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Antimicrobial Agents and Chemotherapy, January 1998, p. 40-44, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Long-Circulating Immunoliposomal Amphotericin B
against Invasive Pulmonary Aspergillosis in Mice
Takakazu
Otsubo,1
Kazuo
Maruyama,2
Shigefumi
Maesaki,1
Yoshitsugu
Miyazaki,1
Eitaro
Tanaka,2
Tomoko
Takizawa,2
Kunikazu
Moribe,2
Kazunori
Tomono,1
Takayoshi
Tashiro,1 and
Shigeru
Kohno1,*
Second Department of Internal Medicine,
Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki
852,1 and
Faculty of Pharmaceutical
Science, Teikyo University, Sagamiko, Kanagawa
199-01,2 Japan
Received 6 June 1997/Returned for modification 21 July
1997/Accepted 17 October 1997
 |
ABSTRACT |
We investigated the efficacy of long-circulating immunoliposomal
amphotericin B (AmB) against invasive pulmonary aspergillosis in mice
using three types of liposomal AmB: conventional liposomal AmB
(AmBisome), a long-circulating liposomal AmB and prepared by coating
the liposome surface with polyethylene glycol (PEG; PEG-L-AmB),
long-circulating immunoliposomal AmB (34A-PEG-L-AmB). The survival
rates for mice with invasive pulmonary aspergillosis treated with an
intravenous dose of 2 mg of AmBisome, PEG-L-AmB, or 34A-PEG-L-AmB per
kg of body weight were 16.7, 83.3, and 100%, respectively. Treatment
with 34A-PEG-L-AmB produced a marked reduction in the number of
Aspergillus fumigatus organisms in the lungs. Pharmacokinetic studies showed the presence of high AmB concentrations in the plasma of mice treated with PEG-L-AmB (40.8 µg/ml) and in the
lungs of mice treated with 34A-PEG-L-AmB (42.3 µg/g). We conclude
that 34A-PEG-L-AmB, a long-circulating immunoliposomal AmB, is a
promising form of AmB against invasive pulmonary aspergillosis.
| |
INTRODUCTION |
There has been a dramatic rise in
the number of invasive fungal infections in immunocompromised patients
in recent years. Accordingly, there is an urgent need to improve the
treatments for invasive fungal infections because the overall prognosis
for patients with these infections remains poor. Amphotericin B (AmB) is a broad-spectrum and potent antifungal agent, but its clinical use
is sometimes limited due to adverse reactions, such as renal toxicity,
hypokalemia, and anemia. Furthermore, it is usually necessary to
initiate therapy with a small dose of AmB, and it usually takes a few
days to achieve effective therapeutic concentrations in serum.
A promising approach to the treatment of invasive fungal infections is
the use of liposome-encapsulated AmB (4, 12). The
development of a drug carrier that encapsulates AmB allows for the
administration of a high dose of AmB due to the reduced toxicity of AmB
(7, 11). Liposomal AmB (AmBisome) is commercially available
(5, 16); however, certain problems with the liposomal formation of AmB still make the drug an easy target for the
reticuloendothelial system (RES). Thus, an increased dosage is needed
to establish adequate therapeutic effects (19, 21).
Immunoliposal AmB is a newly developed form of AmB modified by
monoclonal antibodies for active targeting to specific sites. A few
investigators have already examined the efficacies of immunoliposomes in animals and humans (6, 18). While immunoliposomes show a
high degree of efficiency in vitro, their targeting efficiency in vivo
is relatively low (13). This is probably due to the appearance of antibodies on the surfaces of liposomes, leading to
enhanced uptake of immunoliposomes by the RES. In our previous reports
(10, 14), the use of a long-circulating liposome prepared by
coating the liposome surface with polyethylene glycol (PEG) (PEG-L)
allows the liposome to evade the RES. Van Etten et al. (20)
reported that the therapeutic efficacy of liposomal AmB coated with PEG
(PEG-L-AmB) was better than that of AmBisome against invasive
candidiasis in neutropenic mice. We reported previously that monoclonal
antibodies could be attached to the distal ends of chains of
long-circulating liposomes prepared by coating the liposome surface
with PEG (15). Monoclonal antibody 34A recognizes surface
glycoproteins (8) that are expressed on the luminal surface
of the pulmonary capillary vessel wall in the mouse lung (9,
17). Binding of this immunoliposome to the lung is very rapid,
and it is not captured by the RES.
In this study, we compared the in vivo efficacy of long-circulating
immunoliposome (34A-PEG-L-AmB) with those of AmBisome and
long-circulating liposome (PEG-L-AmB) in mice with invasive aspergillosis.
| |
MATERIALS AND METHODS |
Compounds.
