Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 794

9.2.2 Targeted Delivery to Bradyzoites

Atovaquone is a highly lipophilic hydroxynaphthoquinone that has potent in vitro
activity against T. gondii , but it is poorly absorbed after oral administration and
shows poor therapeutic efficacy against toxoplasma encephalitis. I.v. injection of an
atovaquone solution is not a feasible alternative to oral administration because of
the poor solubility of this compound in the solvent mixtures acceptable for i.v.
administration. Atovaquone nanosuspensions (either of 0.3% Tween 80, 0.3%
Poloxamer 188 and 0.05% sodium cholate or of 1.0% Tween 80, 280 nm) for i.v.
administration were prepared (Schöler et al. 2001 ). At concentrations higher than
1 mg/ml nanosuspensions did not exert cytotoxicity and was as effective as free
atovaquone against T. gondii in freshly isolated peritoneal macrophages.
A murine model of toxoplasma encephalitis that closely mimics reactivated toxo-
plasmosis in immunocompromised hosts was used. Mice have a targeted mutation in
the gene encoding the interferon consensus sequence binding protein. Mice were
treated with sulfadiazine in drinking water for 3 weeks beginning 2 days after infection.
Treatment of infected mice with sulfadiazine resulted in latent infections involving the
development of brain cysts. Following discontinuation of sulfadiazine, remarkable
histological changes were observed in brains. At day 8 brains showed inflammatory
changes associated with parasitophorous vacuoles and/or free parasitic antigen, consis-
tent with toxoplasma encephalitis, characterized by infiltration of mononuclear cells
around vessels and, to a lesser extent, in meninges, and mice died by day 14.
Two days after discontinuation of sulfadiazine, nanosuspension were i.v. admin-
istered (every other day from day 2 until day 16), at doses of 10 mg/kg of body
weight 50% of animals survived until day 24 (the end of the study period). On the
other hand, mice orally treated with free atovaquone (100 mg/kg every other day)
died within 22 days. Brains of mice treated with nanosuspensions showed neither
inflammatory foci nor foci of parasitophorous vacuoles and/or parasite antigen.
Oral treatment with atovaquone suspension at 100 mg/kg resulted in serum, lung
and brain drug levels comparable to those measured after i.v. treatment with 10 mg
/kg. The amount of atovaquone in liver was nearly six folds higher after i.v. admin-
istration of nanosuspensions than after oral administration of free atovaquone.

References

Adams LB, Sinha I, Franzblau SG, Krahenbuhl JL, Mehta RT (1999) Effective treatment of acute
and chronic murine tuberculosis with liposome-encapsulated clofazimine. Antimicrob Agents
Chemother 43: 1638-1643
Aditya NP, Patankar S, Madhusudhan B, Murthy RSR, Souto EB (2010 a). Arthemeter-loaded
lipid nanoparticles produced by modified thin-film hydration: Pharmacokinetics, toxicological
and in vivo anti-malarial activity. Eur J Pharm Sci 40: 448-455
Aditya PN, Tiyaboonchai W, Patankar S, Madhusudhan B, Souto EB (2010 b) Curcuminoids-
loaded lipid nanoparticles: Novel approach towards malaria treatment. Colloids Surf B
Biointerfaces 81: 263-273