Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 754

2.2.1 Oral and Parenteral Administration

Biodistribution and Therapeutic Efficacy of Non Liposomal Nanoparticles

Between 2003 and 2005 there were published a series of articles where first line
drugs were loaded into poly(lactic- co -glycolic acid) (PLGA) nanoparticles that
were orally administered to different healthy or infected animal models. In an early
article RIF, INH and PYZ loaded in 190-290 nm PLGA nanoparticles administered
to mice, resulted in drugs detection in plasma for up to 9 days while therapeutic
concentrations in tissues were maintained for 9-11 days. Five oral doses every
10 days of drug-loaded PLGA nanoparticles effectively eliminated the pathogen
from the different organs (Pandey et al. 2003a ). In a next step, the same drug-loaded
PLGA nanoparticles were administered to guinea pig infected with aerosolized M.
tuberculosis , at PLG-NP 250 mg/kg, RIF 12 mg/kg, INH 10 mg/kg and PYZ
25 mg/kg of body weight (bw), in five oral doses every 10 days. It was found that
the bacterial count and lung histopathology were reduced to the same extent than
free drugs daily administered by 6 weeks (Johnson et al. 2005 ).
A further work showed that RIF, INH, PYZ and ETB loaded in 190-290 nm
PLGA nanoparticles orally administered to mice i.v. infected with 1.5 × 10 7 bacilli of
M. tuberculosis at RIF 10 mg/kg, INH 25 mg/kg, PYZ 150 mg/kg and ETB 100 mg/
kg bw, rendered therapeutic levels maintained for 5-8 and 9 days in plasma and brain,
respectively. Additionally five oral doses every 10 days of drug-loaded PLGA nano-
particles eliminated the bacteria in the meninges (Pandey and Khuller 2006 ).
Azoles have the potential to replace INH and RIF in murine tuberculosis and are
effective against latent tuberculosis (Ahmad et al. 2006a ), while quinolones may be
used to shorten the duration of chemotherapy (Duncan and Barry 2004 ). Therefore,
the antimicrobial activity of azoles and quinolones loaded in PLGA nanoparticles
has also been determined. It a recent work, econazole (ECZ, an antifungal imida-
zole) and moxifloxacin (MOX, a fourth-generation synthetic fluoroquinolone)
loaded in 220 nm PLGA nanoparticles were orally administered to mice at MOX
8 mg/kg and ECZ 3.3 mg/kg bw (Ahmad et al. 2008 ). A single dose of drug-loaded
PLGA nanoparticles rendered therapeutic drug concentrations in plasma for up to
5 (ECZ) or 4 days (MOX), whilst in lungs, liver and spleen it was up to 6 days. In
comparison, free drugs were cleared from the same organs within 12-24 h. In
M. tuberculosis -infected mice, eight oral doses of drug-loaded PLGA nanoparticles
administered weekly were found to be equipotent to 56 doses of MOX daily admin-
istered or 112 doses of ECZ administered twice daily. Furthermore, the combina-
tion of MOX plus ECZ proved to be significantly efficacious compared with
individual drugs. Addition of RIF to this combination resulted in total bacterial
clearance from the organs of mice in 8 weeks.
More recently, similar results were obtained with alginate nanoparticles. In a
first approach, RIF, INH, PYZ and ETB were loaded in 235 nm alginate nanopar-
ticles and orally administered to mice at two dose levels (Ahmad et al. 2006b ).
While free drugs were cleared from circulation after 12-24 h after administration