AmB was kindly donated by Bristol-Myers Squibb
Pharmaceutical Research (Tokyo, Japan). AmBisome was obtained from
Vestar Inc. (San Dimas, Calif.) as a sterile lyophilized product.
Dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylethanol
amine (DSPE), monomethoxy polyethylene glycol succinimidyl succinate
(PEG-OSu), and polyethylene glycol bissuccinimidyl succinate (PEG-2OSu)
were kindly provided by Nippon Oil and Fats (Tokyo, Japan). Cholesterol
was purchased from Wako Pure Chemicals (Osaka, Japan). The average
molecular weights of PEG-OSu and PEG-2OSu measured by gel permeation
chromatography were 2,219 and 2,230, respectively. The other chemicals
used were of high grade.
DSPE-PEG and DSPE-PEG-COOH were synthesized by the methods described
previously (10, 15). In brief, 1 ml of 5% DSPE in chloroform-methanol (3:1, vol/vol) was added to 9.5 ml of 10% PEG-OSu
or PEG-2OSu in chloroform, followed by the addition of 20.5 µl of
triethylamine. The reaction mixture was stirred vigorously overnight at
room temperature. Full conversion of the primary amino group in DSPE
was confirmed by negative ninhydrin reactivity after separation of the
products by thin-layer chromatography. The phospholipid phosphorus
assay showed the appearance of new phosphate-positive spots at a higher
Rf value than the value for phosphate-positive
spots from DSPE. A small amount of water was added to the evaporated
reaction residues to form micelles. The micelles were dialyzed for 5 days against water by using a dialysis bag with large pores
(Spectra-por CE 300000 MWCO; Spectrum Medical, Houston, Tex.) and were
then lyophilized.
Rat immunoglobulin G2a (IgG2a) antibody 34A was a generous gift from S. Kennel (Oak Ridge National Laboratory, Oak Ridge, Tenn.). The antibody
recognizes surface glycoproteins (gp112) which are expressed
exclusively and abundantly on the luminal surface of the pulmonary
capillary vessel wall in the mouse (8, 17).
Preparation of liposomes.
To prepare PEG-L-AmB, a
chloroform-lipid solution (DPPC, 7.92 mg; cholesterol, 2.08 mg) was
mixed with a methanol solution (3.0 ml) of AmB (1.50 mg) and DSPE-PEG
(2.88 mg) and evaporated in a round-bottom flask at 65°C. The lipid
film was hydrated by vortex mixing in 1.2 ml of 9% saccharose. The
procedure of freezing and thawing was repeated four times. Liposomes
were extruded through a Nuclepore polycarbonate membrane (Costar
Science Co. Cambridge, Mass.), with a resultant average particle size
of 125 nm (range, 115 to 140 nm), as measured by dynamic light
scattering (model N4SD; Coulter, Hialeah, Fla.). This was followed by
centrifugation (2 × 105 × g for 15 min)
to separate nonentrapped AmB.
We also used the method described above to prepare 34A-PEG-L-AmB,
except that DSPE-PEG was replaced by DSPE-PEG-COOH. The
centrifuged
liposomes were resuspended in 1.0 ml of 5 mM morpholineethanesulfonic
acid (MES) buffer (pH 5.5), and this combination was mixed with
240 µl of 0.25 M 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(Pierce,
Rockford, Ill.) and 240 µl of
N-hydroxysulfosuccinimide
(Pierce). After allowing the mixture to stand at room temperature
for
10 min, the reaction mixture was adjusted to pH 7.5 with 1
N NaOH and
was then mixed with antibody (0.25 µg) at a weight
ratio of 1/4 in
antibody-lipid, and the whole mixture was incubated
for 2 h at
room temperature. Immunoliposomes were separated from
the unbound
protein and were concentrated by centrifugation (2
× 10
5 ×
g for 15 min). The centrifuged liposomes
were suspended in
9% saccharose to prepare predetermined
concentrations of AmB for
injection. AmBisome was suspended in 5%
glucose for injection.
Animals and fungus.
