively, compared to free rifampicin. Furthermore, mannose-functionalized SLNs loaded with coumarin-6 exhibit a higher macrophage uptake than that of unfunctionalized SLNs. Finally, higher intramacrophage clearance of M. tuberculosis H37Ra was observed with M-RIF-SLNs compared to RIF-SLNs and free rifampicin. Hence, the overall results support that the developed M-RIF-SLNs can be a promising approach for improving the antibacterial activity of rifampicin against intracellular mycobacteria residing in the alveolar macrophages.

Repurposing artemisinin as an anti-mycobacterial agent in synergy with rifampicin.

The current anti-TB treatment consists of a prolonged multi-drug therapy. Interventional strategies are required to reduce the chemotherapeutic load. In this regard, we have previously identified a synergistic interaction between hydroperoxides and rifampicin. This strategy has been extended here to repurpose a new drug against TB. A hydrophobic antimalarial drug, artemisinin, with an unstable endoperoxide bridge structure, has been investigated as a potential candidate. In combination with rifampicin, artemisinin was found to be synergistic against M. bovis BCG and M. tuberculosis H37Ra. Furthermore, artemisinin was observed to induce peroxides in a time and concentration dependent manner and the levels of the peroxides were significantly higher in cells treated with the drug pair. Coupled with rapid disintegration of the membrane, this enhanced the clearance of the bacterial culture in vitro. On the other hand, formation of the peroxides was significantly reduced in the presence of ascorbic acid, an antioxidant. This translated to a loss of the synergistic effect of the combination, indicating the importance of peroxide formation in the mode of action of artemisinin. Interestingly, artemisinin also had a synergistic interaction with isoniazid, amikacin and ethambutol and an additive interaction with moxifloxacin, other drugs commonly used against TB.

Formulation and evaluation of tacrolimus-loaded galactosylated Poly(lactic-co-glycolic acid) nanoparticles for liver targeting.

OBJECTIVE: The aim of this investigation was to formulate liver targeted tacrolimus-loaded nanoparticles for reducing renal distribution and thereby decreasing nephrotoxicity. METHOD: Poly lactic-co-glycolic acid (PLGA) was galactosylated, and confirmation of galactosylation was performed by Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. Tacrolimus-loaded PLGA nanoparticles (Tac-PLGA NP) and galactosylated PLGA nanoparticles (Tac-Gal-PLGA NPs) were prepared by ultrasonic emulsification solvent evaporation technique and characterized. KEY FINDINGS: The size of both the formulations was below 150 nm and negative zeta potential indicated the stability and reticuloendothelial system targeting efficiency. The in-vitro release and pharmacokinetics showed sustained release of tacrolimus from nanoparticles in comparison to plain drug solution. The biodistribution studies revealed the potential of both the nanoparticulate systems to target tacrolimus to the liver for prolonged periods of time compared with the plain drug solution. However, significantly higher liver and spleen targeting efficiency of Tac-Gal-PLGA NPs compared with Tac-PLGA NPs was evident indicating its active targeting. Significantly lower distribution in the kidney from nanoparticles indicated the possibility of reduced nephrotoxicity - the principal reason for patient non-compliance. Both nanoparticles showed stability at refrigerated condition (5°C ± 3°C) upon storage for 1 month. CONCLUSION: Galactosylated PLGA nanoparticles seem to be a promising carrier for liver targeting of tacrolimus.