Biomedical Engineering Reference
In-Depth Information
site, and antibacterial efficacy are significantly altered both by the liposome size
(Hwang 1987 ; Zou et al. 1995 ) and by the rate of drug leakage. In the following
study, the zwitterionic molecule CIP was actively loaded of into three different
unilamellar liposomes (DPPC: chol; distearoylphosphatidylcholine (DSPC): chol
or sphingomyelin (SM): chol) with a transmembrane gradient of methylammonium
sulfate. Drug pharmacokinetics after i.v., i.p. and i.t. administration and antibacte-
rial efficacy of liposomal CIP at 20 mg/kg against an S. typhimurium infected mice
was determined. Intravenous liposomal CIP increased the circulation lifetime of
CIP by >15-fold. Increased circulation lifetimes were associated with enhanced
delivery of the drug to the liver, spleen, kidneys, and lungs of mice. The retention
of CIP in liposomes in the circulation decreased in the sequence SM: chol > DSPC:
chol > DPPC: chol. Encapsulation of CIP also conferred significant increases in the
longevity of the drug in the plasma after i.p. administration and in the lungs after
i.t. administration in comparison to free CIP. At 20 mg/kg SM: chol liposomal CIP
resulted in 10 3 - to 10 4 -fold fewer viable bacteria in the liver and spleens of infected
mice than was observed for animals treated with free CIP (Webb et al. 1998 ).
Finally, GEN was loaded in pH-sensitive liposomes (dioleoylphosphatidyletha-
nolamine (DOPE): N-succinyl-DOPE: chol: Peg-ceramide, 35:30:30:5% mol)
especially formulated against pathogens residing in the cytosol. The pharmacokinetics
and biodistribution of the free and liposomal GEN were examined in mice bearing
a systemic S. enterica serovar Typhimurium infection. Encapsulation of GEN in
pH-sensitive liposomes significantly increased the concentration of GEN in plasma
compared to those of free GEN, precluded accumulation in kidneys and redirected
the antibiotic to the liver and spleen. While the accumulation of drugs in the liver
and spleen is well known for liposomal formulations, the rate of pH-sensitve lipo-
somal GEN accumulation in these organs was substantially faster than that for
neutrally charged DPPC-chol liposomes. Furthermore, the levels of accumulation of
drug in the infected liver and spleen were increased by 153- and 437-fold, respec-
tively, as a result of liposomal encapsulation. The increased accumulation of GEN
in the liver and spleen affected by liposomal delivery was associated with 10 4 -fold
greater antibacterial activity than that associated with free GEN in a murine salmo-
nellosis model. However, the antibacterial effects observed with the pH-sensitive
liposomes were also achieved with two different nonfusogenic control formulations
of GEN. Hence, the therapeutic benefits that were achieved by fusogenic carrier-
mediated intracellular delivery of GEN were outweighed by those benefits that arise
from the substantial increases in the AUC for the antibiotic at the infection site for
both fusogenic and nonfusogenic liposomes (Cordeiro et al. 2000 ; Kumana and
Yuen 1994 ). It should be noted that the numbers of bacteria that survived in the
spleens of mice treated with liposomal gentamicin were similar to those that were
present at the start of gentamicin therapy (Richter-Dahlfors et al. 1997 ). Therefore,
it cannot be excluded that the liposomal formulations may be exerting cytostatic
rather than cytotoxic effects. However, since the infection is exclusively present
intracellularly, these data demonstrate that the use of these liposomal formulations
enhanced the intracellular delivery of the drug to increase either the cytotoxic or the
cytostatic activities of the drug compared to those achieved with free GEN.
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