Male BALB/c mice were purchased from SLC
Japan (Hamamatsu, Japan) and were used in the present experiments at
the age of 6 weeks. The experimental protocol was approved by the
Ethics Review Committee for Animal Experimentation of Nagasaki
University School of Medicine. All mice were housed in a pathogen-free
environment and received sterilized food and water at the Laboratory
Animal Center for Biomedical Research of Nagasaki University School of Medicine. Aspergillus fumigatus MF-13 was isolated from the
sputum of a patient with a pulmonary aspergilloma at the Nagasaki
University Hospital and was maintained at 
80°C. The strain was
subcultured on Sabouraud dextrose agar (Becton Dickinson, Cockeysville,
Md.) at 30°C for 7 days; and the conidia were harvested with sterile saline containing 0.02% Tween 80 (Wako Pure Chemical Industries), counted in a hemocytometer, and diluted with sterile saline for inoculation.
Effect of liposomal AmB against murine invasive pulmonary
aspergillosis.
The experimental design of the study was basically
similar to that for a previously described model of pulmonary
aspergillosis in mice (2), with several modifications. The
initial step of the experiment included the implementation of
immunosuppression in the mice by injecting 2.5 mg of cortisone acetate
(Wako Pure Chemical Industries) subcutaneously every day for 5 days,
beginning 4 days before infection. With the mice under general
anesthesia induced by intraperitoneal injection of pentobarbital
(Nembutal; Abbott Laboratories, North Chicago, Ill.), 0.08 ml
containing 2 × 106 conidia of A. fumigatus
was instilled intranasally. Animals were housed in groups of three mice
per cage and were given drinking water containing tetracycline (250 mg/800 ml; Achromycin; Lederle Japan, Tokyo, Japan) throughout the
experiment to prevent bacterial infection.
Liposomal AmB was administered into the tail vein once a day starting
2 h after infection for a total of 5 days. Each of six
mice
received a similar dose of liposomal AmB. AmBisome was used
at a dose
of 1, 2, 5, 10, or 20 mg/kg of body weight/day, and
PEG-L-AmB and
34A-PEG-L-AmB were used at a dose of 1 or 2 mg/kg/day.
Mice were
observed daily for survival up to 28 days after infection.
The survival
rates for the different treatment groups were compared
by the
generalized Wilcoxon test.
Mycological, histopathological, and pharmacokinetic studies.
For mycological examination, mice were infected in a manner similar to
that described above, followed by treatment for 3 days with 2 mg of one
of the three liposomal forms of AmB per kg/day. On the third day, a
laparotomy was performed after the mice were placed under general
anesthesia by inhalation of 0.5 to 1.0% enflurane (4 to 5 liters/min;
Ethrane; Abbott Laboratories), and the iliac arteries were dissected
and cut. This was followed by thoracotomy and infusion of 2 ml of
sterile saline into the right ventricle to perfuse the lungs and wash
out the remaining AmB in lung blood vessels. The lungs were dissected
under sterile conditions and were carefully excised and removed,
weighed, and homogenized with sterile saline. The homogenized lungs
were diluted serially with sterile saline (1:10), 0.1 ml of each lung
specimen was inoculated onto a Sabouraud dextrose agar plate, and the
plates were incubated at 30°C. Two days later, the fungal colonies
were counted and the results were compared by Student's t
test. For the pathological examination, lungs were examined 3 days
after inoculation and treatment and were stained with periodic
acid-Schiff stain.
The three liposomal forms of AmB (2 mg/kg) were administered
intravenously once on day 3 postinfection. At 1 and 6 h after
administration, the animals were laparotomized while they were
under
general anesthesia induced with enflurane, and blood from
the inferior
vena cava was collected in heparinized tubes. The
lungs and livers were
dissected and removed as described above.
The plasma and organs were
homogenized with 99% methanol (Wako
Pure Chemicals Industries) and 10 mM phosphate buffer (pH 7.4;
Wako Pure Chemicals Industries) containing
2 mg of 1-amino-4-nitronaphthalene
(Aldrich, Milwaukee, Wis.) per ml.
AmB was extracted from supernatants
of the homogenates with BOND-ELUT
(Varian, Harbor City, Calif.)
and was measured by high-pressure liquid
chromatography (PU-980;
Nihon Bunko, Tokyo, Japan). A Wakosile 5C18
column (4.0 mm by
30 cm; Wako Pure Chemical Industries) was used for
all analyses.
A mobile phase of 40% acetonitrile in 10 mM acetate
buffer (pH
4.0) and a flow rate of 1.0 ml/min were used. The retention
times
of AmB and internal standard were 8.0 and 11.0 min, respectively.
The absorbance of the column effluent was monitored at 408 nm.
| |
RESULTS |
Efficacy of each form of liposomal AmB against invasive pulmonary
aspergillosis.
