epiglucan and Tuberculosis

Mycobacterium tuberculosis which causes tuberculosis, is primarily resident within macrophages. 1,3-β-glucan has been proposed as a ligand to target drug loaded nanoparticles (NPs) to macrophages. In this study we characterized the intracellular pharmacokinetics of the anti-tubercular drug rifampicin delivered by 1,3-β-glucan functionalized PLGA NPs (Glu-PLGA). We hypothesized that Glu-PLGA NPs would be taken up at a faster rate than PLGA NPs, and consequently deliver higher amounts of rifampicin into the macrophages.. Carbodiimide chemistry was employed to conjugate 1,3-β-glucan and rhodamine to PLGA. Rifampicin loaded PLGA and Glu-PLGA NPs as well as rhodamine functionalized PLGA and Glu-PLGA NPs were synthesized using an emulsion solvent evaporation technique. Intracellular pharmacokinetics of rifampicin and NPs were evaluated in THP-1 derived macrophages. A pharmacokinetic model was developed to describe uptake, and modelling was performed using ADAPT 5 software.. The NPs increased the rate of uptake of rifampicin by a factor of 17 and 62 in case of PLGA and Glu-PLGA, respectively. Expulsion of NPs from the macrophages was also observed, which was 3 fold greater for Glu-PLGA NPs than for PLGA NPs. However, the ratio of uptake to expulsion was similar for both NPs. After 24 h, the amount of rifampicin delivered by the PLGA and Glu-PLGA NPs was similar. The NPs resulted in at least a 10-fold increase in the uptake of rifampicin.. Functionalization of PLGA NPs with 1,3-β-glucan resulted in faster uptake of rifampicin into macrophages. These NPs may be useful to achieve rapid intracellular eradication of Mycobacterium tuberculosis.

Topics: Antibiotics, Antitubercular; beta-Glucans; Cell Culture Techniques; Cell Line; Drug Carriers; Drug Compounding; Humans; Macrophages; Models, Biological; Mycobacterium tuberculosis; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin; Tuberculosis

Beta-1,3-glucan is a potent stimulator of macrophage functions and has a protective effect against a range of infections in rodent models. We examined whether the agent could also protect against the intracellular Mycobacterium bovis, bacillus Calmette-Guérin (BCG) infection in mice. BCG-susceptible BALB/c mice were injected intravenously (i.v.) with beta-glucan or vehicle 3 days before, or with beta-glucan 7 days after i.v. challenge with live BCG bacilli. The animals were killed 4 or 8 weeks later, their organs were homogenized and applied to object slides and stained with auramin for counting of bacilli, or seeded onto agar in Petri dishes. Mice treated with beta-glucan both pre- and postchallenge had significantly lower numbers of BCG bacilli and BCG colony-forming units in spleen homogenates compared with controls 4 weeks after challenge. A similar, but not statistically significant, tendency was observed in spleen homogenates from mice killed 8 weeks after challenge. In homogenates of liver and lungs there were similar findings, but less pronounced. There was a dose-dependent effect of beta-glucan injected before BCG challenge on the number of BCG bacilli found in spleen and liver homogenates. In addition, antibody cross-reactivity was demonstrated between M. tuberculosis cell wall and beta-glucan. The results suggest that beta-glucan has a protective effect against M. bovis, BCG infection in susceptible mice.

Topics: Animals; Antigens, Bacterial; Antitubercular Agents; beta-Glucans; Cell Wall; Colony Count, Microbial; Cross Reactions; Disease Models, Animal; Female; Glucans; Injections, Intravenous; Liver; Lung; Mice; Mice, Inbred BALB C; Mycobacterium bovis; Spleen; Tuberculosis