Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 755

and were detectable in spleen, liver and lung only until day 1, when loaded in alg-
inate nanoparticles were observed in plasma up to 7, 9, 11 and 11 days after admin-
istration for ETB, RIF, INH and PYZ, respectively, and in tissues until day 15. In a
second approach, eight oral doses of ECZ at 3.3 mg/kg bw loaded in 230 nm alg-
inate nanoparticles or 112 doses of free ECZ administered twice daily, reduced
bacterial burden by more than 90% in the lungs and spleen of mice i.v. infected with
10 5 -10 7 bacilli of M. tuberculosis . ECZ (free or loaded in nanoparticles) could
replace RIF and INH during chemotherapy of murine tuberculosis. Alginate nano-
particles reduced the dosing frequency of azoles and antitubercular drugs by
15-fold (Ahmad et al. 2007 ).
In a different approach, solid lipid nanoparticles (SLN) were loaded with RIF,
INH and PYZ and administered to mice. A single oral dose resulted in drug con-
centrations detectable after 3 h and for up to 8 days in therapeutic concentrations in
plasma and lungs, and for 10 days in liver and spleen. Free drugs on the other hand,
were cleared within 1-2 days. Also in M. tuberculosis infected mice, no tubercle
bacilli was detected in the lungs and spleen after five oral doses of drug-loaded
SLN administered every 10 days; whereas 46 daily doses of oral free drugs were
necessary to reach the same therapeutic effect (Pandey et al. 2005 ).
The performance of experimental drugs loaded in cyclodextrins has also been
explored, as the case of PA-824 (a poorly aqueous soluble three-substituted
nitroimidazopyran), which is highly specific for the M. tuberculosis complex
( M. avium , M. smegmatis , M. chelonae , and M. fortuitum) and showed only modest
or no activity against other mycobacteria. PA-824 was included in hydroxypropyl-
bcyclodextrin /lecithin and orally administered to mice infected with a low dose of
aerosolized M. tuberculosis Erdman (a short-course mouse infection model).
PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as free MOX at 100 mg/
kg and INH at 25 mg/kg and was slightly more active than RIF at 20 mg/kg, admin-
istered in nine daily consecutive doses. Long-term treatment with PA-824 at
100 mg/kg in cyclodextrin/lecithin administered in 5 days per week along 12 weeks
reduced the bacterial load below 500 colony forming units (CFU) in lungs and
spleen. No significant differences in activity between PA-824 and the other single
drug treatments tested at INH 25 mg/kg, RIF 10 mg/kg, gatifloxacin 100 mg/kg and
MOX 100 mg/kg bw, could be observed (Lenaerts et al. 2005 ).
An active targeting strategy that did not lead to superior results as compared to
non targeted carriers, was explored by employing RIF, INH and PYZ loaded in
350-400 nm PLGA nanoparticles surface grafted with lectins recognizable by gly-
cosylated structures in the gut and the lung mucosa (Sharma et al. 2004 ). Drug-
loaded PLGA nanoparticles were orally or aerosol administered to guinea pigs at
RIF 12 mg/kg, INH 10 mg/kg and PYZ 25 mg/kg bw. Plasma half life times of the
different drugs loaded into these surface-modified nanoparticles were extended
from 4 to 9 days (uncoated) to 6-14 days upon oral or inhalation administration,
respectively. In addition, total bacterial clearance was achieved in lungs, liver and
spleen after only three orally or aerosolized doses (one every 14 days) on guinea
pigs infected intramuscularly with 1.5 × 10 5 bacilli of M. tuberculosis .