In the first step, we investigated the therapeutic
efficacy of various doses of AmBisome against experimental invasive
pulmonary aspergillosis (Fig. 1). All
mice in the control group treated with 5% glucose died within 6 days
of infection. The effect of AmBisome on the survival rate was dependent
on the dose; all mice treated with 10 or 20 mg/kg/day survived. In the
next series of experiments, we compared the efficacies of AmBisome,
PEG-L-AmB, and 34A-PEG-L-AmB and their effects on the survival rate
(Fig. 2). The survival rates following
treatment with 2 mg of AmBisome, PEG-L-AmB, and 34A-PEG-L-AmB per
kg/day were 16.7, 83.3, and 100%, respectively. These results
indicated that 34A-PEG-L-AmB was the most effective type of liposomal
AmB among the three types of liposomal AmB used in the present study.
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FIG. 1.
Effects of AmBisome on survival rates of mice with
experimental invasive pulmonary aspergillosis. AmBisome and 5% glucose
were given to two groups of six mice each by intravenous administration
once a day for 5 days after infection with 2.0 × 106
conidia of A. fumigatus per mouse. ×, 5% glucose;  ,
AmBisome at 1 mg/kg;  , AmBisome at 2 mg/kg;  , AmBisome at 5 mg/kg;  , AmBisome at 10 mg/kg;  , AmBisome at 20 mg/kg.
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FIG. 2.
Effects of AmBisome, PEG-L-AmB, and 34A-PEG-L-AmB on
survival rates of mice with experimental invasive pulmonary
aspergillosis. Liposomal AmB was injected intravenously into six mice
once a day for 5 days after infection with 2.0 × 106
conidia of A. fumigatus per mouse. ×, 5% glucose, ,
AmBisome at 2 mg/kg; , PEG-L-AmB at 1 mg/kg; , PEG-L-AmB at 2 mg/kg; , 34A-PEG-L-AmB at 1 mg/kg; , 34A-PEG-L-AmB at 2 mg/kg.
N.S., not significant; *, significant difference (P < 0.01), generalized Wilcoxon test.
|
|
Mycological, histopathological, and pharmacokinetic studies.
The number of A. fumigatus organisms in the lungs 3 days
after the administration of AmBisome was lower than that in the lungs of control mice treated with 5% glucose only. The number of fungi in
the lungs of PEG-L-AmB-treated mice was lower than that in the lungs of
AmBisome-treated mice, but the difference was not significant
(P = 0.2478). On the other hand, the number of fungi in
the lungs of 34A-PEG-L-AmB-treated mice was significantly lower than
that in the lungs of AmBisome-treated mice (P < 0.01)
and PEG-L-AmB-treated mice (P < 0.01). The numbers
(mean ± standard deviation) of A. fumigatus organisms
in the lungs of mice treated with control (5% glucose) and AmBisome-,
PEG-L-AmB-, and 34A-PEG-L-AmB-treated mice were 6.24 ± 0.08 log10 CFU/g, 5.79 ± 0.13 log10 CFU/g
(P < 0.01 compared with the control group), 5.70 ± 0.05 log10 CFU/g (P < 0.01 compared
with the control group), and 5.39 ± 0.11 log10 CFU/g
(P < 0.01 compared with the control group,
P < 0.01 compared with the AmBisome-treated group, and
P < 0.01 compared with the PEG-L-AmB-treated group)
(Student's t test), respectively. Pathological examination
of the lungs of control mice showed hyphal invasion in the lung
parenchyma through the bronchial wall (Fig.
3A), and only a few hyphae were seen in
mice treated with 34A-PEG-L-AmB (Fig. 3D). Hyphal proliferation was
observed inside the bronchi of mice treated with AmBisome and PEG-L-AmB
(Fig. 3B and C).
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FIG. 3.
Histopathological findings for lung tissues of mice
treated with 5% glucose (A), AmBisome at 2.0 mg/kg (B), PEG-L-AmB at
2.0 mg/kg (C), and 34A-PEG-L-AmB at 2.0 mg/kg (D) on day 3 after
injection. The tissues were stained with periodic acid-Schiff stain.
|
|
The results of the pharmacokinetic study with AmBisome, PEG-L-AmB, and
34A-PEG-L-AmB are summarized in Table
1.
Injection
of PEG-L-AmB resulted in plasma AmB concentrations at 1 and
6
h higher than those after injection of AmBisome and
34A-PEG-L-AmB.
Studies examining the distribution of AmB in tissue
showed that
injection of 34A-PEG-L-AmB resulted in the highest
concentration
of AmB in the lung at 1 and 6 h compared with those
after the
injection of AmBisome and PEG-L-AmB. The concentration of AmB
in the liver was very low at both time intervals in mice treated
with
34A-PEG-L-AmB.
| |
DISCUSSION |
In the present study, we investigated the efficacy of
long-circulating immunoliposomal AmB (34A-PEG-L-AmB) against
experimental invasive aspergillosis and compared its effects with those
of AmBisome and long-circulating liposomal AmB (PEG-L-AmB). The
development of AmBisome was intended to circumvent the toxicity and
enhance the efficacy of AmB by allowing for the administration of
higher doses of the drug. Previous studies have shown that 5 mg of
AmBisome per kg/day was effective against invasive candidiasis but was only marginally effective against invasive pulmonary aspergillosis (3, 16). Our results suggested that a high dose of AmBisome is necessary for the treatment of invasive pulmonary aspergillosis.
Unfortunately, AmBisome is an easy target for the RES (19),
thus disallowing its use to achieve the high concentrations of AmB
necessary to kill Aspergillus spp. in the lungs. In the present studies, we used two types of liposomal compounds against pulmonary aspergillosis. The first preparation was a long-circulating liposome prepared by coating the liposome surface with amphipathic PEG
(10). This coating of the liposome allows the liposome to evade uptake by the RES, allowing AmB to remain in the systemic circulation for a long period of time. We reported previously that the
half-life for the clearance of liposomes from the blood of healthy mice
is estimated to be 1.5 h for conventional liposomes and 5.6 h
for PEG-coated liposomes (14). The present study extended these early results by demonstrating that the concentration of AmB in
the sera of mice with invasive pulmonary aspergillosis treated with
PEG-L-AmB was approximately 250% of that in the sera of mice treated
with AmBisome. The pharmacokinetic difference may explain the high
degree of efficacy of PEG-L-AmB against invasive pulmonary
aspergillosis compared with that of AmBisome. It should be noted,
however, that histological examination of the lung tissue showed no
significant differences in the number of A. fumigatus organisms in the lungs of mice treated with AmBisome or PEG-L-AmB. It
is possible that the difference in the size of the fungal population in
the lung tissue could be due to the timing of examination.
The other liposomal preparation was the long-circulating
immunoliposomal AmB prepared by coating the PEG-coated liposomal surface with a monoclonal antibody. Our results indicated that the peak
concentration of immunoliposome in blood lasted for a short period of
time compared with that for the long-circulating liposome, because the
immunoliposome is easily captured by the RES due to the opsonization
induced by the surface antibody (13, 15). In the present
study, we evaluated a new type of long-circulating immunoliposome using
monoclonal antibody 34A. This monoclonal antibody recognizes surface
glycoproteins that are expressed on the pulmonary vessel. The
immunoliposome with monoclonal antibody 34A rapidly binds to the lung
tissue and evades the RES (15). This explains why
34A-PEG-L-AmB was more effective than AmBisome and PEG-L-AmB against
invasive pulmonary aspergillosis. High concentrations of 34A-PEG-L-AmB
accumulated in the lungs, causing a larger decrease in the numbers of
A. fumigatus organisms in murine lungs compared with the
decreases associated with AmBisome and PEG-L-AmB treatments.
It should be noted, however, that immunoliposomes, which have already
been used as anticancer agents (14), have certain disadvantages, e.g., inactivation by anti-idiotype antibodies, a
process that develops rapidly after injection. Several methods are
being developed to combat this phenomenon, e.g., modification of the
liposome and antibody. The Fab priming method that deletes the Fc
portion from the IgG antibody (18) and the chimera antibody method, which combines the Fc portion of human IgG and the Fab portion
of IgG of other species (1), have been proposed as means of
overcoming the problem of inactivation by anti-idiotype antibodies.
In conclusion, our encouraging results obtained with the
long-circulating immunoliposomal AmB against murine pulmonary
aspergillosis suggest that the agent may be effective against invasive
pulmonary aspergillosis in humans.
| |
ACKNOWLEDGMENTS |
We are grateful to Junzo Seki and Yoshifumi Tomii, Research
Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan, for technical advice about the high-pressure liquid chromatographic assay of AmB
concentrations in plasma and tissue. We also thank F. G. Issa, Department of Medicine, University of Sydney, Sydney, Australia, for
careful reading and editing of the manuscript.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Second
Department of Internal Medicine, Nagasaki University School of
Medicine, Sakamoto 1-7-1, Nagasaki 852, Japan. Phone: 81-95-849-7271. Fax: 81-95-849-7285. E-mail:
sk1227{at}net.nagasaki-u.ac.jp.
| |
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Antimicrobial Agents and Chemotherapy, January 1998, p. 40-44, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
